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Skeletal growth and development of the human fetus : effect of maternal and nutritional factors. Roberts, Jill Anne 1971

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SKELETAL GROWTH AND DEVELOPMENT OF THE HUMAN FETUS: EFFECT OF MATERNAL AND NUTRITIONAL FACTORS by  B . H o E o ,  J I L L ANNE ROBERTS U n i v e r s i t y o f B r i t i s h Columbia, 1966  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN HUMAN NUTRITION i n the Department o f Home Economics  We accept t h i s  t h e s i s as conforming t o the r e q u i r e d standard  THE UNIVERSITY OF BRITISH COLUMBIA A p r i l , 1971  In  presenting  an  advanced  the I  Library  this  degree shall  f u r t h e r agree  for  scholarly  by  his  of  this  written  thesis at  it  purposes  for  may  financial  is  of  of  Columbia,  of  fiCrrrrj^.  The U n i v e r s i t y o f B r i t i s h V a n c o u v e r 8, C a n a d a  a/«^  4f% in/  for  for extensive by  shall  s  Columbia  ^Li  the  that  not  requirements I  agree  r e f e r e n c e and copying  t h e Head o f  understood  gain  fis^ttrrrr  British  available  be g r a n t e d  It  fulfilment  permission.  Department  Date  freely  permission  representatives. thesis  partial  the U n i v e r s i t y  make  that  in  of  be a l l o w e d  or  that  study.  this  thesis  my D e p a r t m e n t  copying  for  or  publication  without  my  i  A B S T R A C T Growth i s a s s o c i a t e d w i t h the a v a i l a b i l i t y o f e s s e n t i a l n u t r i e n t s and i t seems p o s s i b l e t h a t these n u t r i ents c o u l d a f f e c t the growth mechanism i n v o l v e d i n s k e l e t a l development.  To t e s t t h i s h y p o t h e s i s 76 normal human  f e t u s e s aged 9 t o 20 weeks were c o l l e c t e d from t h e r a p e u t i c abortions.  Sex, weight,  l e n g t h , head c i r c u m f e r e n c e ,  l e n g t h and a s k e l e t a l index were recorded; age was  foot  developmental  c a l c u l a t e d from crown-rump l e n g t h , and g e s t a t i o n a l  age estimated from the mother's menstrual Bones from the r i g h t arm cleaned f o r biochemical a n a l y s i s .  history.  and l e g were removed and Calcium,  i n o r g a n i c phos-  phorus, magnesium, sodium and c o l l a g e n c o n t e n t o f 60 femora and humeri were determined,  a f t e r length, fresh  weight,  c o n s t a n t d r y weight and f a t - f r e e weight were r e c o r d e d . Length o f o s s i f i c a t i o n i n the bones o f the l e f t arm l e g was  measured v i a s i l v e r r a d i o g r a p h y .  and  Assuming b i l a t e r a l  symmetry, b i o c h e m i c a l and p h y s i c a l d a t a c o u l d then be compared.  A l l f e t a l d a t a were grouped a c c o r d i n g t o develop-  mental age:  9-10,  11-12, 13-14, 15-16, 17-20  A n a l y s i s o f v a r i a n c e and Duncan's New were performed effect.  Simple  t o determine  weeks.  M u l t i p l e Range T e s t  the s i g n i f i c a n c e o f group  l i n e a r r e g r e s s i o n was  executed on the whole  ii range o f d a t a t o d e t e c t which v a r i a b l e s b e s t p r e d i c t e d other v a r i a b l e s . Maternal i n f o r m a t i o n was o b t a i n e d from an i n t e r v i e w and from m e d i c a l r e c o r d s a t Vancouver General H o s p i t a l . Age, weight, h e i g h t , b i r t h weight, p a r i t y and g r a v i d i t y o f the mother were r e c o r d e d . culated.  A socio-economic index was c a l -  Adequacy o f maternal d i e t d u r i n g pregnancy was  assessed from a d a i l y p a t t e r n r e c a l l , preference questions.  food frequency and  These d a t a were used t o c a l c u l a t e a  t o t a l n u t r i t i o n s c o r e and a p r o t e i n s c o r e .  Maternal data  were coded as p o t e n t i a l independent v a r i a b l e s and m u l t i p l e r e g r e s s i o n a n a l y s i s performed a g a i n s t f e t a l  dependent  variables. As developmental age o f the f e t u s e s i n c r e a s e d , the f r e s h l e n g t h , d r y weight and l e n g t h o f o s s i f i c a t i o n  also  i n c r e a s e d i n both humerus and femur, as d i d the c a l c i u m and phosphorus c o n t e n t .  In most cases long bone growth  as measured by t h e s e v a r i a b l e s advanced w i t h f e t a l age.  proportionately  Thus group means o f most v a r i a b l e s were  s i g n i f i c a n t l y d i f f e r e n t from each o t h e r when d i v i d e d f i v e 2 week age p e r i o d s .  into  Water c o n t e n t dropped propor-  t i o n a t e l y w i t h age, r e f l e c t i n g bone m i n e r a l i z a t i o n . content f e l l markedly i n f e t a l bones a f t e r 10 weeks. nesium and c o l l a g e n remained c o n s t a n t . not change t h e d r y weight o f t h e bones.  Sodium Mag-  Fat extraction d i d  iii S t a t i s t i c a l c o r r e l a t i o n was found between p h y s i c a l and b i o c h e m i c a l d a t a .  Generally  p h y s i c a l v a r i a b l e s were  b e s t p r e d i c t e d by o t h e r p h y s i c a l v a r i a b l e s .  Biochemical  composition o f t h e femur c o u l d b e s t be p r e d i c t e d c o r r e s p o n d i n g data i n t h e humerus. was p l o t t e d a g a i n s t  from  When g e s t a t i o n a l age  physical or biochemical variables,  s t a t i s t i c a l c o r r e l a t i o n was weaker. The  c o r r e l a t i o n found between f e t a l v a r i a b l e s and  maternal age, p a r i t y , weight and socio-economic  status  would i n d i c a t e a d i v e r s i t y o f f a c t o r s i n f l u e n c i n g growth.  fetal  Whereas p r o t e i n s c o r e o f maternal d i e t was n o t  s t a t i s t i c a l l y r e l a t e d w i t h f e t a l parameters, g e n e r a l n u t r i t i o n score showed a c o n s i s t e n t , with length  positive correlation  and d r y weight o f t h e femur and humerus.  This  r e l a t i o n s h i p was s t a t i s t i c a l l y s i g n i f i c a n t when developmental o r g e s t a t i o n a l age remained c o n s t a n t .  The r e s u l t s  o f t h i s study suggest t h a t n u t r i t i o n o f t h e pregnant woman i s p o s i t i v e l y c o r r e l a t e d w i t h some i n d i c e s o f s k e l e t a l growth and development o f t h e human f e t u s .  iv  T A B L E  OF  C O N T E N T S PAGE  ABSTRACT  ..  i  TABLE OF CONTENTS LIST OF TABLES  Iv .  o  LIST OF FIGURES  vii  LIST OF PROCEDURE FORMS LIST OF PLATES  viii  • • • • • © • • • • • • • • • • ( . • • ^ • • • • • © • © © © • • © • • • o © »  LIST OF SCATTERGRAMS  xiii  REVIEW OF LITERATURE  B.  1  Parameters of f e t a l growth and development 1. B i r t h weight 2. S k e l e t a l growth and development (a) o s s i f i c a t i o n and growth (b) composition and development Maternal n u t r i t i o n and f e t a l growth 1. Role o f n u t r i t i o n 2. E f f e c t of n u t r i t i o n on b i r t h weight 3. N u t r i t i o n and bone growth (a) animal s t u d i e s (b) human s t u d i e s  INTRODUCTION • • MATERIALS A.  j_x X  ACKNOWLEDGMENT .  A.  vi  o o o « » » e o e e » * o o o * * * « a * * e o « « o « o o * o o * « o e e < >  37  AND METHODS  F e t a l studies 1. Long bone s t u d i e s : 2. Long bone s t u d i e s : 3. Long bone s t u d i e s :  3^  physical biochemical radiographical  V  PAGE B.  C.  Maternal s t u d i e s 1. Medical h i s t o r y 2. D i e t a r y h i s t o r y 3. Personal h i s t o r y S t a t i s t i c a l analysis  RESULTS A. B.  ^5  .  F e t a l data 1. Whole f e t u s 2 . Long bones Maternal data 1. M e d i c a l growth 2. Socio-economic s t a t u s 3. Sex o f f e t u s 4. N u t r i t i o n a l data  DISCUSSION  69  REFERENCES  80  APPENDIX 1.  -  AP PEND X^X! 2 o  "~ DATA  METHODS  .  .....  o * o o o o o a « * * * * « * 0 « o * o * Q « o * o « » e o o o «  97  117  L I S T  OF  T A B L E S  TABLE I. II. III. IV. V. VI.  PAGE Composition o f the whole femur o f the human fetus .  10  Composition o f the c o r t e x o f the femur d u r i n g fetal life  12  F e t a l and long bone growth r e l a t e d mental age  4-7  to develop-  Composition o f f e t a l long bones a c c o r d i n g to developmental age  48  Means and standard d e v i a t i o n s o f whole variables  49  fetal  Means and standard d e v i a t i o n s o f long bone 51  variables VII. VIII.  IX. X. XI. XII. XIII. XIV.  Change  i n bone weight f o l l o w i n g f a t e x t r a c t i o n  .. 57  Means and standard d e v i a t i o n s o f maternal variables  58  E f f e c t o f maternal v a r i a b l e s on f e t a l data  60  E f f e c t o f n u t r i t i o n a l v a r i a b l e s on f e t a l data ... 6 7 Estimated crown-rump length v s . developmental age o f f e t u s Minimum f o r m a l i n treatment f o r s i l v e r r a d i o graphy Optimum s i l v e r n i t r a t e treatment f o r r a d i o graphy  109  Exposure  110  time f o r f e t a l radiography  98 108  vii  L I S T  OF  F I G U R E S  FIGURE  PAGE Semidiagrammatic p r e s e n t a t i o n o f f e t a l growth o f s e v e r a l p o p u l a t i o n groups ..,  2.  R e l a t i o n of osseous development o f l i v i n g f u l l - t e r m i n f a n t s a t b i r t h to t h e i r mothers' Cl  16  t  Cl  U  3T  X  I"i  Cf  P  3T6  CJ  9  fl  G  y  Q  O  O  O  O  O  O  *  Q  O  O  O  O  O  O  O  3.  Histogram o f f e t a l  4.  Histogram o f maternal socio-economic  5.  Histogram o f maternal n u t r i t i o n scores  6.  Measurement o f o s s i f i e d bOI"16 • o o o e o o e a o e e o o o » o o  O  O  O  O  O  O  O  O  O  O  2  ^  age groups .................. k-6  .........  6k  shaft of f e t a l o e e o * o o e o a o e o e o o o o o a o o a o a  1X1  viii  L I S T  O F P R O C E D U R E  F O R M S  FORM  PAGE  1o  DlSt3iry  2e  Nil t  3o  Socio-economic s t a t u s  tllStOiry  3T i t X O n 3  1  O  O  S t S t U S  O  O  »  O  O  O  O  O  O  «  J  O  «  O  O  O  «  O  O  O  O  O  O  O  «  O  Q  Q  O  O  O  o o o o o e o e o o o o o o o o o o a o o e o o o o o o o  o o o o o o o o o o o o ©  0  o  0  o  0  o » © o o o o o  112 11^ 116  ix  L I S T  OF  P L A T E S  PLATE  PAGE  10  Specimen i n i n t a c t sac  2 ,  Fetus and p i aCenta  3.  Eviscerated 3T©rnOVeCl  o o © © o o o © o o o © < » o & o o © © o o © o o o  99  o o o o o o o o e o o o o o o o o e o o o o a e o a o o o l O O  fetus? r i g h t arm and l e g  © © o o o o o o o o o o o © o © o o © o o o o o a o o o o o o o o © o o o o o ©  jL 0 1  ........... 102  4.  S i x f e t a l long bones; cleaned, f r e s h  5. 6.  S i x f e t a l long bones; d r i e d .................... 103 Fetus prepared f o r radiograph a f t e r s i l v e r n i t r a t e treatment 104  7.  Radiograph; f e t u s i n f o r m a l i n o n l y  8.  Radiography; f e t u s i n s i l v e r n i t r a t e f o r S 15C  9.  ............. 105  d 3y S  ooo00oooooeoooooooooooeoooaoao«©©o©O0oo3.O6  Radiography; f e t u s i n s i l v e r n i t r a t e f o r ten days » o o » o » o © * » o « » o o © © o o © o © o © © o o » o © o o © o  © o © o © o ©  10"7  X  L I S T  OF  S C A T T E  R G R A M S  EXHIBIT  PAGE  1.  Developmental age v s . crown-rump length  ...... 118  2.  Developmental age v s . head circumference  3.  Developmental age v s . f o o t l e n g t h ............  120  4.  Developmental age v s . f e t a l weight  121  5.  Developmental age v s . s k e l e t a l index  .........  122  6.  Developmental age v s . g e s t a t i o n a l age ........  123  7.  G e s t a t i o n a l age v s . f o o t length ..............  12^  8.  G e s t a t i o n a l age v s . crown-rump l e n g t h ........  125  9.  G e s t a t i o n a l age v s . head circumference  .......  126  .............  127  ..... 119  ...........  10.  G e s t a t i o n a l age v s . f e t a l weight  11.  G e s t a t i o n a l age v s . s k e l e t a l index  12.  Developmental age v s . femoral d r y weight  ..... 129  13.  Developmental age v s . humeral d r y weight  ..... 130  14.  Developmental age v s . femoral water C ^5ft.*t@  15.  n t  ...........  o o o e o o o o o o o o o o o o a o o o o o v a o o o o o o o o o o o o o o  3* 3 *^  Developmental age v s . humeral water C O n t © n t  o o o o o o o o e o A o o e o o o o o o o o o o o o o o o o o o o o o e o o  16.  Developmental age v s . femoral  17.  Developmental age v s . humeral length  18.  Developmental age v s . femoral OSSlf lCStlOn  19.  128  length ......... .........  9 0 o e o o o o » o o o e o o o o o a e e o o e o o o o o o o o o  13^ I33 13^ i 3 .5  Developmental age v s . humeral O S S l f lC5ltlOn  o o o o o o o o o o o o o o o o o o o e o o o o o o o o o e o o o  «^  3^  xi EXHIBIT  PAGE  20.  Developmental age v s . femoral c o l l a g e n  .......  137  21.  Developmental age v s . humeral c o l l a g e n  .......  I38  22.  Developmental age v s . femoral c a l c i u m  ........  139  23.  Developmental age v s . humeral c a l c i u m  ........  140  24.  Developmental age v s . femoral i n o r g a n i c pjhOSphOlTUS  25.  O  O  O  O  Q  O  O  O  O  O  O  O  O  O  O  Q  O  O  O  Developmental age v s . humeral p h O S pl"10 ITU S  o  o  o  o  a  o  o  o  o  o  o  o  o  e  o  e  e  o  O  O  0  O  O  O  O  O  O  O  O  O  O  Q  O  X^"J*1  O  inorganic  o  o  «  o  o  o  o  Q  O  O  O  O  o  o  o  o  a  1 ^4*2  26.  Developmental age v s . femoral magnesium ...... 14-3  27.  Developmental age v s . humeral magnesium ......  28.  Developmental age v s . femoral sodium  ......... 145  29.  Developmental age v s . humeral sodium  ... ...... 146  30.  Developmental age v s . femoral c a l c i u m / OOXl  31.  a C J ©  IT,  r a t  10  000000000000000000000000*000000  r a t l O  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  r a t l O  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  1^4*9 1^0  ..........  151  .............  152  34.  Maternal weight v s . maternal h e i g h t  35.  Maternal age v s . maternal p a r i t y  36.  M a t e r n a l age v s . maternal g r a v i d i t y  37.  Maternal p a r i t y v s . maternal g r a v i d i t y  .......... .......  153 154  Socio-economic score v s . socio-economic CJ r O U P  39.  1 ^4*8  Developmental age v s . humeral c a l c i u m / phOSphate  38.  X  Developmental age v s . femoral c a l c i u m / phOSpl*iate  33.  0000000000000000000000000000000  Developmental age v s . humeral c a l c i u m / coXXacjen  32.  r a t l O  144  0000000000000000000000000000000000000000  1 ^ .f?  T o t a l n u t r i t i o n score v s . weighted r i U t r i t l O n  SOOre  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  1  xii  EXHIBIT 40.  PAGE Total  n u t r i t i o n score v s . n u t r i t i o n  iriCl65C  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  index v s . weighted score  O  O  O  O  O  O  O  Q  O  O  O  158  41.  Nutrition  42.  T o t a l n u t r i t i o n score v s . p r o t e i n  score  ......  159  43.  Protein  score v s . n u t r i t i o n  ............  160  44.  Protein  score v s . weighted score  .............  161  index  ...........  1^*^  A C K N O W L E D G M E N T  Acknowledgment i s due t o : e m b r y o l o g i c a l guidance f e t u s e s ; D r . Poland's  D r . B e t t y Poland, f o r  and f o r access t o both mothers and staff,  f o r t h e i r c o o p e r a t i o n and  t e c h n i c a l a s s i s t a n c e ; D r . George Eaton,  for statistical  advice and n e g o t i a t o n s with the computer; and D r . Birkbeck along w i t h the D i v i s i o n o f Human N u t r i t i o n .  1  R E V I E W One  OF  L I T E R A T U R E  o f the fundamental f e a t u r e s o f development i s  growth, d e f i n e d as an i n c r e a s e weight.  Growth may  the number o f c e l l s ,  be  i n s p a t i a l dimensions  accomplished through i n c r e a s e s  the s i z e o f i n d i v i d u a l c e l l s , o r  amount o f i n t e r c e l l u l a r substance ( 1 ) .  components s i m u l t a n e o u s l y .  The  the  observation  by  a l l three  schultz in  (2) i n h i s comprehensive t r e a t i s e on the f e t a l growth  o f man  and o t h e r primates, t h a t more i s known about growth  i n the embryonic and p o s t n a t a l p e r i o d s periods,  is s t i l l valid  than about the  have a r e l a t i v e l y c o n s t a n t  considered  Over the l a s t 20 years  o b s t e t r i c i a n s and p e d i a t r i c i a n s have become aware t h a t human f e t u s , l i k e a l l other  baby has  I t has  to  growth r a t e so t h a t a s m a l l baby  n e c e s s a r i l y a premature one.  variable rate.  fetal  today.  U n t i l r e c e n t l y the human f e t u s was  was  in  F e t a l growth o f a  p a r t i c u l a r organ o r t i s s u e i s u s u a l l y produced by  1926  and  the  l i v i n g t h i n g s , grows at a  a l s o become c l e a r t h a t the s i z e a  a t t a i n e d r e l a t i v e to the p e r i o d o f g e s t a t i o n i s  important i n d e t e r m i n i n g the hazards i t w i l l f a c e i n the perinatal period  (3-13).  2  A.  Parameters o f F e t a l Growth and Development 1.  B i r t h Weight Since i t i s o b v i o u s l y i m p o s s i b l e t o study human  f e t a l growth l o n g i t u d i n a l l y , one must r e l y on b i r t h weight curves t o compare f e t a l growth. the  Such curves are based on  assumption t h a t b i r t h weights a f t e r v a r i o u s lengths o f  g e s t a t i o n a r e r e p r e s e n t a t i v e o f normal f e t a l weight a t those t i m e s . (14),  P u b l i s h e d c h a r t s such as those o f B a t t a g l i a  Lubchenco  (15, 16) and Usher (17) are o f l i m i t e d  v a l i d i t y so f a r as normal f e t a l development i s concerned, as i n f o r m a t i o n has been o b t a i n e d from premature b i r t h s o r spontaneous a b o r t i o n s .  I t i s n o t u s u a l l y known whether t h e  mishap was due t o u t e r i n e anomalies, p l a c e n t a l d e f e c t o r f e t a l abnormality, b u t a t l e a s t i t i s u n j u s t i f i e d t o accept the  l e v e l o f f e t a l growth as r e s u l t i n g from normal g e s t a t i o n . Present workers i n t h e f i e l d o f human p r e n a t a l  development c o n t i n u e t o show how d i f f i c u l t s t r a t e cause and e f f e c t i n growth.  i t i s t o demon-  E x t e n s i v e evidence from  human and animal s t u d i e s i n d i c a t e s t h a t b i r t h weight i s p r i m a r i l y determined b y f a c t o r s r e l a t i n g t o u t e r i n e e n v i ronment r a t h e r than by t h e g e n e t i c c o n s t i t u t i o n o f the f e t u s (18, 1 9 ) . Determinants o f b i r t h weight, v a r y i n g i n s i g n i f i c a n c e and d i r e c t n e s s o f t h e i r e f f e c t , have been c o n s i d e r e d by v a r i o u s authors (20, 21, 2 2 ) . These i n c l u d e : racial origin  (23, 24), p e r i o d o f g e s t a t i o n ( 2 5 , 26), type  and amount o f p r e n a t a l c a r e  (27, 28), s o c i a l and economic  3  s t a t u s (29, 30, 31), maternal age height  (32), maternal weight  (33-38), maternal c i g a r e t t e smoking  and  (39, 40), maternal  d i s e a s e (41, 42), maternal p r e n a t a l n u t r i t i o n  (42-46),  maternal e d u c a t i o n (45), maternal o c c u p a t i o n ( 4 7 ) , p a r i t y and b i r t h o r d e r (48, 49), sex o f i n f a n t location  (84), g e o g r a p h i c a l  and season (143). For  example, Gruenwald  (50) f e e l s t h a t the  effi-  cency w i t h which the maternal organism s a t i s f i e s the needs o f pregnancy can be judged by f e t a l growth.  New  values  f o r b i r t h weight i n r e l a t i o n t o g e s t a t i o n a l age have been proposed, and are i l l u s t r a t e d i n F i g u r e 1 (51). t o Gruenwald  i t i s l i k e l y t h a t the normal b i r t h  According weight  curves o f v a r i o u s p o p u l a t i o n groups do not d i f f e r from one another d u r i n g the f i r s t h a l f o f the t h i r d t r i m e s t e r o r longer.  The l i n e a r course i s i n d i c a t i v e  of unrestrained  growth r e g u l a t e d by the growth p o t e n t i a l  o f the f e t u s i n  the  presence o f an adequate s u p p l y l i n e .  A time comes  when support i s no l o n g e r adequate f o r u n r e s t r a i n e d  growth.  The lower the l e v e l o f growth support r e c e i v e d from the mother v i a the p l a c e n t a , the e a r l i e r the d e p a r t u r e from the straight  l i n e growth,  term (see g r a p h ) .  and the lower i s the b i r t h weight a t  There i s a t r e n d toward h i g h e r b i r t h  weights w i t h i n most p o p u l a t i o n groups as a r e s u l t o f improved n u t r i t i o n a l ,  socio-economic and m e d i c a l c o n d i t i o n s .  The s p e c t a c u l a r change i n b i r t h weights i n Japan d u r i n g a 20 year p e r i o d was  caused o n l y by b e t t e r f e t a l growth  and  not by an i n c r e a s e i n d u r a t i o n o f pregnancy ( 2 1 ) .  I t would  be i n t e r e s t i n g t o apply t h i s h y p o t h e s i s t o Meredith's worldwide comparative t r e a t i s e o f b i r t h weights ( 5 2 ) .  Figure  1.  Semidiagrammatic p r e s e n t a t i o n o f f e t a l growth (determined from b i r t h weight) o f s e v e r a l p o p u l a t i o n groups (51).  5 2.  S k e l e t a l Growth and Development a)  O s s i f i c a t i o n and Growth  H i s t o g e n e s i s o f human c a r t i l a g e and bone has been w e l l d e s c r i b e d (53, 54, 55, 5 6 ) . The f o r e r u n n e r o f t h e skePton  i n t h e f e t a l body i s formed as a c a r t i l a g i n o u s frame-  work, and t h i s b e g i n s t o c a l c i f y a t about the e i g h t h week o f gestation.  Wallgren  (57) has made a d e t a i l e d m i c r o r a d i o -  g r a p h i c a l study o f t h e process o f o s s i f i c a t i o n o f f e t a l bone and has shown t h a t o s s i f i c a t i o n i n t h e long bones b e g i n s a t t h e c e n t e r o f t h e c a r t i l a g e n o u s model.  A thin  l a y e r o f c a l c i f i e d bone m a t r i x i s l a i d down between t h e perichondrium and t h a t p o r t i o n o f the s h a f t c o n t a i n i n g hypertrophic c a r t i l a g e c e l l s , s h a f t , forms a r i n g o r c o l l a r . at f i r s t ,  and by extending around the T h i s c o l l a r i s incomplete  and t h e r a t e o f development v a r i e s from one type  o f bone t o another and even the long bones do n o t a l l develop e q u a l l y r a p i d l y .  The c l a s s i c review o f t h e h i s t o -  g e n e s i s o f c a r t i l a g e and bone u s i n g t h e f e t a l humerus as an example has been presented by S t r e e t e r (58).  Recently  Gray has o u t l i n e d t h e p r e n a t a l development o f t h e human femur (59) and humerus ( 6 0 ) . Many t a b l e s are found i n t h e e a r l y c a t e g o r i z i n g t h e developmental and endochondral o s s i f i c a t i o n  literature  sequences o f both membranous (61-68).  Using S t r e e t e r ' s  o r Boyd's (69) method o f s t a g i n g human f e t u s e s , a rough approximation o f age can be o b t a i n e d by p l o t t i n g crown-  6 rump l e n g t h on a standard c u r v e .  Time o f occurence o f  primary o s s i f i c a t i o n c e n t e r s can then be r e l a t e d t o developmental  age.  Several l i m i t a t i o n s o f t h i s  must be c o n s i d e r e d .  procedure  Fetuses o f a g i v e n age c o u l d v a r y  c o n s i d e r a b l y i n l e n g t h , and two f e t u s e s o f s i m i l a r l e n g t h may d i f f e r s i g n i f i c a n t l y i n degree o f development.  Again,  the m a j o r i t y o f s t u d i e s have been performed on spontaneo u s l y aborted o r s t i l l - b o r n f e t u s e s , development o f which may n o t n e c e s s a r i l y be c o n s i d e r e d normal.  I n i t i a l recogni-  t i o n o f an o s s i f i c a t i o n c e n t e r v a r i e s w i t h the technique used, and t h e f o l l o w i n g methods are l i s t e d by Noback (70) i n what he c o n s i d e r e d t o be t h e i r o r d e r o f d e c r e a s i n g sensitivity: radiography  s e c t i o n i n g , c l e a r i n g and a l i z a r i n and g r o s s d i s s e c t i o n .  staining,  With the development o f  heavy metal s t a i n i n g by Hodges (71) i n t h e f e t a l p i g and O ' R a h i l l y (72) i n the human f e t u s , s i l v e r radiography i s now c o n s i d e r e d t o be as s e n s i t i v e as a l i z a r i n Regardless o f technique,  staining.  several principles  i n g o s s i f i c a t i o n and growth have e v o l v e d .  concern-  Ossification  c e n t e r s may be regarded as i n d i c e s o f anatomical  maturity,  and v a r i a b i l i t y i n t h e i r appearance may r e f l e c t t h e v a r i a b i l i t y o f maturation  o f t h e s k e l e t a l system.  One p a r t o f  the body i s a c r i t e r i o n o f normalcy f o r t h e o t h e r p a r t s ; whereas one o f a p a i r o f b i l a t e r a l o s s i f i c a t i o n c e n t e r s may appear a t a d i f f e r e n t time than the o t h e r c e n t e r o f the p a i r , the degree o f such asymmetry i s u s u a l l y s l i g h t b e f o r e birth.  Uses o f t h i s p r i n c i p l e as a d i a g n o s t i c t o o l are many.  7 R a d i o l o g i c a l assessment  o f f e t a l maturation i n u t e r o can  p r e d i c t the date o f d e l i v e r y more a c c u r a t e l y than menstrual history  (73, 74).  E p i p h y s e a l maturation o f c e r t a i n c e n t e r s  at b i r t h i s g a i n i n g r e c o g n i t i o n as a means o f e s t i m a t i n g the age o f the i n f a n t a t b i r t h  (75, 76, 77) and o f p r e d i c t -  i n g n e o n a t a l r e s p i r a t o r y d i s t r e s s syndrome ( 7 8 ) .  Use o f  r a d i o l o g i c a l techniques t o determine bone age i n c h i l d r e n (79) i s w e l l known. %  I t would seem o f p r a c t i c a l  significance  t o have a s i m i l a r standard curve o f f e t a l bone ages from e i g h t weeks g e s t a t i o n t o term; u n f o r t u n a t e l y these d a t a cannot be found i n the  literature.  Many r e s e a r c h e r s , have r e c o g n i z e d the importance o f h e r e d i t y , r a c e , sex, n u t r i t i o n , endocrine s e c r e t i o n  and  d i s e a s e as f a c t o r s which i n f l u e n c e bone growth and the i n i t i a l appearance  of o s s i f i c a t i o n centers.  The weight o f  the s k e l e t o n i s an important f a c t o r i n the understanding o f body composition and o f problems i n n u t r i t i o n and d i s e a s e , as found i n the l i v i n g  subject (80).  Recently, T r o t t e r  determined the weight o f the dry, f a t - f r e e osseous s k e l e t o n o f 124 American,  white and Negro f e t u s e s o f both sexes,  ranging i n age from 16-44  weeks (81, 82, 83).  A  significant  c o r r e l a t i o n e x i s t e d between the weight o f the t o t a l s k e l e t o n and body weight,  osseous  as w e l l as l e n g t h s o f osseous  diaphyses o f humerus and femur; a l l i n c r e a s e d w i t h  age.  From the r e g r e s s i o n e q u a t i o n s , the weights o f the long limb bones were found t o r e s u l t i n s l i g h t l y more r e l i a b l e e s t i m a t e s o f s k e l e t a l weight than d i d bone l e n g t h s .  Either  weight or  length of  estimates  of  age, but  total  long  skeletal  b i r t h weight or not  sex  tibia  The  or  Roche's  the  f o r the (84)  female than  total  at b i r t h the  longer  race,  of  long those  of  femur t o humerus and  of  d i f f e r e n c e s , with nor  sex  than  female  ossification  the  differences  89,  90)  i s a result  ossification,  on  relatively with  the  a c c o m p a n i e d by  during the  last  three  to  months  i s more a d v a n c e d  i n composition dates  in  the  t h a t the  increment  cause o f  i n the  1925  study The  during  degree  of  percentage  progressive  in organic  part  i n the  i n the  long  humerus.  o f a bone  increase a fall  of  from the  r a t femur and  growth i s the  insignificant age.  i s in contrast  the  composition  o f an  Hammett c o n c l u d e d  and  free  Development  changes  f u n d a m e n t a l change i n t h e  o f bone a s h  and  development probably  (85,  development  This  that during  Composition  bones d u r i n g b y Hammett  skeleton.  ratios  male.  Knowledge o f  occurs  Significant  f o r lengths  n e i t h e r race  observation  b)  o f water,  fetus.  length of  showed s e x  reliable  f o r the w e i g h t o f s e l e c t e d p a r t s o f the  p r e n a t a l and  water.  of  more  than d i d g e s t a t i o n a l  bones o f Negros b e i n g  than male, but  were f o u n d limbs  length  ratio of  to radius  higher  weight  d i f f e r e n c e s were f o u n d  limb bones, w i t h whites.  bones p e r m i t t e d  the  of  deposition displacement  matter plays  dehydration  a  which  T h i s g e n e r a l i z a t i o n seems t o h o l d  for  9 most s p e c i e s , e s p e c i a l l y when the composition o f the bones is  expressed on a f a t - f r e e b a s i s * T a b l e I from D i c k e r s o n (86) shows the composition o f  the  whole human femur between 12 to 14 weeks g e s t a t i o n  term. of  The changes are v e r y c l e a r - the f a l l  of  i n percentage  water and the i n c r e a s e i n c o l l a g e n and bone m i n e r a l , as  i n d i c a t e d by the c a l c i u m and phosphorus the  and  content.  A rise in  c a l c i u m / n i t r o g e n r a t i o i n d i c a t e s the i n c r e a s e i n degree c a l c i f i c a t i o n o f the bone.  The c l e a n i n g o f bone  samples  for  a n a l y s i s takes c o n s i d e r a b l e time and c a r e f u l p r e c a u t i o n s  are  n e c e s s a r y i f the percentage o f water i s t o be  determined.  I t has t h e r e f o r e been customary  accurately  t o express the  composition o f bone t i s s u e on a d r y f a t - f r e e b a s i s .  When  t h i s i s done, the amounts o f o r g a n i c m a t r i x and m i n e r a l b e a r an i n v e r s e r e l a t i o n t o each o t h e r .  No d e t e c t a b l e f a t  has been found i n the femora o f f e t u s e s up t o 28 weeks g e s t a t i o n and at term i t amounted t o 0.14%  (86).  These changes i n whole bone r e p r e s e n t changes i n a composite s t r u c t u r e , f o r a long bone c o n s i s t s o f bony t i s s u e , marrow and c a r t i l a g e , and a l l o f these are changing in  composition and r e l a t i v e s i z e .  development  Over t h i s p e r i o d o f  the weight o f the epiphyses expressed as a  percentage o f the weight o f the femur was  found t o f a l l  from  73% t o 50%, at the same time the percentage o f water i n the epiphyses f e l l  and the c o n c e n t r a t i o n o f c o l l a g e n and c a l c i u m  Table I .  Composition o f the whole femur o f the human  fetus  3  F e t a l age (weeks) 12-14  15-16  20-24  Weight o f femur (gm)  0.11  0.22  Fat  0  0  Constituent  i n f r e s h bone (gm/lOOgm)  Composition 77.8  Water  78.4  of  25-28  30-34  1.96  4.7  9.2  0  0  0.15  fresh fat-free bone  72 .9  68.4  Term 16.6 0.14  b  63 .8  63.9  Total N  1.61  1.66  2.01  2.19  2 .35  2 .71  Collagen N  0.61  0.81  1.11  1.36  1.52  1.67  Ca  2 .42  3.47  4.33  5.25  5.63  6.06  P  1.50  1.61  1.97  2 .36  2 .59  2 .84  Ca/N  1.50  2 .09  2.18  2 .40  2 .42  2 .24  a  From Dickerson (86)  b  In g/lOOg  i n c r e a s e d by a f a c t o r of approximately  three.  c a l c i u m to n i t r o g e n rose and  also a considerable  there was  i n c r e a s e i n the r a t i o o f c a l c i u m to phosphorus. (86) suggested t h a t the i n c r e a s e was  due  The  ratio  of  Dickerson  to a f a l l  i n the  p r o p o r t i o n o f phosphate from e s t e r phosphates, a l a r g e p a r t of the phosphorus i n the bone o f the immature f e t u s b e i n g present  in this  Dickerson  has  form. a l s o t a b u l a t e d the main developmental  changes i n c o r t i c a l bone composition, dry f a t - f r e e s o l i d s  (Table I I ) .  percentage o f t o t a l N f e l l and somewhat i r r e g u l a r i l y .  expressed  per lOOg o f  From 12 to 34 weeks the  t h a t o f c o l l a g e n N rose, i f  T h i s p r o p o r t i o n o f t o t a l N accounted  f o r by c o l l a g e n has been shown to i n c r e a s e at c e r t a i n d u r i n g development o f bone i n man,  stages  the p i g , r a t , fowl,  but  the stage o f development at which the r i s e occurs v a r i e s from one  s p e c i e s to another.  Thus, i n the human bone the  main i n c r e a s e takes place b e f o r e 22 weeks g e s t a t i o n and the p i g , before  65 days g e s t a t i o n .  In the r a t and  in  fowl, on  the o t h e r hand, the same i n c r e a s e occurs d u r i n g  postnatal  growth (87) .  Dickerson  In the c o r t e x o f the human femur,  (86) observed t h a t c o l l a g e n accounted f o r 89-96% o f the t o t a l N a f t e r 9 months o f age The  percentage o f c a l c i u m  u n t i l the 34th week and o f the Ca/N  (88). i n the t i s s u e  so d i d the Ca/N  ratio.  increased The  validity  r a t i o as a measure o f the degree o f c a l c i f i c a t i o n  12  Table  I I . Composition o f the c o r t e x o f the femur d u r i n g the f e t a l l i f e * * 9  F e t a l Age Constituent  12 -14  (Weeks)  20-24  30 -34  Term  T o t a l N (gm/100 gm)  5 .95  5 .25  5 .03  5.06  C o l l a g e n N (gm/lOOgm)  2 .9  4.05  4 .03  4.20  18 .9  23.4  24 .7  24.6  P (gm/lOOgm)  9 .1  10.5  10 .9  10.8  R a t i o Ca/N  3 .2  4.45  4 .9  4.9  Ratio Ca/collagen N  6 .5  5.8  6 .1  5.8  R a t i o Ca/P  2 .4  2 .2  2 .3  2 .3  Ca (gm/lOOgm)  a  Dry, f a t - f r e e bone  k From D i c k e r s o n (86)  13 o f bone depends upon the c l e a n l i n e s s o f the samples o f bone analysed  (91).  Bone begins  t o be  l a i d down i n the  cartilage  model o f the human femur at about e i g h t weeks g e s t a t i o n . Before  t h i s the Ca/N  a l l y n i l (92).  r a t i o may  be c o n s i d e r e d  By 12 weeks, the r a t i o had  and by 22 weeks g e s t a t i o n i t had  to be  practic-  increased to  i n c r e a s e d t o 4.5  3.0  (86).  These changes i n the degree o f c a l c i f i c a t i o n o f the human bone d u r i n g f e t a l development and  a l s o the r e l a t i v e degree  o f c a l c i f i c a t i o n o f bone from f u l l term b a b i e s  and t h a t from  a d u l t s agree w e l l w i t h the f i n d i n g s o f Wallgren  (57), based  on b i o p h y s i c a l methods. Since the c r y s t a l s  of bone m i n e r a l  are m a i n l y  down i n a s s o c i a t i o n w i t h the c o l l a g e n f i b r i l s ,  laid  the C a / c o l -  lagen r a t i o g i v e s a measure of the degree o f s a t u r a t i o n o f the c o l l a g e n f i b r i l s .  As seen from Table I I , t h i s  changed v e r y l i t t l e d u r i n g growth i n humans. agreement w i t h the c u r r e n t l y accepted  ratio  This i s i n  view t h a t the c o l l a g e n  f i b r i l s are r a p i d l y m i n e r a l i z e d t o about 80% s a t u r a t i o n soon a f t e r they are l a i d down (93). Ca/P  r a t i o remained c o n s t a n t with age when  per lOOg o f dry f a t - f r e e  solids.  T h i s confirms  o b s e r v a t i o n o f Swanson and l o b (94, 95) who  the  expressed earlier  found a l s o t h a t  the c o n c e n t r a t i o n o f magnesium, sodium and c h l o r i d e i n bone ash decreased  w i t h f e t a l development.  r i s e i n the Ca/Mg and Ca/Na r a t i o s .  T h i s would imply  a  V a r i o u s workers (85,  96)  have o b t a i n e d d i f f e r e n t r e s u l t s f o r Ca/Na r a t i o s depending on the s p e c i e s and stage o f development, f o r the f o l l o w i n g reasons.  Sodium i s found  f l u i d s , i n the hydrated  i n the bone i n e x t r a c e l l u l a r  l a y e r o f bone c r y s t a l s , and  bone c r y s t a l s themselves.  The  i n the  sodium o f the bone c r y s t a l s ,  and a l s o the magnesium, are thought t o be absorbed on c r y s t a l s u r f a c e s , (97, 98,  99).  percentage o f e x t r a c e l l u l a r f l u i d  the  With development, the i n bone drops,  sodium i n t h i s f r a c t i o n a l s o f a l l s .  thus  the  A t t h e same time the  bone i s becoming p r o g r e s s i v e l y c a l c i f i e d and the sodium a s s o c i a t e d with the c r y s t a l s i n c r e a s e s .  F i n a l l y , as bone  c r y s t a l s enlarge i n s i z e there i s correspondingly  less  sodium on t h e i r s u r f a c e . The  c i t r a t e o f f e t a l bone i n c r e a s e s p r o g r e s s i v e l y  w i t h development a c c o r d i n g to one a c c o r d i n g to another  (101).  author  (100)  and  McCance e t a l (96)  l a r g e but temporary r i s e i n the c o n c e n t r a t i o n o f  falls  found  a  citric  a c i d 4 weeks a f t e r b i r t h i n the c o r t i c a l bone o f p i g s . The to  c o n c e n t r a t i o n of f l u o r i n e i n human bone has been i n c r e a s e d u r i n g p r e n a t a l (102)  and p o s t n a t a l  found  (103)  growth., I t s r a t e o f d e p o s i t i o n i s more r a p i d i n those areas o f bone where the m e t a b o l i c The v a l u e found  activity is greatest  0  i n a d u l t bones i s t o some e x t e n t dependent  on the f l u o r i d e content o f the d r i n k i n g water but even where t h e r e i s none i n the water t h e r e may  be an  appreciable  i n t a k e o f the element, because t e a i s an important  source.  Strontium i n f e t a l bones has been e s t i m a t e d as 0.016% o f the bone ash, whereas the mean v a l u e f o r a l l the p o s t n a t a l samples was  0.022% (104).  The membrane bones o f the s k u l l develop r a t h e r d i f f e r e n t l y from the long bones, as i n d i c a t e d both by radiography  (105)  McDonald (106)  and c h e m i c a l a n a l y s i s  (106).  In  micro-  man,  found a s m a l l i n c r e a s e i n the c o n c e n t r a t i o n  o f c a l c i u m , a l a r g e r i n c r e a s e i n t h a t o f carbonate,  and  no  change i n the c o n c e n t r a t i o n o f phosphorus o r c o l l a g e n per u n i t weight o f d r y bone between 28 weeks g e s t a t i o n and term. He  suggested  t h a t the apparent  i n c r e a s e i n the p r o p o r t i o n  o f bone m i n e r a l p r e s e n t i n the form o f carbonate might be p a r t o f the  'hardening' o f the f e t a l head a s s o c i a t e d w i t h  maturity.  B.  Maternal N u t r i t i o n and F e t a l Growth and Development 1.  Role o f N u t r i t i o n The c o n t i n u e d normal growth o f the f e t u s throughout  pregnancy, assuming g e n e t i c p o t e n t i a l and optimum e n v i r o n ment, depends upon the i n t e g r a t e d development o f  maternal  and f e t a l p l a c e n t a l c i r c u l a t i o n , with an adequate concent r a t i o n o f n u t r i e n t s i n maternal b l o o d and an adequate area o f normal p l a c e n t a l membrane f o r f e t a l t r a n s f e r .  Poor  f e t a l growth c o u l d i n t h e o r y r e s u l t from a) c o n d i t i o n s a f f e c t i n g the n u t r i e n t c o n t e n t o f the maternal b l o o d o r i t s supply to the p l a c e n t a ; b) poor development o f .  16 damage t o , o r s p e c i f i c a b n o r m a l i t i e s o f t h e p l a c e n t a l membrane a f f e c t i n g t r a n s f e r across the p l a c e n t a , o r c) d i s o r d e r s o f the f e t a l p l a c e n t a l c i r c u l a t i o n . evidence  Available  suggests t h a t f e t a l n u t r i t i o n may be impaired a t  any o f these s i t e s  (10, 107).  Evidence f o r the r o l e o f n u t r i t i o n i n human pregnancy i s d e r i v e d from t h r e e g e n e r a l sources:  a) r e c o r d s o f l a r g e  p o p u l a t i o n groups w i t h v a r y i n g socio-economic and h e a l t h s t a t u s ; b) data from s u p e r v i s e d h o s p i t a l and c l i n i c groups; and c) c o n t r o l l e d , p r o s p e c t i v e s t u d i e s o f p a t i e n t s r e c e i v i n g p r e s c r i b e d d i e t s and/or n u t r i t i o n a l supplements, f r e q u e n t l y with  laboratory observations.  These and o t h e r p e r t i n e n t  i n f o r m a t i o n have been reviewed by Burke (108) and have been c o n s i d e r e d more r e c e n t l y i n the 1970 N.R.C. maternal n u t r i t i o n study  (109,  The  100).  r a t e o f growth b e f o r e b i r t h , l i k e the r a t e o f  growth afterwards,  depends p r i m a r i l y upon t h e food  supply  and upon the a b i l i t y o f the f e t u s t o take i n and make use o f the f o o d . 115)  Widdowson (111) and o t h e r s  (112, 113, 114,  have reviewed how the f e t u s i s f e d g e n e r a l l y , body  composition  and p l a c e n t a l t r a n s f e r o f n u t r i e n t s .  Co nt ro ve rsy  still  pregnancy.  F o r example, i n a r e c e n t l e t t e r i n the American  rages over n u t r i t i o n a l needs d u r i n g  Journal o f C l i n i c a l N u t r i t i o n , Gam little  (116) remarks on how  i s known about a c t u a l c a l c i u m requirements i n man,  17 e i t h e r f o r bone development, o r f o r s k e l e t a l maintenance. During  pregnancy, l e s s than 20g c a l c i u m i s i n c o r p o r a t e d  i n t o the f e t a l s k e l e t o n , assuming the weight o f the s k e l e t o n at b i r t h t o be lOOg (81).  Therefore,  c a l c i u m r e t a i n e d as  new bone approximates 75mg/day d u r i n g pregnancy and Garn f e e l s i t i s d o u b t f u l whether a b s o r p t i v e e f f i c i e n c y i s then so d i m i n i s h e d  as t o j u s t i f y an a d d i t i o n a l allowance o f  400mg/day a t t h a t t i m e .  Armstrong (117)  determined b l o o d  plasma c a l c i u m o f women i n t h e i r n i n t h month o f pregnancy. H i s data suggest t h a t e i t h e r a c a l c i u m  'pump' operates i n  the p l a c e n t a s u p p l y i n g a h i g h e r c o n c e n t r a t i o n o f c a l c i u m to t h e f e t a l b l o o d supply than i s found i n the maternal c i r c u l a t i o n , o r t h a t t h e c a l c i u m homeostatic mechanism operates isms.  a t d i f f e r e n t l e v e l s i n maternal and f e t a l organ-  Widdowson and McCance (118)  however, suggest t h e  amounts o f c a l c i u m , phosphorus and magnesium i n the maternal serum a r e n o t n e a r l y enough t o p r o v i d e  f o r the developing  f e t u s near term. C l e a r l y , t h e p r e c i s e nature o f the maternal r e l a t i o n s h i p i s not known..  The s t o r e s o f t h e maternal  t i s s u e a c t as b u f f e r s which prevent developing  fetal  deprivation o f the  f e t u s as long as p o s s i b l e (119).  I t was assumed  u n t i l r e c e n t l y t h a t these maternal s t o r e s e i t h e r p r o t e c t the o f f s p r i n g e n t i r e l y , p r e m i t t i n g d e l i v e r y o f normal young, o r t h a t i n t h e case o f extreme d i e t a r y d e f i c i e n c y the f e t u s dies i n utero.  Although t h e r e i s some t r u t h i n t h e ' a l l o r  18 none' t h e o r y i t i s not two  e n t i r e l y c o r r e c t s i n c e between these  extremes t h e r e e x i s t s a narrow range i n which maternal  n u t r i t i o n a l d e f i c i e n c y may  r e s u l t in arrest of f e t a l  opment w i t h o u t c a u s i n g death (120, growth o f the  2.  f e t u s may  be  121).  In t h i s case,  retarded.  E f f e c t on N u t r i t i o n on B i r t h Weight  I t appears c l e a r from both animal (122-125) human d a t a (126-129, 120), r i o u s e f f e c t s on  t h a t s t a r v a t i o n can  s t i l l b i r t h s and  tudes o f these e f f e c t s are g r e a t e r longer gestation  p e r i o d s and  abortion.  an i n c r e a s e  (131-141).  magniwith  (130).  as i n time o f war, reported.  exposures to s l i g h t l y reduced d i e t a r y i n t a k e fetus  The  l a r g e r term f e t u s e s  o f mass d e p r i v a t i o n ,  a f f e c t the  have d e l e t e -  i n those s p e c i e s  b i r t h weight i n f a n t s were f r e q u e n t l y  may  and  f e t a l growth, r e s u l t i n g i n i n t r a - u t e r i n e  growth r e t a r d a t i o n ,  In i n s t a n c e s  devel-  Even  and  Dokladah (142)  low  quality attributed  i n b i r t h weight i n a C z e c h o s l o v a k i a n sample over  a p e r i o d of 50 y e a r s to an improvement i n d i e t , although o t h e r f a c t o r s may (143)  have c o n t r i b u t e d  t o t h i s change.  Toverud  i n an a n a l y s i s o f s t a t i s t i c s gathered i n Norway,  found a s i g n i f i c a n t i n c r e a s e  i n the weight o f i n f a n t s born  between August and October.  In d i s c u s s i n g  the  possible  cause o f t h i s d i f f e r e n c e i n weight, she mentioned increase  i n sunlight during  the  the  summer months, the  a v a i l a b i l i t y o f f r e s h f r u i t s and v e g e t a b l e s and  the  greater longer  19 time t h e mothers probably months.  spent  a t r e s t d u r i n g t h e warm  Toverud was i n c l i n e d t o a t t r i b u t e the seasonal  d i f f e r e n c e s i n weight i n h e r s e r i e s t o a combination o f these f a c t o r s . Attempts t o r e l a t e t h e p r o t e i n i n t a k e o f a populat i o n o f pregnant women t o b i r t h weight i n d i c a t e d t h a t t h e p r o t e i n requirements are h i g h e r d u r i n g pregnancy, t h a t t h e requirement i s f u r t h e r e l e v a t e d d u r i n g the l a s t t r i m e s t e r and t h a t an i n t a k e below 70g p r o t e i n p e r day r e s u l t s i n a s m a l l i n f a n t (128).  A study o f o v e r n u t r i t i o n (144)  r e v e a l e d t h a t although  t h e b i r t h weights o f obese a d u l t  women f e l l w i t h i n the normal range, t h e b i r t h weights o f i n f a n t s from obese mothers tended t o be somewhat e l e v a t e d . Thomson (145)  a l s o r e p o r t e d an u n u s u a l l y accurate  t i o n between maternal i n t a k e o f c a l o r i e s and f e t a l  correlasize.  I f the maternal i n t a k e was below 1800 Cal/day, t h e mean b i r t h weight was 3.09kg and the i n c i d e n c e o f 'prematurity' was  8.5%. I f the i n t a k e was g r e a t e r than 3,000 Cal/day,  the mean b i r t h weight was 3.3kg and t h e i n c i d e n c e o f 'prematurity' was 1.5%, (the i n t e r n a t i o n a l d e f i n i t i o n o f prematurity:  ^ 2,500g a t b i r t h ) .  I f there i s a m u l t i p l i c i t y  o f causes f o r low b i r t h weight o f i n f a n t s , i t would be d i f f i c u l t t o e x p l a i n these data u n l e s s t h e r e a l s o happened to be an i n v e r s e r e l a t i o n s h i p between c a l o r i c i n t a k e and the i n c i d e n c e o f toxemia, mothers who smoke, e t c .  20  Other i n v e s t i g a t o r s have r e p o r t e d t h a t t h e r e no s i g n i f i c a n t d i f f e r e n c e i n the d i e t o f women who f u l l term b a b i e s and those who  was  delivered  had premature i n f a n t s ,  but  a normal r a t e o f i n t r a - u t e r i n e growth can be a s s o c i a t e d w i t h e i t h e r f u l l - t e r m o r premature i n f a n t s (146-158).  If  the food d e p r i v a t i o n i s severe, the i n c i d e n c e o f prematuri t y may  rise.  s t a r v a t i o n was was  Experiments w i t h r a t s demonstrated t h a t i f i n i t i a t e d at the midpoint  o f pregnancy, t h e r e  a 40% r e d u c t i o n i n weight o f the o f f s p r i n g  (159) .  The  same experiment repeated w i t h o n l y moderate food d e p r i v a t i o n did  not reduce f e t a l or p l a c e n t a l weight (160).  I t has  been r e p o r t e d t h a t pregnant r a t s with o n l y a poor d i e t a r y h i s t o r y may  d e l i v e r low b i r t h weight f e t u s e s but t h a t food  d e p r i v a t i o n d u r i n g pregnancy i s a more s i g n i f i c a n t (124).  Although  f e t a l s t u n t i n g i s more severe  factor  i f food  d e p r i v a t i o n occurs d u r i n g the l a t t e r p a r t o f pregnancy, f e t a l growth r e t a r d a t i o n has been r e p o r t e d as e a r l y as days when maternal  sheep were undernourished  f i r s t h a l f of pregnancy (161). t h a t may and  during  Other -experimental  i n a d v e r t e n t l y i n t e r f e r e w i t h maternal  i n f l u e n c e b i r t h weight.  90  the techniques  nutrition  Pregnant r a t s s u b j e c t e d t o  i r r a d i a t i o n o f the head produced s t u n t e d young at term (162).  Not o n l y were the f e t u s e s reduced  i n s i z e but  the  mother a l s o d i d not g a i n a normal amount o f weight d u r i n g her pregnancy.  Poor i n t a k e and poor maternal  nutrition  c o u l d have c o n t r i b u t e d d i r e c t l y t o f e t a l l o s s and  fetal  21 growth r e t a r d a t i o n .  3.  N u t r i t i o n and Bone Growth a)  Animal S t u d i e s  The normal shape o f a bone i s the r e s u l t o f a b a l a n c e between r a t e o f growth i n t h i a k n e s s and r a t e o f growth i n l e n g t h .  These two processes may  be a f f e c t e d t o  d i f f e r e n t degrees by changes i n the l e v e l o f n u t r i t i o n . Experiments hypothesis.  w i t h growing animals appear t o support  this  In r a t s h e l d at b i r t h weight f o r two weeks by  underfeeding, the s k e l e t o n c o n t i n u e d t o grow v e r y s l o w l y w h i l e o s s i f i c a t i o n a l s o proceeded  s l o w l y (163).  The bones  o f o t h e r young animals r e a r e d on a maintenance o r s u b s i s tance d i e t c o n t i n u e d t o grow but a t a much slower r a t e than normal (164-168).  F o r example, r e t a r d i n g growth o f c h i c k e n s  by underfeeding was  found t o depress  i n c r e a s e i n femoral  t h i c k n e s s t o a g r e a t e r e x t e n t than i n c r e a s e i n l e n g t h (87). Appleton  (169)  a t t r i b u t e d v a r i a t i o n s i n the s i z e o f young  r a b b i t s o f the same age t o d i f f e r e n c e s i n n u t r i t i o n a l background, c o n c l u d i n g t h a t the l e v e l o f n u t r i t i o n a f f e c t s both the r a t e o f growth and the r a t e o f bone o s s i f i c a t i o n . The c o r t e x o f the long bones o f p i g s and c o c k e r e l s whose growth was  g r e a t l y r e t a r d e d f o r long p e r i o d s o f time  by underfeeding was lagen r a t i o was  very t h i n and b r i t t l e and the C a / c o l -  s i g n i f i c a n t l y h i g h e r than i n w e l l n o u r i s h e d  animals o f e i t h e r the same body weight o r same c h r o n o l o g i c a l  age,  (170).  The s t r u c t u r e o f the c o r t e x o f the bones o f  these animals was a l s o abnormal and the chemical were p o s s i b l y r e l a t e d t o t h i s .  findings  The abnormality i n t h e  composition o f the c o r t e x induced by underfeeding was comp l e t e l y masked when the composition o f the whole bone was c o n s i d e r e d , f o r i n both s p e c i e s the C a / c o l l a g e n r a t i o was the same as o r lower than i n normal bones o f the same age. Other animal experiments have been conducted i n which food i n t a k e was i n c r e a s e d m a t e r i a l l y d u r i n g the f i r s t few days o f l i f e throughout  (171) .  Rats i n t h i s group grew much f a s t e r  t h e i r whole growth p e r i o d than t h e i r  so t h a t they became l a r g e r a d u l t s and remained the r e s t o f t h e i r l i f e .  littermates large f o r  Using a l i z a r i n s t a i n i n g , weight and  l e n g t h measurements and d e t e r m i n a t i o n o f the composition o f rat  femur, D i c k e r s o n (172) s t u d i e d t h i s e f f e c t o f a c c e l e r a t e d  growth on s k e l e t a l development.  He found t h a t f a s t e r growth  r a t e a f f e c t e d maturation t o d i f f e r e n t e x t e n t s although body l e n g t h was always p r o p o r t i o n a l t o body weight. appearance and f u s i o n o f the epiphyses was seen. were s h o r t f o r body weight and l e n g t h i n r a p i d l y  Earlier Long bones growing  animals, suggesting t h a t t h e s k e l e t o n o f a h i g h l y n o u r i s h e d animal i s i n a l e s s advanced s t a t e o f o s s i f i c a t i o n than the s k e l e t o n o f a p o o r l y n o u r i s h e d animal which has f i n a l l y reached the same s i z e a f t e r a l o n g e r p e r i o d o f growth. Thus t h e m o r p h o l o g i c a l l y immature femora o f t h e a c c e l e r a t e d r a t s may be due t o a h i g h plane o f n u t r i t i o n having i n c r e a s e d  growth i n t h i c k n e s s to a g r e a t e r e x t e n t than growth i n length. Hammond (173)  and h i s a s s o c i a t e s have c a r r i e d  number o f i n v e s t i g a t i o n s on the e f f e c t o f d i f f e r e n t o f n u t r i t i o n upon the s k e l e t o n o f the p i g and one o f these, Wallace  (174)  out a  levels  sheep.  In  showed t h a t the s k e l e t a l  devel-  opment of lambs depends on the l e v e l of n u t r i t i o n o f  the  mother d u r i n g the l a s t s i x weeks o f pregnancy and on  the  number o f lambs c a r r i e d by the ewe.  The  s k e l e t o n s o f lambs  born o f mothers which had been maintained nutrition,  and more e s p e c i a l l y  on a h i g h  l e v e l of  i f they were s i n g l e t o n s ,  were i n a more advanced s t a t e of development than those  of  twins o r t r i p l e t s and o f lambs born o f ewes reared on a  low  plane o f n u t r i t i o n .  Ossification  to be more advanced w i t h  o f bones was  the former group.  suggested t h a t s i z e o f s k e l e t o n was s k e l e t a l development than was The  c a l c i u m content  to the growth and  study  a b e t t e r reference for  body weight.  of the d i e t  i s o f prime importance  d u r i n g pregnancy (175) . d i e t appears t o be (176)  The  i n the newborn r a t seemed to be  u n a f f e c t e d by o n l y reducing  Kon  This  development of the animal s k e l e t o n .  p r o p o r t i o n of c a l c i u m  Henry and  a l s o found  The  the c a l c i u m i n t a k e o f the mother calcium/phosphate r a t i o o f  the c r i t i c a l f a c t o r  in this  showed, i n r a t s , t h a t low  the  species. concentration  o f phosphorus i n the d i e t reduced the r e t e n t i o n o f  calcium.  Warkany  (177)  noted  d i e t s were b r e d , that  57  out  compared paired  of  t o no  animal  t h a t when r a t s r a i s e d  alizarin  164  had  a  longer  abnormalities  increments  on  i n the  c o n t r o l group.  ample  I t was food  varying  were a b l e a l s o found  that animals  c a l c i u m b u t were s t u n t e d  Marginal has  skulls  same age  or  are  rats  (179)  zinc  (181). and  tion  and  had  thiamine,  calcium  the  in severly  i n monkeys  Even d e f i c i e n c i e s  manganese has  produced  regarding  the  of  than  reproductive in  the  depressed  (180).  When g r o w i n g  p h o s p h o r u s and  i n the  bones  t r a c e elements such  skeletal  as  retardation (4).  o f s t u d i e s , t h e o r i e s have b e e n  specific  effect  of endochondral o s s i f i c a t i o n  calcium,  sturd-  (178).  concentration of that mineral  From s i m i l a r k i n d s proposed  had  f e d d i e t s c o n t a i n i n g o n l y t r a c e amounts o f magnesium  sodium the  falls  which  r e s u l t e d i n l o w e r bone g r o w t h p o t e n t i a l  e n d o c h o n d r a l bone f o r m a t i o n rats  rats  ( v i t a m i n A,  protein d e f i c i e n c y during  o f newborn  With  i n growth  higher concentration of skeletal  normal r a t s o f the  cycle  female  t o r e a r more young,  because of o t h e r d i e t a r y d e f i c i e n c i e s  did  Many  levels of calcium.  of d i e t a r y calcium,  s p a n and  ier offspring.  p r o t e i n ) had  young i n d i c a t e d  e x p e r i m e n t s have showed s k e l e t a l d i f f e r e n c e s  life  received  o f the  rachitogenic  multiple skeletal deformities,  when young were r a i s e d increasing  staining  on  Vitamin  of d i e t a r y manipula-  (182).  D will  Deficiencies of  impair erosion  of  h y p e r t r o p h i c c a r t i l a g e c e l l s and thus r e t a r d  calcification.  Maternal h y p e r v i t a m i n o s i s D 2 has r e s u l t e d i n s m a l l e r d i a physes o f f e t a l bones and has produced  alteration in ossif-  i c a t i o n w i t h the appearance of p a t h o l o g i c a l types o f c a r t i l age c e l l s i n the e p i p h y s e a l a r e a . a c t i v i t y causes overgrowth  Uncontrolled osteoblast  o f bone i n V i t a m i n A d e f i c i e n c y ,  whereas i n h y p e r v i t a m i n o s i s A, bone formation ceases  and  f r a c t u r e s o c c u r from depressed o s t e o b l a s t i c a c i t i v i t y .  In  r i b o f l a v i n d e f i c i e n c y there i s a gradual c e s s a t i o n of c a l c i f i c a t i o n , the primary spongeosa d i s a p p e a r s , the e p i p h y s e a l c a r t i l a g e narrows and i s f i n a l l y s e a l e d o f f w i t h bone.  Pantothenate  and pyridoxime d e f i c i e n c i e s ,  d e f i c i e n c y and i n a n i t i o n show the above e f f e c t s  protein also,  presumably due t o i n t e r f e r e n c e w i t h m a t r i x formation r a t h e r than w i t h c e s s a t i o n o f c a l c i f i c a t i o n .  Ascorbic acid  d e f i c i e n c y i n t e r f e r e s w i t h the a c t i v i t y o f o s t e o b l a s t s , which then r e v e r t back to f i b r o b l a s t - l i k e c e l l s ; bone weakness and f r a c t u r e s r e s u l t .  V i t a m i n E does not appear t o be  d i r e c t l y i n v o l v e d i n endochondral  b)  ossification.  Human S t u d i e s  Although t h e r e i s a c o n s i d e r a b l e amount o f i n f o r m a t i o n a v a i l a b l e c o n c e r n i n g the r o l e o f maternal n u t r i t i o n on  the  development o f the f e t u s i n e x p e r i m e n t a l animals, the r e l e v a n c e o f these d a t a t o the problem  o f human f e t a l  d e p r i v a t i o n , p a r t i c u l a r i l y i n the area o f s k e l e t a l  develop-  26 ment, i s hard t o a s s e s s .  U s u a l l y the d i e t a r y d e f i c i e n c y o r  d e f i c i e n c i e s u t i l i z e d are g r o s s to ensure major d e f e c t s ; the g e s t a t i o n p e r i o d s  are v e r y d i f f e r e n t from t h a t o f  humans; most l a b o r a t o r y animals are h i g h l y p o l y t o c o u s ;  and  f i n a l l y the i n t r a - u t e r i n e development i s v e r y d i f f e r e n t from t h a t i n man,  i n t h a t the f e t a l organism i s more h i g h l y  d i f f e r e n t i a t e d at b i r t h compared t o  man.  A l i m i t e d number o f s t u d i e s o f newborn i n f a n t s , and c o n s i d e r a b l y more s t u d i e s o f growing c h i l d r e n , have r e l a t e d n u t r i t i o n t o s k e l e t a l development. the r e l a t i o n s h i p t h a t S t u a r t  (183)  F i g u r e 2 shows  o b t a i n e d between maternal  d i e t and osseous development o f the hand, knee and based on X-Rays taken at b i r t h .  foot,  In t h i s study, "poor d i e t "  c o u l d be s t r o n g l y c o r r e l a t e d w i t h r e t a r d a t i o n i n the i n f a n t ' s osseous development.  The  d i f f e r e n c e between a  "good" o r " e x c e l l e n t " maternal d i e t and not  a "fair" diet  as s t r i k i n g , although there were more r e t a r d e d  i n the  " f a i r " maternal d i e t group than i n the o t h e r  I t was  obvious t h a t few  retarded  i n the  was  infants groups.  i n f a n t s were advanced and many were  "very poor" d i e t group.  S t u a r t found an even s t r o n g e r  r e l a t i o n s h i p when  p r o t e i n c o n t e n t o f the maternal d i e t was osseous development at b i r t h .  In the  c o r r e l a t e d with  "excellent" protein  d i e t group, 57% o f the i n f a n t s were advanced and r e t a r d e d , whereas i n the  14% were  "poor" p r o t e i n group, none were  27  65  ••  60 •• 55  0)  T3  ro  +J  a)  OS  'O S-l  ro 0)  <D  CD (0  ro  U  U  >  >  <D  o c ro >  J7.<o  tea jCM  Good o r Excellent (29 Cases)  *6  Fair (147 Cases)  A?. 3 4/. 9  Poor o r Very Poor (21 cases)  Mean G e n e r a l Rating o f P r e n a t a l D i e t  F i g u r e 2.  R e l a t i o n o f osseous development o f l i v i n g , f u l l term i n f a n t s a t b i r t h to t h e i r mothers' d i e t s d u r i n g pregnancy (183)  28 advanced and 71% o f the newborns were r e t a r d e d i n osseous development.  A somewhat l e s s marked r e l a t i o n s h i p was  when maternal  d i e t a r y c a l c i u m was c o n s i d e r e d :  found  "excellent"  c a l c i u m d i e t s g i v i n g 32% advanced w i t h 23% r e t a r d e d , and "poor" c a l c i u m d i e t s g i v i n g 6% advanced and 64% r e t a r d e d . Stuart  (183) found  a s i m i l a r r e l a t i o n s h i p between  the c a l c i f i c a t i o n o f t e e t h b e f o r e e r u p t i o n and q u a l i t y o f the d i e t d u r i n g pregnancy. (184)  T h i s r e i n f o r c e d Berk's c o n c l u s i o n  t h a t an adequate p r e n a t a l d i e t seemed t o be an  e s s e n t i a l f a c t o r i n c a l c i f i c a t i o n o f a c h i l d ' s t e e t h during the f i r s t ten months o f l i f e .  Massler  (185), however, i n  h i s d i s c u s s i o n o f p r e n a t a l c a l c i f i c a t i o n o f t e e t h commented t h a t almost p e r f e c t c a l c i f i c a t i o n o f c e r t a i n t i s s u e s b e f o r e b i r t h was n o t s u r p r i s i n g - the f e t u s o r embryo i s a paras i t e d e r i v i n g a l l i t s n u t r i e n t s from the mother and drawing on h e r c a l c i u m r e s e r v e s i n the bone where n e c e s s a r y .  Thus  o n l y severe d e f i c i e n c y i n the mother c o u l d a f f e c t t i s s u e s c a l c i f i e d before b i r t h .  G e n e r a l l y , t h e " p a r a s i t e " concept  i s not a c c e p t e d . The c a l c i f i c a t i o n o f the t i b i a o f newborn i n f a n t s was found t o be u n a f f e c t e d even when the mothers were o n l y 14-17 years o l d and were p r o b a b l y c a l c i f y i n g t h e i r own bones (186).  However, the s i g n i f i c a n c e o f t h i s  must be questioned determined.  as maternal  finding  c a l c i u m i n t a k e was n o t  I n d i v i d u a l bones may d i f f e r i n t h e s u s e p t i -  29 b i l i t y t o a low c a l c i u m Toverud (187) r e p o r t e d  i n t a k e by the mother.  Toverud and  t h a t the percentage o f c a l c i u m i n  the p a r i e t a l bones and r i b s o f newborn i n f a n t s was lower when the d i e t o f the mother c o n t a i n e d  p r a c t i c a l l y no m i l k  and was t h e r e f o r e v e r y low i n c a l c i u m .  The degree o f  c a l c i f i c a t i o n o f the i n f a n t ' s s k u l l a t b i r t h may be i n f l u e n c e d by p r e n a t a l f a c t o r s .  Boder (188) s p e c i f i c a l l y  i m p l i c a t e d maternal exposure t o sun and supplemental a d m i n i s t r a t i o n o f d i c a l c i u m phosphate together D.  with Vitamin  A review o f l i t e r a t u r e on p r e n a t a l r i c k e t s i n d i c a t e d  t h a t maternal h e a l t h , d i e t , frequent  pregnancy, and l a c k o f  exposure t o sunshine may be c o n t r i b u t i n g f a c t o r s which e x e r t an i n f l u e n c e on the development o f r i c k e t s i n v e r y young i n f a n t s (189).  Toverud (190) s t u d i e d the e t i o l o g y  of congenital osteoporosis,  f i n d i n g t h a t poor c a l c i f i c a t i o n  o f f e t a l bone c o r r e l a t e d w i t h t h e n e g a t i v e phosphorus b a l a n c e common d u r i n g pregnancy.  Cockburn  c a l c i u m and  the l a s t 2 t o 3 months o f  (191) i n e x p l o r i n g some  biochemical  aspects o f i n t r a - u t e r i n e growth r e t a r d a t i o n , r e p o r t e d  that  plasma c a l c i u m was s i n g i f i c a n t l y reduced and i n o r g a n i c phosphate s i g n i f i c a n t l y i n c r e a s e d  i n u m b i l i c a l v e i n plasma  o f low b i r t h weight i n f a n t s . Sontag (192) attempted t o c l a r i f y the r e l a t i o n s h i p between c e r t a i n maternal c o n d i t i o n s  d u r i n g pregnancy and  the s t a t e o f w e l l - b e i n g by  o f the f e t u s a t b i r t h , as measured and length, weight and b l o o d calcium development o f bone. A  30 No c o r r e l a t i o n factors:  was shown between the f o l l o w i n g s e t s o f  (a) the c a l c i u m content o f the serum o f the  mother and the t o t a l f e t a l e p i p h s e a l area; of infant  a t b i r t h and t h e f e t a l e p i p h y s e a l area;  adequacy o f the maternal area;  content o f the serum i n the c o r d ; i n the maternal i n the c o r d ;  birth;  (c) the  d i e t and the f e t a l e p i p h y s e a l  (d) the adequacy o f the maternal  at b i r t h ;  (b) the l e n g t h  d i e t and the c a l c i u m  (e) the amount o f c a l c i u m  d i e t and the c a l c i u m content o f the serum  ( f ) the mother's g a i n i n weight and the weight  (g) the mother's c a l o r i c i n t a k e and the weight a t  (h) the mother's p r o t e i n i n t a k e and the f e t a l e p i -  p h y s e a l area;  ( j ) the amount o f f a t i n the mother's d i e t  and the f e t a l e p i p h y s e a l area;  (k) the amount o f c a l c i u m  i n the mother's d i e t and the f e t a l e p i p h y s e a l area; (1) the amount o f phosphorus i n the mother's d i e t and the f e t a l e p i p h y s e a l area;  (m) the menstrual  the t o t a l e p i p h y s e a l area; the home c o n d i t i o n s .  age o f the f e t u s and  (n) the d i e t o f the mother and  From what was known about the seeming  independence o f the growth o f new bone transformation of c a r t i l a g e rickets,  (or a t l e a s t the  i n t o osteod t i s s u e ) and  Sontag f e l t t h a t the i n t a k e o f c a l c i u m , phosphorus,  and v i t a m i n D was p r o b a b l y more important t i o n o f bone d e n s i t y than annotated  i n bone growth.  i n the  determina-  Although  an  b i b l i o g r a p h y (193) on bone d e n s i t y has r e c e n t l y  been p u b l i s h e d , no l i t e r a t u r e i s a v a i l a b l e on the d e n s i t y o f human f e t a l bones and i t s r e l a t i o n to maternal  nutrition.  31 Tompkins  (194)  has  r e l a t e d e p i p h y s e a l maturation  in  the newborn to maternal n u t r i t i o n a l s t a t u s . H o s p i t a l i z e d pregnant women were g i v e n v a r y i n g amounts of n u t r i t i o n a l supplements ( p r o t e i n , v i t a m i n s , minerals) 16 weeks of pregnancy.  The  measured from radiographs  area o f o s s i f i c a t i o n  the three c e n t e r s s t u d i e d .  whites, than was  and  i n the time o f  Negros developed  Among p a t i e n t s who  a significant  formation than  more advanced  took supplements there  p r o b a b i l i t y t h a t the t i b i a l  c e n t e r of the knee would be present  knees.  earlier  the female, r e g a r d l e s s o f race, was  the male.  final  was  o f the newborns' h e e l s and  I n d i v i d u a l d i f f e r e n c e s were found of  during the  epiphyseal  i n female  infants.  These supplements d i d not a l t e r the time of appearance o f the e p i p h y s e a l c e n t e r .  I n t e r e s t i n g l y , Tompkins' p o p u l a t i o n  was  not e x p e r i e n c i n g any s e r i o u s n u t r i t i o n a l  The  p a t i e n t s who  deficiencies.  d i d not r e c e i v e supplements reported a  d a i l y d i e t i n the l a s t h a l f of pregnancy which i n c l u d e d , on the average, 76g  p r o t e i n and  86o"^:alcium.  Other r e s e a r c h e r s have reported t h a t e p i p h y s e a l development during delayed  the i n t r a - u t e r i n e p e r i o d was  i n f e t a l m a l n u t r i t i o n a l syndrome.  t i b i a l epiphyses undernourished  markedly  Femoral and  were absent i n a h i g h e r percentage o f the  group than the c o n t r o l s , and even when  present, the c e n t e r s i n the malmourished i n f a n t s were s m a l l e r (195).  P o s t n a t a l bone growth o f i n f a n t s with  growth r e t a r d a t i o n has a l s o been i n v e s t i g a t e d (196).  fetal  Infants with  birth  weights  f o r g e s t a t i o n a l age opment o f t h e with  (197).  from  these  a t the  Unfortunately,  but  o f appearance this  bolic and  schedule  (199).  may  nutrition  of  neonatal  drawn  status of  the  from p l a c e n t a l  rating  and  be  interrupted or distrubances.  than  may  Vitamin  (201).  rating  be D  i n the d i e t  Studies  on  German c h i l d r e n (203)  the  usual effects  and  John  (204)  meta-  Weight, body  maturity in  and  the  and  (202)  r a t e a t w h i c h a bone d e v e l o p s ,  postulated  bone marrow, t h e r e were no  level  and  thus  Although  of  in nutrition  masking Dickerson  a d e f i c i e n c y of protein in d i f f e r e n c e s i n the  of  epiphyseal  have shown t h a t  o f c h r o n o l o g i c a l age.  (200).  availability  the g e n e r a l  kwashiorkor  their  i n growth  the development o f  malnourished the  r e t a r d e d by  i s the e a r l i e s t  i n f l u e n c e d by  as  ossification,  measures o f w e i g h t o r h e i g h t  in children with  alter  of  show i r r e g u l a r i t i e s  ossification  may  s e q u e n c e as w e l l  indicator of disturbances  i s more d e l i c a t e  minerals  c a n n o t be  is a definite  Epiphyseal  the o n l y  Epiphyseal  to infants  majority  poor n u t r i t i o n a l  e v e n m e n t a l d e v e l o p m e n t may  frequently and  conclusions  f o r secondary centers  or constitutional  progress  The  devel-  (198).  In c h i l d r e n t h e r e date  knee when compared  been c l e a r l y d i f f e r e n t i a t e d  dysfunction  retarded  grew a t a n o r m a l r a t e d u r i n g  experiments unless  m o t h e r had  tenth p e r c e n t i l e  and  f o r g e s t a t i o n a l age.  small at b i r t h  life  the  shorter fibulas  epiphyses  normal w e i g h t  infants  had  lower than  the  composition  33 of the femur as a whole, o r o f the epiphyses o r the c o r t e x , t h a t could be a t t r i b u t e d s p e c i f i c a l l y marasmus.  to kwashiorkor o r  3^ I N T R O D U C T I O N The continutn  nutritional  that begins with  to e x t r a - u t e r i n e beginning.  life  the  assessed length,  by  certain  the  circumference  birth  evidence  regarded  and  skeletal  as  i n which  nutritional  end  a  emergence  rather  status of  g r o w t h and  determined  the  fetal  and  head, c h e s t ,  (17).  than  development  has  been  length,  parameters.  For  foot  abdomen and  been  shown t o  example,  thigh, during  affect  there  i s some  secondary o s s i f i c a t i o n  centers,  i s r e l a t e d to maternal d i e t  (183,  195) . contrast,  growth d u r i n g largely  the  to reach  the  term.  described  available information  pre-birth period  p r e g n a n c y was Dickerson  bone c o m p o s i t i o n  (81-83) has  d e n s i t y o f the  related  the  from p r e m a t u r e b i r t h s o r  In e a c h c a s e  Trotter  a  the  Maternal n u t r i t i o n  f a c t o r t h a t has  at b i r t h ,  period  as b i r t h w e i g h t  of the  one  size  of  t h a t development o f  By  and  affect  s k i n - f o l d thicknesses  194,  conception  the  such c r i t e r i a  pregnancy i s but  as  be  fetus. Growth a t  and  can  i s merely a t r a n s i t i o n  Intuitively,  p r e g n a n t woman c o u l d of  process  and of  has  obtained  spontaneous  abortions.  abnormal because colleagues fetuses  recently studied human f e t u s .  socio-economic  been  f a c t o r s to  regarding  (86,  i t failed  106)  12 weeks t o bone  Gruenwald  length, (49-51)  have birth. weight has  f e t a l b i r t h weight,  24  35 weeks t o t e r m . impressive,  Whereas t h e c o n t r i b u t i o n  no c o r r e l a t i o n h a s b e e n made between  various  studies.  studied  by Dickerson,  ative  Trotter  and G r u e n w a l d were  In a d d i t i o n ,  t o g r o w t h o f t h e human  no r e s e a r c h fetus,  representrelating  8-20 weeks  old,  available.  The define  purpose o f t h i s p r o j e c t  maternal that  i s two-fold:  (a) t o  c e r t a i n p a r a m e t e r s o f s k e l e t a l g r o w t h and d e v e l o p -  ment i n t h e n o r m a l human f e t u s , factors with  these  and (b) t o c o r r e l a t e  fetal  parameters.  t h e f e t a l model d e v e l o p e d w i l l  further  research  in this  project  through  those  fetus.  I t i s hoped  direction to  were made a v a i l a b l e  for this  the cooperation o f D r . Betty Poland  Department o f O b s t e t r i c s U.B.C.  give  Length, weight  certain  area.  N o r m a l human f e t u s e s  to  these  I t i s n o t known w h e t h e r t h e f e t u s e s  o f normal growth.  maternal d i e t is  o f e a c h work i s  and D i v i s i o n o f Human  and e x t e r n a l  Genetics,  measurements  t a k e n on newborns were r e c o r d e d  o f the  analogous  f o r the i n t a c t  The humerus and femur were c h o s e n as  representative  m o d e l s o f e n d o c h o n d r a l bone g r o w t h and, t h u s , o f s k e l e t a l growth. on  B e c a u s e most o f t h e r e s e a r c h  t h e femur, t h e humerus was i n c l u d e d  compare g r o w t h  rate  i n the f e t a l  has been  i n t h i s study t o  arm and l e g .  were w e i g h e d , m e a s u r e d , and r a d i o g r a p h e d physical for  indices  o f bone g r o w t h .  c e r t a i n minerals  and c o l l a g e n  conducted  Both bones  to provide  The b o n e s were to provide  assayed  biochemical  i n d i c e s o f bone development.  Three c r i t e r i a o f f e t a l  growth were t h e r e f o r e a v a i l a b l e ; whole f e t a l  measurements,  p h y s i c a l data and b i o c h e m i c a l data o f long bones. Maternal  f a c t o r s o t h e r than n u t r i t i o n have been  r e l a t e d to f e t a l growth and development  (20-49).  To  p r o v i d e p e r s p e c t i v e between n u t r i t i o n a l and n o n - n u t r i t i o n a l f a c t o r s , s e l e c t e d medical and socio-economic  i n f o r m a t i o n , growth data,  scores were a l s o c o l l e c t e d  w i t h f e t a l parameters.  and c o r r e l a t e d  37  M A T E R I A L S A.  AND  M E T H O D S  F e t a l Studies Seventy-six  human f e t u s e s o f v a r y i n g ages and  were c o l l e c t e d immediately f o l l o w i n g t h e r a p e u t i c v i a hysterotomy. opmental age (205)  graph  naval and sex and  Crown-rump length was  (Table XI) .  the  The  weighed.  Head  limb measurements were recorded.  devel-  Streeter's  u m b i l i c a l cord was  i n t a c t f e t u s was  abortion  measured and  c a l c u l a t e d from a m o d i f i c a t i o n of  sex  c u t at  the  circumference,  Where p o s s i b l e ,  l e n g t h of cord and weight of p l a c e n t a were noted.  The  f e t u s was  autopsy  d i s s e c t e d and  e v i s c e r a t e d using  standard  procedure at Vancouver General H o s p i t a l . and  right  l e g were c a r e f u l l y removed at the c l a v i c l e and  pelvic The  The  j o i n t s , r e s p e c t i v e l y , f o r biochemical  remainder of the f e t u s was  placed  i n 10%  f o r m a l i n , f o r l a t e r r a d i o l o g i c a l study. Pathology Lab examined a l l p l a c e n t a s f e t u s e s , detected  The  arm the  analysis. buffered V. G.  for lesions.  H. Abnormal  e i t h e r by autopsy o r by p l a c e n t a l  h i s t o l o g y , were excluded from t h i s  study.  A photographic study of the  following  fetal  m a t e r i a l s and methods has been i n c l u d e d  i n Appendix 1  ( P l a t e s 1-9).  a l l tables,  f i g u r e s and  Appendix 1 a l s o c o n t a i n s  forms r e l a t i n g to methods.  38 1.  Long Flesh  Bone S t u d i e s and  bones o f the r i g h t were t e a s e d a p a r t .  t e n d o n s were c a r e f u l l y arm  and  elbow  and  Humerus, r a d i u s ,  ulna,  femur,  remove t h e p e r i o s t e u m .  including  c a r t i l a g e was  B a l a n c e was All  used  leg.  c u t from  The  f i b u l a were washed b y w a t e r to  Physical  pressure, The  to weight  t h e bones were d r i e d  the  then wiped  content  (% f r e s h bone) o f femur  tibia, thoroughly bone  i n d i v i d u a l b o n e s t o 0.01  Mean p e r c e n t d r y m a t t e r p e r l o n g t o p r o v i d e an  joints  A Metier Analytic  to c o n s t a n t weight  culated  knee  length o f the f r e s h  recorded.  limb  at  105°C.  bones p e r f e t u s was  index o f s k e l e t a l weight. and humerus was  mg.  The found  calwater by  subtraction.  F a t was  extracted  from e a c h  G o l d f i s c h Fat E x t r a c t i o n Apparatus then d r i e d  (206).  to constant f a t - f r e e weight.  between d r y w e i g h t expressed  f e t a l bone u s i n g  and  as a p e r c e n t a g e .  The b o n e s were  The  f a t - f r e e w e i g h t was  the  difference  calculated  and  39 2.  Long Bone S t u d i e s - B i o c h e m i c a l Sixteen  dissection. analysis,  Because  A total  o f these  of sixty  individually.  After  acid  l m l 6N p o t a s s i u m pipetted  i n the case with  the mixture  hydroxide.  to dissolve  by  flame  emission  colorimetric line  (208),  method  was n e u t r a l i z e d  collagen  were e x p r e s s e d  then  water,  f o restimation of  absorption  (207),  (209).  The p e r c e n t a g e  of  by Leach  (211) was  o f c o l l a g e n on t h e a s s u m p t i o n  contains  with  precipitate.  e s t i m a t e d b y Neuman and L o g a n s p r o c e d u r e  percentage  hours.  sodium  and i n o r g a n i c p h o s p h o r u s b y a  the m o d i f i c a t i o n suggested into  f o r 48  deionized-distilled  s a m p l e s o f t h e s o l u t i o n were t a k e n  not large  1ml 6N h y d r o c h l o r i c  the c a l c i u m phosphate  and magnesium b y a t o m i c  weighing  o f those  S u f f i c i e n t H C l was  A f t e r making up t o volume w i t h  calcium  s p e c i m e n s was n o t  i n a 100°C b l o c k h e a t e r  hydrolysis,  biochemical  f e m o r a and h u m e r i were  enough f o r p o w d e r i n g , were h e a t e d i n s e a l e d tubes  impairs  Samples o f bone powders  50mg o r w h o l e bone f r a g m e n t s  acid  i n formalin before  f o r m a l i n treatment  bone c o m p o s i t i o n  considered. analysed  f e t u s e s were p l a c e d  14.1% h y d r o x y p r o l i n e  as g/lOOg d r y f a t - f r e e  (212). bone.  hydroxypro(210) w i t h converted t h a t human A l l values  3.  Long Bone S t u d i e s The  removed was Following the  eviscerated fixed  silver the  length of  then  method  immersed  nitrate  fetus with  in formalin  O'Rahilly's  f e t u s was  - Radiological  f o r 2 to (72)  i n a 0.5%  specimen  specimens underwent t h i s A  lOma p o r t a b l e  f e t u s e s were r a d i o g r a p h e d 10-40mas The  ( T a b l e XIV)  and  X-Rays were p r o c e s s e d The  using  radiographs  on  ossified  & Co.,  leg  (Table  XII).  radiography,  11 d a y s d e p e n d i n g  and  pinned  The  fetus  flat,  a styrofoam  on  was  dorsal slab.  side  All  treatment.  r o e n t g e n u n i t was non-screen  a target-film  employed.  film  at  distance  The  58kv, of  24".  manually. were i l l u m i n a t e d on  a m i l l i m e t e r eyepiece  (Flubacher  7 days  (Table XIII) .  rinsed, d r i e d thoroughly  and  aqueous s o l u t i o n o f  down, u s i n g wooden t o o t h p i c k s , on 76  arm  of s i l v e r  f o r a period o f 2 to the  right  with  eight-fold  Horgen, S w i t z e r l a n d )  bone s h a f t s were measured  a screen  magnification,  l e n g t h and  according  and,  width  to Figure  of 6.  Jf-1 Bo  Maternal lo  Medical The  either  Studies History  p a t i e n t ' s h i s t o r y was  preceding  the t h e r a p e u t i c  taken by Dr. Poland  abortion  hours t h e r e a f t e r .  Information  included  and  of children  (parity),  f a t h e r , number  nancies  i n c l u d i n g the present  one  number  (gravidity),  or stillbirths,  obstetric  and f a m i l y h i s t o r y , method o f b i r t h  and p r e n a t a l  o f p r e g n a n c y , was of  factors.  of  reason  at  were  Dietary  information  A standard  literature  was  this  estima-  (213-215) .  and t h e method  of indications  normal f e t u s e s  three  obtained  to five  p r o c e d u r e was  First  a daily  from an  from  interview  days a f t e r the  followed  form d i e t a r y h i s t o r i e s  by asking  control  included.  History  on s h o r t  obtained  The m a j o r i t y  Dietary  the p a t i e n t ' s b e d s i d e  based  medical,  14 d a y s t o t h e d a t e  abortion  p s y c h i a t r i c reasons but three  abortion.  past  and s u b t r a c t i n g  f o r the present  spontaneous a b o r t i o n s  2.  previous  from the d a t e o f a b o r t i o n .  a b o r t i o n were r e c o r d e d .  involved  o f preg-  G e s t a t i o n a l age o r d u r a t i o n  the l a s t menstrual period  The  origin,  c a l c u l a t e d by adding  tion o f conception  24  age o f t h e m o t h e r  abortions  used,  ethnic  or within  (Form 1 ) ,  presented  i n the  dietary pattern  was  t h e p a t i e n t what she u s u a l l y a t e d u r i n g  the  course  precise  o f a day throughout h e r pregnancy.  i n d i c a t i o n o f maternal  food  frequency  food  consumed was  period  food  questions. minute  likes  concerning  from  under g e n e r a l  t h e 15  comments.  previous  any h i s t o r y o f n u t r i t i o n a l or very e r r a t i c the g e n e r a l  Maternal  This  nutritional  following  e a t i n g h a b i t s , and comments  n u t r i t i o n was  assessed  on p r e v i o u s  D a i l y Allowances  s e r v i n g s p e r week  ailments,  a u t h e n t i c i t y of the h i s t o r y .  (45) w h i c h was b a s e d  Recommended  from  asked  t o v a l i d a t e the preceding  relevant information recorded  then  d i f f e r e n c e b e t w e e n p r e g n a n t and n o n - p r e g n a n t  fad diet  rating  o r f o r m and amount o f  The p a t i e n t was  and d i s l i k e s  Any o t h e r  from a  and t h e p a t i e n t c h o s e t h e t i m e  involve family preferences,  nutrition,  on  The t y p e  recorded,  i n t e r v i e w was  status,  of  d i e t was o b t a i n e d  ( i . e . d a y , week, m o n t h ) .  specific  could  question.  A more  using  Crump's  studies  (216, 217) .  (115) and  Number o f  f o r e a c h o f 6 f o o d g r o u p s was c a l c u l a t e d  interview data  and e x p r e s s e d  i n f o u r p o s s i b l e ways;  (Form 2) (a)  Total Nutrition  Score  number o f s e r v i n g s p e r week  ( 0 - 1 3 3 ) ; sum o f across  a l l food  groups. (b)  Weighted N u t r i t i o n  f o o d g r o u p was and (c)  assigned  response s c a l e d Nutrition  Index  Score  (0-30);  each  a maximum v a l u e  of 5  accordingly (0-5); based  on W e i g h t e d  Score (d)  d i v i d e d by  number o f f o o d g r o u p s i n v o l v e d  P r o t e i n Score  servings cheese  (0-40);  p e r week i n m i l k  food  diet  based  types  this  on  in Vitamin and  and  o f number  of  e g g s , meat,  fish,  groups.  Comments c o n c e r n i n g maternal  sum  D,  the g e n e r a l calcium,  amounts o f  food  adequacy o f  p r o t e i n and  eaten,  the  iron,  were n o t e d  on  form.  3.  Personal History Following  the d i e t a r y h i s t o r y  the p a t i e n t  was  u s u a l l y r e l a x e d enough t o answer more p e r s o n a l  questions.  Age,  and  weight, height, e t h n i c o r i g i n ,  o f s c h o o l c o m p l e t e d were r e c o r d e d f a t h e r o f the was  sought.  g i v e n by  the  fetus.  occupation  f o r both  grade  the mother  and  In a d d i t i o n , b i r t h w e i g h t o f mother  Information  which c o u l d not  p a t i e n t was  obtained  o r would not  from h o s p i t a l  be  records  where p o s s i b l e .  A s h o r t form socio-economic using  Crump's  father,  rating  education  (23),  score the  (0-72) and  outline  (Form  as  f a t h e r and  Information  Socio-economic Group  3).  calculated  i n which the o c c u p a t i o n  o f m o t h e r and  o f m o t h e r were c o n s i d e r e d .  i n d e x was  was  of  marital status coded  (1-4)  as  total  according  to  44 C.  Statistical Analysis Whole  chemical  f e t a l measurements, o s s i f i c a t i o n  d a t a o f femora and h u m e r i , n u t r i t i o n a l ,  g r o w t h and s o c i o - e c o n o m i c coded  i n f o r m a t i o n from  d e v i a t i o n s , degrees  relation  m a t r i c e s were g e n e r a t e d .  regression  a n a l y s i s was  for lines  mination taken  of least  Simple  performed squares,  Means, cor-  and m u l t i p l e  on t h e w h o l e r a n g e o f coefficients  This procedure  of deterwas  under-  t o d i s c o v e r which v a r i a b l e s b e s t p r e d i c t e d o t h e r The C o e f f i c i e n t  the C o e f f i c i e n t  variables,  this  of expression.  of Correlation  of Determination  p r o p o r t i o n o r percentage v a l u e was  i s on t h e r e g r e s s i o n  v?  means  i s t o 1.0, t h e b e t t e r t h e  then  classified  according to  Two week age g r o u p s were  to allow comparison w i t h Dickerson's  data  to t e s t  16 chosen  (86). Analysis  a l o n g w i t h Duncan's New  Range T e s t a t t h e 5% l e v e l g r o u p mean.  a more u s e f u l  11-12, 13-14, 15-16, o v e r  age) .  executed  b y t h e two  line.  g r o u p o f f e t u s (9-10,  o f v a r i a n c e was  is  ( R ^ ) . B e c a u s e R^ g i v e s t h e  considered  The c l o s e r  weeks d e v e l o p m e n t a l  (r) squared  o f the v a r i a n c e shared  E a c h v a r i a b l e was age  t h e m o t h e r were  o f f r e e d o m and s i m p l e  and F p r o b a b i l i t i e s .  variables.  fit  medical,  f o r a n a l y s i s on U.B.C.'s IBM 360/67 c o m p u t e r .  standard  data  and b i o -  Multiple  the s i g n i f i c a n c e  o f each  45  R E S U L T S A.  F e t a l Data F e t a l data were grouped a c c o r d i n g t o developmental  age i n t o f i v e age p e r i o d s o f two weeks each. of specimens i n F i g u r e 3.  i n each group  ( t o t a l 76 specimens)  i s presented  Experimental e r r o r , and the f a c t t h a t o n l y  60 femora and humeri were analysed, sample s i z e .  The number  reduces the t o t a l  The s m a l l e s t v a r i a b l e s i z e i s 57.  R e s u l t s o f a n a l y s i s o f v a r i a n c e are expressed i n Tables I I I and IV.  T o t a l number o f o b s e r v a t i o n s , means  of each age group, and u n i t s o f e x p r e s s i o n are g i v e n .  F  p r o b a b i l i t y i n d i c a t e s the l i k l i h o o d o f o b t a i n i n g an age group e f f e c t f o r t h a t v a r i a b l e by chance a l o n e .  If a  s i g n i f i c a n t F was found a t the 5% l e v e l , Duncan's New M u l t i p l e Range T e s t  (218) was executed t o determine which  means were s i g n i f i c a n t l y d i f f e r e n t from each o t h e r . Duncan's T e s t a d j u s t s the " l e a s t s i g n i f i c a n t d i f f e r e n c e " t - t e s t so t h a t the number o f means i n comparison are i n c l u d e d i n the c a l c u l a t i o n .  Means s h a r i n g the same l e t t e r  are not s i g n i f i c a n t l y d i f f e r e n t from each o t h e r ; means assigned  a d i f f e r e n t l e t t e r are s i g n i f i c a n t l y d i f f e r e n t a t  the 5% l e v e l .  46  Figure 3.  Histogram o f f e t a l age groups  26 -• 24 —  25  •  22 20  • 18  ro 18 o  -P  E-i  16 • c  15  14  tr  2 12  11  fa  10 •• •P  ro rH  8 6  -  4 .. 2 ••  9-/o  /3-/v  is-if,  Developmental age  n-aa  (weeks)  Table I I I . F e t a l and Long Bone Growth r e l a t e d  Variables Crown-rump length Developmental age G e s t a t i o n a l age F e t a l weight S k e l e t a l index F-dry weight H-dry weight F-water content H-water content F - f r e s h length H - f r e s h length F-ossification H-ossification  n  Unit  9-10  76 76 74 67 58 60 60 58 58 57 57 76 76  mm days days g % mg mg % % mm mm mm mm  61 .00a 69 .87a 69 .60a 14 .20a 16 .58a 3 ,40a 4 .20a 86 .16a 83 .57a 13 .32a 13 ,11a 5 .51a 6 .23a  to Developmental Age  Age of Fetus (weeks) 15-16 11 -12 13-14 87 • 04b 83 .76b 86 .50b 41 .03b 20 .65b 17 .2 0a 18 .18b 83 .61b 79 .83b 21 .93b 20 .88b 11 .52b 12 .06b  115 ,44c 97 .94c 102 .06c 94 ,55c 25 .11c 75 .09b 64 .20c 78 .78c 75 .62c 31 .29c 28 .92c 18 .99c 19 .12c  139.91d 110.91d 109.09c 169.77d :2 9.35d 181.21c 12 7.34d 75.73d 71.80d 39.43d 3.621d 25.39d 2 5 .2 8d  16 171 .71e 131 • 71e 132 .86d 340 .96e 31 .13d 384 .06d 2 52 ,19e 73 .49d 69 .88d 48 .50e 43 .50e 32 .50e 32 .01e  F Prob. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0  F = femur, H = humerus 0.0 i n d i c a t e s  F p r o b a b i l i t y < 10~  8  I f F p r o b a b i l i t y ^ 0 . 0 5 Duncan's New M u l t i p l e Range Test was performed a t the 5% l e v e l . Means s h a r i n g the same l e t t e r are not s i g n i f i c a n t l y d i f f e r e n t from each o t h e r ; means assigned a d i f f e r e n t l e t t e r are s i g n i f i c a n t l y d i f f e r e n t a t the 5% l e v e l .  T a b l e IV.  Composition o f F e t a l  Long Bones A c c o r d i n g to Developmental Age  Age of Fetus (weeks) Unit  Variable F-collagen H-collagen F-calcium H-calcium F-phosphorus H-phosphorus F-magnesium H-magnesium F- sodium H-sodium F-calcium/collagen H-calcium/collagen F-Oa/P H-Ca/P  c  -0Q o •  9-10  11- -12  18.23 16.72a 10.26a 9.72a 6.09a 5.75a 0.57  21 .18 20 .95b 13 . l i b 14 .80b 6 . 51a 7 .23b 0 .52 0 .55 1 .35b 1 ,06b 0 .64a 0 .72b 2 .02b 2 .05b  0 o 5 8  4.72a 4.12a 0.56a 0.57a 1.68a 1.68a  <• "0  ratio ratio ratio ratio  13-14  15-16  20.86 21.55b 16.60c 17.57c 7.77b 7.88bc 0.52  21.32 21.60b 17.62cd 17.84c 8.80b 8.18bc 0.47 0.48 1.06b 1.09b  0.55  0.98b 0.91b 0.79b 0.82bc 2 .15b 2 .22c  0.83b 0.83bc  2 .18b 2.18bc  16 21 .36 20 ,86b 19 .90d 19 .81c 8 .87b 8 .80c 0 .51 0 .50 0 .98b 0 .86b 0 .93b 0 .95c 2 .25b 2 .25c  F prob. 0.1285 0.0013  0.0 0.0 0.0000 0.0000 0.2584 0.3811 0.0000 0.0 0.0000 0.0000 0.0000 0.0  n = 59 f o r each v a r i a b l e F = femur,  H = humerus  0.0 s i g n i f i e s F prob. 10~ 0.0000 s i g n i f i e s 1 0 < : F p r o b . < 1 0 ~ 8  _8  5  I f F p r o b a b i l i t y 4:0.05 Duncan's New M u l t i p l e Range T e s t was performed a t the 5% l e v e l . Means s h a r i n g the same l e t t e r are not s i g n i f i c a n t l y d i f f e r e n t from each o t h e r ; means assigned a d i f f e r e n t l e t t e r are s i g n i f i c a n t l y d i f f e r e n t a t the 5% l e v e l .  49 1.  Whole f e t u s Means, standard d e v i a t i o n s and sample  s i z e s o f the  whole range of v a r i a b l e s computed are presented i n Table V. S i x t y - e i g h t p e r c e n t (mean t 1 standard d e v i a t i o n ) o f the specimens c o l l e c t e d were 70-138mm i n l e n g t h from crown to rump and t h e r e f o r e had a developmental age o f 74-112 days or  about 11-16 weeks.  Table V.  Means and standard d e v i a t i o n s o f whole variables Unit  Standard Deviation  Sample Size  Mean  76 76 74 67 67 76 58 76  104.1 92 .72 94.39 89.40 105.4 18.34 22 .29 1.553  mm days days g mm mm %  C. R. Length Developmental Age G e s t a t i o n a l Age F e t a l Weight Head Circumference Foot Length S k e l e t a l Index Sex  1=S  fetal  34.15 18.55 22 .57 91.32 36.32 8.057 5 .423 0.5005  2=*  From Table I I I , as developmental age o f the f e t u s e s i n c r e a s e d , CR l e n g t h , g e s t a t i o n a l age, weight, head circumf e r e n c e , f o o t length and s k e l e t a l index i n c r e a s e d ionately.  Developmental age was b e s t p r e d i c t e d by  proportfetal  l e n g t h , as would be expected from the method o f d e t e r m i n a t i o n 2 (R  = 0.995).  Because o f e x t r a p o l a t i o n from the graph v i a  a t a b l e , t h i s value was (R = 2  0.96),  not 1.00.  foot length  and s k e l e t a l index (R  2  (R  2  Head c i r c u m f e r e n c e  = 0.95), weight  = 0.77)  (R  2  = 0.85),  a l l p r e d i c t e d developmental  age w i t h an F p r o b a b i l i t y o f < 1 0 ~ .  As seen i n Table I I I ,  a  each o f the above v a r i a b l e s separated c l e a n l y i n t o the 5 age p e r i o d s , except s k e l e t a l index which 16 weeks.  tapered o f f a f t e r  Whereas g e s t a t i o n a l age was s t i l l  a significant  p r e d i c t o r o f developmental age, s c a t t e r reduced the C o e f f i c i e n t o f Determination t o 0.67, and o n l y 4 d i s t i n c t groups were found i n Table I I I .  Scattergrams o f these  v a r i a b l e s are presented i n Appendix complete  r e g r e s s i o n data have been d e p o s i t e d w i t h the School  o f Home Economics  and are a v a i l a b l e upon r e q u e s t .  G e s t a t i o n a l age i t s e l f (R  2  (R  2  i s p r e d i c t e d by f o o t  = 0.70), C.R. length o f f e t u s  ference  2 ( E x h i b i t s 1-6)„ The  (R = 0.67), weight 2  = 0.49).  length  (R = 0.67), head circum2  (R = 0.58) and s k e l e t a l index 2  A l l the above r e l a t i o n s h i p s were s i g n i f i c a n t  at p =<10~4 b u t g r e a t e r s c a t t e r was e v i d e n t compared to s i m i l a r r e g r e s s i o n a g a i n s t developmental age ( E x h i b i t s 7-11) . More male specimens collected  ( r a t i o 42:34).  than female specimens were  Because sample s i z e was s m a l l  and sex was unevenly d i s t r i b u t e d throughout the age range, performing separate r e g r e s s i o n a n a l y s i s on each group would not have been m e a n i n g f u l .  51 2.  Long Bones Means, standard  d e v i a t i o n s and sample s i z e s f o r the  v a r i a b l e s computed are presented  i n Table V I .  Generally,  data from the femora and humeri were comparable, w i t h the suggestion  t h a t the humerus i s s l i g h t l y more  f o r i t s d r y weight than  Table V I .  developed  i s the femur.  Means and standard variables  d e v i a t i o n s o f long bone  femur  humerus  Variables  Unit  n  Mean  Stand. Deviat.  Mean  Stand. Deviat.  Dry weight Water content Fresh l e n g t h Ossification Collagen calcium phosphorus magnesium sodium Ca/collagen Ca/P  mg % mm mm  60 58 57 76 59 59 59 59 59 59 59  69.15 81.66 25.80 16.04 20.44 14.14 7.03 0.52 2 .02 0.70 2.00  104.4 4.55 10.97 8.65 3 .60 3 .68 1.29 0.10 1.90 0.16 0.27  52 .53 78.28 24.13 16.33 20.14 14.86 7.23 0.55 1.75 0.73 2 .03  68.03 4 .99 9.54 8.24 3 .68 4 .03 1.45 0.11 1.67 0.16 0.26  CP O  CD  o >, c r-t U 0  ratio ratio  i  The  constant d r y weight of both  femora and humeri  i n c r e a s e d with developmental age ( E x h i b i t s 12-13).  The  n o n - l i n e a r r e l a t i o n s h i p may e x p l a i n why the femoral  data  separated  i n t o o n l y 4 s i g n i f i c a n t age groups, suggesting a  l a g p e r i o d followed by a p r o p o r t i o n a t e l y l a r g e r d e p o s i t i o n o f m i n e r a l and o r g a n i c matter a f t e r 12 weeks.  However each  o f the 5 group means f o r humeral d r y weight were s i g n i f i c a n t .  The weight o f the i n t a c t fetus was the b e s t p r e d i c t o r o f the d r y weight o f both bones (femur R^ = 0.99).  = 0.98, humerus  Dry weight o f the corresponding  bone, d e v e l -  opmental age o f f e t u s , o s s i f i c a t i o n o f the bone,  fetal  length and length o f the f r e s h bone were a l s o good p r e d i c t o r s o f a bone's d r y weight  (R^ =0.80).  Whereas g e s t a t i o n a l age  p r e d i c t e d bone weight with p < 1 0 ^ , s c a t t e r around the -  r e g r e s s i o n l i n e was g r e a t l y i n c r e a s e d chemical  (R^ = 0.54).  Bio-  v a r i a b l e s were even poorer p r e d i c t o r s o f the d r y  weight o f both femura and humeri. An content  i n v e r s e r e l a t i o n s h i p was found between water  o f femora and humeri, developmental age and a l l  o t h e r v a r i a b l e s computed  ( E x h i b i t s 14-15) .  i c a n t age groups were found suggesting  Four s i g n i f -  t h a t as the f e t u s  ages, o r g a n i c and m i n e r a l m a t e r i a l r e p l a c e s the water i n f e t a l bones, reaching content  a p l a t e a u a t 15 weeks.  o f the corresponding  The water  bone, length and o s s i f i c a t i o n  o f bone, f e t a l length and developmental age best the percentage o f water i n both bones (R^ =0.90) . calcium  content  The  The  o f the bone r e s u l t e d i n l e s s s c a t t e r when  p l o t t e d a g a i n s t water content a g a i n s t water  predicted  than d i d g e s t a t i o n a l age  content. lengths o f the f r e s h long bones  increased  p r o p o r t i o n a t e l y with developmental age and could be separated  i n t o 5 d i s t i n c t age groups.  The lengths of the  femora and humeri were b e s t p r e d i c t e d by the o s s i f i c a t i o n the bone (R responding  2  = 0.99)  bone.  and  a l s o by the wet  of  l e n g t h of the c o r -  F e t a l l e n g t h , developmental age, weight o f  f e t u s , d r y weight and water content o f the bone were a l s o good p r e d i c t o r s , i n t h a t o r d e r . the femora and humeri was little  s c a t t e r and was  than was  of  more u s e f u l i n p r e d i c t i n g bone length  g e s t a t i o n a l age.  ossification  v a r i a b l e was = 0.96).  i n c r e a s e d so d i d l e n g t h of  i n both bones; t h i s e f f e c t was  each of the 5 age groups  2  c a l c i u m content  the o n l y b i o c h e m i c a l v a r i a b l e with  As developmental age  (R  Again,  the best  ( E x h i b i t s 18-19).  s i g n i f i c a n t in Indeed, t h i s  long bone p r e d i c t o r o f f e t a l  age  Length of o s s i f i c a t i o n o f the humerus b e s t  predicted o s s i f i c a t i o n  length of the femur and v i c e v e r s a .  F r e s h bone lengths p r e d i c t e d o s s i f i c a t i o n n e a r l y as w e l l (R  2  = 0.99), followed by C.R.  l e n g t h , developmental  age,  weight o f f e t u s , dry weight and water content o f the bone. G e s t a t i o n a l age  and c a l c i u m content  t i o n w i t h bone o s s i f i c a t i o n  (R  2  A n o n - l i n e a r e f f e c t was of  femora and humeri was  ( E x h i b i t s 20-21) .  18.23  = 0.68). seen when c o l l a g e n content  p l o t t e d a g a i n s t developmental  As r e s u l t when f e t a l age was  i n t o two-week p e r i o d s l i t t l e found.  showed a good c o r r e l a -  age  grouped  s i g n i f i c a n t d i f f e r e n c e was  Group means f o r femoral c o l l a g e n ranged between - 21.36  g/lOOg dry bone, w i t h a 12.85% p r o b a b i l i t y of  5h  a s i g n i f i c a n t d i f f e r e n c e between age groups. gen  i n the humeri of f e t u s e s 9-10  However, c o l l a -  weeks o l d was  l e s s than t h a t found i n f e t u s e s 11-20  significantly  weeks o l d .  This  suggests t h a t the t o t a l amount of c o l l a g e n i n c r e a s e s more r a p i d l y with  age  i n younger f e t u s e s and  a f t e r ten weeks.  d e p o s i t i o n slows  There were no h i g h l y s i g n i f i c a n t p r e d i c t -  ors of c o l l a g e n i n f e t a l bone. p r e d i c t e d by humeral c o l l a g e n  Femoral c o l l a g e n was (R  = 0.50)  2  whereas humeral  phosphate b e s t p r e d i c t e d humeral c o l l a g e n There was  2  = 0.65)  according  and  (R  2  = 0.56).  a l i n e a r r e l a t i o n s h i p ( E x h i b i t s 22-23)  between developmental age (R  of f e t u s and  humeral c a l c i u m  (R  2  femoral  = 0.55).  calcium When  to f e t a l age group the amount of c a l c i u m  humerus was week and  s i g n i f i c a n t l y d i f f e r e n t i n 9-10  13-20  week f e t u s e s .  week,  Femoral c a l c i u m  s i g n i f i c a n t group e f f e c t i n t o 4 ages, with  the  i n the humerus d u r i n g  femur, followed by a p l a t e a u  i t i o n appears more g r a d u a l same f i n a l value and  the 11-12  humeri.  cannot be  content  (femur R  c a l c i u m was  from 13-20  2  11-12  some o v e r l a p . depos-  weeks.  Depos-  i n the femur; approximately  I n d i v i d u a l v a r i a t i o n and  phosphorus content  i n the  week p e r i o d than i n  per lOOg dry bone was  r u l e d out  analysed  showed a  Group means suggest a g r e a t e r i n c r e a s e i n c a l c i u m ition  best  seen i n both femora experimental  error  i n d i f f e r e n c e s o f t h i s magnitude. o f the bone best  = 0.76,  humerus R  the b i o c h e m i c a l  The  predicted i t s calcium 2  = 0.85).  v a r i a b l e t h a t best  p h y s i c a l v a r i a b l e s i n t h a t bone.  the  In each bone, predicted  55 A n o n - l i n e a r e f f e c t was suggested  by the s c a t t e r -  gram o f phosphorus content p l o t t e d a g a i n s t age  ( E x h i b i t s 24-25) .  effect  developmental  There was a s i g n i f i c a n t grouping  i n t o 2 f e t a l age p e r i o d s f o r femoral phosphorus and  i n t o 3 f o r the humeral v a l u e s , although some o v e r l a p was seen.  Humeral P was s i g n i f i c a n t l y lower than femoral P i n  the 9-10 week age group but was s i g n i f i c a n t l y h i g h e r a t 11-12  weeks and about the same p e r lOOg d r y bone i n the  remaining  age groups.  C o r r e l a t i o n between femoral and  humeral P v a l u e s produced  R  2  = 0.69.  Humeral P had o n l y  one good p r e d i c t o r ; humeral c a l c i u m with R other variables  2  = 0.92.  Many  showed p <10"^ i n d i c a t i n g a non-zero s l o p e ,  but much s c a t t e r was e v i d e n t .  S i m i l a r i l y , s c a t t e r was high  w i t h femoral phosphate and i t s best p r e d i c t o r was femoral calcium  (R = 0.87). 2  With advancing o f both bones decreased  age o f the f e t u s e s , magnesium content ( E x h i b i t s 26-27) .  The r e l a t i o n s h i p  was so s l i g h t t h a t the means were not s i g n i f i c a n t l y d i f f e r ent when grouped i n t o 5 f e t a l age p e r i o d s .  The o n l y pre-  d i c t o r o f the magnesium content o f femora and humeri was the sodium content o f the same bone (R^ = 0.30). a l s o the o n l y v a r i a b l e s i g n i f i c a n t a t p-^lO""^.  T h i s was Correlation  between femoral and humeral magnesium was 0.51, suggesting e i t h e r g r e a t v a r i a t i o n s between the two bones o r poor method sensitivity.  An  i n v e r s e , n o n - l i n e a r r e l a t i o n s h i p was seen  when sodium content  o f f e t a l bones was p l o t t e d a g a i n s t  developmental age ( E x h i b i t s 28-29).  As r e s u l t , i n both  humeri and femora the sodium content was s i g n i f i c a n t l y higher  i n the bones o f 9-10 week o l d f e t u s e s than the  remaining but  p e r i o d o f 11-20 weeks.  Group means were s i m i l a r  there was l e s s sodium per lOOg d r y humerus than per  lOOg d r y femur.  The b e s t p r e d i c t o r o f the sodium  o f one bone of a f e t u s was the sodium content responding  content  o f the cor-  bone of the same f e t u s (R = 0.96) b u t 7-9 2  v a r i a b l e s showed p <10~^ i n d i c a t i n g t h a t the slope o f the r e g r e s s i o n l i n e was not 0. The  Ca/collagen  increased i n a non-linear  fashion  when p l o t t e d a g a i n s t developmental age ( E x h i b i t s 30-31). The  Ca/collagen  r a t i o i n the femur o f 9-12 week o l d f e t u s e s  was s i g n i f i c a n t l y lower than t h a t i n the 13-20 week p e r i o d . In the humerus, some o v e r l a p p i n g periods was seen. value  i n t o 3 s i g n i f i c a n t age  The r a t i o had the same s t a r t and end  i n both bones; humeral C a / c o l l a g e n bowed more i n the  middle range.  The b e s t p r e d i c t o r was the C a / c o l l a g e n  o f the corresponding  bone a t R  2  = 0.80, b u t 6-8 v a r i a b l e s  c l u s t e r e d below t h i s w i t h p <10"^. d r y weight, and water content  ratio  These i n c l u d e d  length,  o f the bone, length o f f e t u s ,  weight, developmental and g e s t a t i o n a l age. A n o n - l i n e a r r e l a t i o n s h i p was seen when the  calcium/phosphate developmental  r a t i o o f both bones was  age o f f e t u s ( E x h i b i t s  plotted against  (32-33) .  9-10  weeks o l d , t h i s r a t i o i n the femur was  less  than 2.0.  In the remaining  g r e a t e r than 2.0 humerus was  i n t h i s bone.  13-20  In f e t u s e s  significantly  weeks, the r a t i o  The Ca/P  r a t i o i n the  s i m i l a r but separated i n t o 3 s i g n i f i c a n t  groups w i t h some o v e r l a p .  was  age  The b e s t p r e d i c t o r o f t h i s  ratio  was  the Ca/P  r a t i o i n the corresponding bone, although i t  was  seen from the r e g r e s s i o n data t h a t a l l o t h e r v a r i a b l e s  except one were s i g n i f i c a n t  a t p<10~^.  The percent change i n weight of each long bone f o l l o w i n g f a t e x t r a c t i o n was expressed  calculated.  i n Table VII can be e x p l a i n e d by  e r r o r , no f a t was  found  I f the  results  experimental  i n the bones o f f e t u s e s aged  9-20  weeks.  Table V I I .  Change i n bone weight f o l l o w i n g f a t e x t r a c t i o n  Long Bone  (%) Mean  femur tibia fibula humerus radius ulna  -1.5256 -0.5943 0.4847 -0.6093 -0.4572 -0.0900  Standard Deviation 2 .62 1.98 3 .69 3 .29 3 .66 2 .89  58 B.  Maternal Data S e l e c t e d v a r i a b l e s were coded and compared a g a i n s t  each other f o r simple  linear regression data.  p o t e n t i a l independent  v a r i a b l e s were then c o r r e l a t e d w i t h  the f e t a l data as dependent v a r i a b l e s u s i n g regression a n a l y s i s .  These  stepwise  Independent v a r i a b l e s which c o r r e l a t e d  s i g n i f i c a n t l y w i t h each o t h e r ( r = 0.3)  were i s o l a t e d  from  each o t h e r i n s u c c e s s i v e runs.  1.  Medical-Growth Information Means, standard d e v i a t i o n s and number of observa-  t i o n s f o r the s i x  Table V I I I .  Variable  v a r i a b l e s are shown i n Table V I I I .  Means and standard d e v i a t i o n o f variables Sample Size  Unit  76 67 66 45 75 75  years cm kg kg no. c h i l d . no. pregn.  Age Height Weight B i r t h Weight Parity Gravidity  Mean  2  no r e l a t i o n s h i p was and present weight  0.24,  Standard Deviation  29 164 57.6 2.9 1.8 3.3  A s i g n i f i c a n t r e l a t i o n s h i p was maternal weight and h e i g h t (R =  maternal  8 6 8.2 0.8 2.0 2 .3  seen between  p = 0.0001), whereas  d e t e c t e d between maternal b i r t h weight ( p = 0.6253) .  P a r i t y and  gravidity  59 c o r r e l a t e d s i g n i f i c a n t l y w i t h maternal age; had  the o l d e r woman  a g r e a t e r chance o f having more c h i l d r e n and more preg-  nancies than a younger woman.  A highly significant  relation-  s h i p was found between p a r i t y and g r a v i d i t y f o r obvious reasons.  Scattergrams  f o r the above a r e presented i n  Appendix 2 ( E x h i b i t s 34-37) . a l l combinations  No o t h e r r e l a t i o n s h i p s between  o f the above v a r i a b l e s were d e t e c t e d .  When these p o t e n t i a l independent analysed i n stepwise r e l a t i o n s were seen. F i r s t developmental  v a r i a b l e s were  regression, c e r t a i n s i g n i f i c a n t corR e s u l t s a r e presented  i n Table IX.  age was h e l d c o n s t a n t ; then g e s t a t i o n a l  age was chosen as the s i g n i f i c a n t independent  variable.  The data suggest t h a t younger women produced with  fetuses  longer, more o s s i f i e d bones a t each age o f development,  w i t h a l a r g e r head circumference and a h i g h e r Ca/P r a t i o i n the humeri.  None o f the above r e l a t i o n s h i p s were seen  when g e s t a t i o n a l age was h e l d c o n s t a n t . Maternal weight appeared  t o be i n v e r s e l y c o r r e l a t e d  w i t h b i o c h e m i c a l i n d i c e s o f the f e t a l humerus. t h a t l i g h t e r women produced  This  suggests  f e t u s e s with more phosphorus,  magnesium, c a l c i u m and a h i g h e r C a / c o l l a g e n r a t i o i n the humeri than f e t u s e s o f the same developmental h e a v i e r women.  age from  When g e s t a t i o n a l age was h e l d c o n s t a n t the  same r e l a t i o n s h i p h e l d o n l y f o r humerus phosphorus and magnesium.  Interpretation of this finding  is difficult;  60  Table I X .  E f f e c t o f maternal v a r i a b l e s  Independ . Var.  Developmental Age constant Depend. F Var. prob . Rel.  Age  We i g h t  F-Len H-Len HeadC H-Ca/P F-oss H-Oss  0.0000 0.0000 0.0152 0.0177 0.02 76 0.0415  H-Pho H-Mag H-Cal H-Ca/C  0.0007 0.0079 0.12 9 0.0311  on f e t a l data  G e s t a t i o n a l Age constant Depend. F Var. prob. Rel.  --  —  -  Height  H-Pho H-Mag  0.0013 0.0116  -  H-Pho  0.0381  -  H-Col HeadC DeAge  0.0085 0.0134 0.0210  + + +  H-Ca/P  0.0058  —  H-Ca/P  0.0135  —  —  F-Len H-Len H-Ca/C FootL F-Oss GeAge H-Dry H-Col F-Len H-Len H-Ca/P FootL  0.0000 0.0000 0.0054 0.0071 0.0142 0.0159 0.0244 0.0238 0.0000 0.0000 0.0009 0.0098  _  F-Len H-Len H-Ca/P HeadC FootL F-Oss We ig ht  0.0000 0.0000 0.0000 0.0072 0.0338 0.0401 0.0445  _  Socio-econ Score Socio-econ Group  We igh t  0.0116  +  Weight  0.0066  +  Weight  0.0356  +  F e t a l Sex  HeadC  0.0020  _  H-Pho We i g h t  0.0207 0.0422  + +  Birth Weight  Parity  Gravidity  F = femur  H = humerus  -  +  — —  -  -  femora and humeri data were s t r o n g l y c o r r e l a t e d w i t h each o t h e r y e t maternal weight only a f f e c t e d humeral v a r i a b l e s . A l s o , maternal height,  which c o r r e l a t e d w i t h maternal  weight, showed no s i g n i f i c a n t c o r r e l a t i o n w i t h any o f the fetal  variables. Maternal b i r t h weight was i n v e r s e l y  with certain physical f e t a l data. developmental age was held  correlated  F o r example, when  constant, mothers who weighed  more a t b i r t h appeared to produce fetuses w i t h bones, s h o r t e r humeri.  shorter  f e e t , l e s s o s s i f i e d femora and l i g h t e r  However there appeared t o be a d i r e c t c o r r e l a t i o n  between maternal b i r t h weight and humeri c o l l a g e n . d i r e c t r e l a t i o n s h i p s were discovered was held  Certain  when g e s t a t i o n a l age  constant. There i s the suggestion that mothers w i t h fewer  c h i l d r e n produced fetuses which had longer f e e t and longer bones than women w i t h a l a r g e r f a m i l y , was held  constant.  i f developmental age  There appeared to be l i t t l e  relationship  between p a r i t y and these dependent v a r i a b l e s when expressed as a f u n c t i o n o f g e s t a t i o n a l age. S i m i l a r responses were found when number o f pregnancies was c o n s i d e r e d . age  In a d d i t i o n , when developmental  was kept constant, as g r a v i d i t y i n c r e a s e d ,  f e t a l head  c i r c u m f e r e n c e , weight and femoral o s s i f i c a t i o n decreased. As w i t h p a r i t y , no c o n c l u s i v e  r e s u l t s were seen when  62 g r a v i d i t y was expressed as a f u n c t i o n o f g e s t a t i o n a l age.  2.  Socio-economic  Status  Mean socio-economic score out o f a p o s s i b l e 72 was 33.4 t 12.9; mean group was 2.7 t 0.74. There were 52 o b s e r v a t i o n s i n each case as the remaining 24 women were u n w i l l i n g t o supply the i n f o r m a t i o n . R e l a t i v e f r e q u e n c i e s o f the socio-economic groups  i s shown i n F i g u r e 4. The  scattergram o f socio-economic score versus socio-economic group  ( E x h i b i t 38) i s presented i n Appendix  2.  As seen i n  Table IX, socio-economic data were p o s i t i v e l y c o r r e l a t e d w i t h f e t a l weight, whether expressed as a score o r group, as a f u n c t i o n o f developmental o r g e s t a t i o n a l age.  3.  Sex o f Fetus R e s u l t s o f stepwise r e g r e s s i o n a n a l y s i s  suggest  t h a t females o f the same developmental age had a g r e a t e r head circumference than males, whereas when g e s t a t i o n a l age was c o n s i d e r e d , females had lower humeral and weighed l e s s than  4.  phosphate  values  males.  N u t r i t i o n a l Data R e l a t i v e f r e q u e n c i e s , means and standard d e v i a t i o n s  f o r each n u t r i t i o n v a r i a b l e are presented i n F i g u r e 5. Sample s i z e was 70 s i n c e 6 women were d i s c h a r g e d from the  63  Figure 4 .  Histogram o f Socio-economic Groups  2 6  low.  .high 2 4  2 4  2 2  Mean  CN  in  2 0  2  ro o U  c  S.D.  2 0 o 7  0 „ 7  1 8  1 6  1 4  3  tr  1 2  CD  U  fa > -H -P  ro  1 0  8  r-i  CD  a;  6  4  2  I  II  I I I 3V  o-/v  IS-J9  so-74.  Socio-economic  Socio-economic group Socio-economic score Status  F i g u r e 5a.  Histograms o f g e n e r a l maternal n u t r i t i o n  r.f. 40  ^. high  low.  Nean  S.D.  90  16 14  13  no  low  36 •  high Wean S.D. i 4  34  32  28  28  10 •  20  8-  16  16'  6  12 3  2+  d  3 1  3a- *»- S0-i0-7flSCr fO39 49 S9 it 79 i i 19  ItXt ICI  136; in 1*9 133  TOTAL NUTRITION SCORE  11  3.5  8 •  4  4 Jt>-  /* 19 *H  *s-  A9  WEIGHTED NUTRITION SCORE  22  21  15  12 •  8  jo- is-  high Neon  24  22  20  4  v  36  32  24  low  A  13  12  r.f. 40  score  _3 A&-*J-3-0-3£-to- MSJ.1 Jt.1 At 3.9 *V V.9  NUTRITION INDEX  S.O.  65  F i g u r e 5b.  Histogram o f maternal p r o t e i n score  high  low. 22  21 Me an 28  20 18  17  16  16 -o c  14 -  C  12  CD 3  > •P  re CO  12.  10 • 8 •• 6 -4 2 0-9  /0-/9  Z0T*9  30-39  TOTAL PROTEIN SCORE  S .D. 12  66 h o s p i t a l b e f o r e the d i e t a r y h i s t o r y c o u l d be taken. scores were arranged  on a continuum from low to high  grouped a r b i t r a r i l y .  A normal d i s t r i b u t i o n was  f o r t o t a l n u t r i t i o n score, weighted score and  and  obtained  nutrition  index; probably o n l y 4 women c o u l d be d e s c r i b e d as an inadequate  All  having  d i e t a c c o r d i n g to the c r i t e r i a used.  Protein  scores clumped at the upper range of the d i s t r i b u t i o n ; o n l y a s m a l l number c o u l d be c l a s s i f i e d  as having  again  a low  animal p r o t e i n i n t a k e . T o t a l n u t r i t i o n , weighted score and manipulations  o f the same data and as such c o r r e l a t e d w e l l  w i t h each o t h e r  (R  2  = 0.85) .  A direct relationship  a l s o seen between p r o t e i n score and (R  2  index were  = 0.44), weighted score  (R  2  total  = 0.32)  nutrition  and  index  (R  In a l l of the above c o r r e l a t i o n s , F p r o b a b i l i t y was i c a n t a t p <10~4.  Scattergrams  ( E x h i b i t s 39-44).  No  2  = 0.33).  signif-  are i n c l u d e d i n the Appendix  f u r t h e r r e l a t i o n s h i p s were detected  between n u t r i t i o n a l , maternal 5% l e v e l o f  was  or socio-economic  data a t the  significance.  Table X presents the s i g n i f i c a n t  relationships  t h a t r e s u l t e d when n u t r i t i o n a l f a c t o r s were t e s t e d as p o t e n t i a l independent v a r i a b l e s i n m u l t i p l e r e g r e s s i o n analysis. P r o t e i n score o f the maternal  d i e t d i d not  any f e t a l v a r i a b l e s , e i t h e r when developmental  affect  or g e s t a -  67 Table X.  E f f e c t of n u t r i t i o n a l variables of f e t a l  Developmental Age constant Independent Variable  Depend Var.  F prob.  Total nutrition  F-Len H-Len H-Dry F-Dry F-Pho  Weighted score  data  G e s t a t i o n a l Age constant  Rel.  Depend Var.  F prob.  Rel.  0.0000 0.0000 0.0001 0.0015 0.0365  + + + + +  H-Dry F-Dry F-Pho F-Len H-Len  0.0165 0.0199 0.0317 0.0404 0.0435  + + + + +  F-Len H-Len F-Dry H-Dry F-Pho  0.0000 0.0000 0.0000 0.0000 0.0496  + + + + +  H-Dry F-Dry: F-Len, H-Len F-Pho  0.0010 0.0012 0.0087 0.0117 0.0262  + + + + +  Nutrition index  F-Len H-Len F-Dry H-Dry  0.0000 0.0000 0.0000 0.0000  + + + +  H-Dry F-Dry F-Len H-Len F-Pho  0.0010 0.0012 0.0079 0.0105 0.0284  + + + + +  Protein score  no s i g n i f i c a n t r e l .  F = femur,  H = humerus  no s i g n i f i c a n t r e l  68 t i o n a l ages were h e l d c o n s t a n t . score and  T o t a l n u t r i t i o n , weighted  index were comparable i n e f f e c t , w i t h  total  n u t r i t i o n score p r e d i c t i n g the g r e a t e s t number of v a r i a b l e s w i t h the lowest p r o b a b i l i t y . n u t r i t i o n of the mother was and  dry weight o f both  Results suggest  d i r e c t l y r e l a t e d to the  long bones s t u d i e d .  r e l a t i o n s h i p held when g e s t a t i o n a l age was p r o b a b i l i t y of chance r e l a t i o n s h i p was s c a t t e r was  seen.  that general  Although  length this  considered,  g r e a t e r and more  69  D I S C U S S I O N I t can be the age  shown t h a t there are drawbacks to b a s i n g  o f the f e t u s on  experimental  i t s crown-rump l e n g t h .  Aside  from  e r r o r i n measurement fetuses o f the same  l e n g t h are not n e c e s s a r i l y the same age and v i c e v e r s a .  J u s t as the estimated  from  conception,  g e s t a t i o n a l age  of  a newborn i s an important c l i n i c a l datum which must not disregarded  whatever the  e s t i m a t i o n o f f e t a l age sidered. age  i n f a n t ' s b i r t h weight o r  (a) f e t u s e s the same age  menstruation o r poor memory, the mother was  conception  Any  (219)  o r a l l o f these reasons c o u l d  has  (c) i f  g e s t a t i o n a l age would  to e r r o r s i n the g e s t a t i o n a l age Battaglia  unable t o g i v e  14 days a f t e r the s t a r t of her  menstrual p e r i o d , estimated inaccurate.  irregular  date o f her l a s t menstrual p e r i o d ; d i d not occur  i n three  i n utero grow at h i g h l y  v a r i a b l e r a t e s ; (b) f o r p s y c h i a t r i c reasons,  an accurate  con-  from g e s t a t i o n a l  a g a i n s t a l l o t h e r v a r i a b l e s can be e x p l a i n e d  ways:  length,  from maternal dates must be  Large s c a t t e r i n r e g r e s s i o n data  be  assigned  last  be  contribute  to each specimen.  suggested t h a t r e l i a b l e menstrual  h i s t o r i e s be s e l e c t e d .  Since  such s e l e c t i o n c o u l d  eliminate  10-40% of the sample, does t h i s remainder c o n s t i t u t e a normal r e f e r e n c e group (220)?  A number o f  researchers  70 ignore t h i s s i t u a t i o n by proposing a v a r i e t y o f o t h e r specimens as models f o r the study of f e t a l b i o l o g y , e.g. rhesus monkey.  Because normal f e t u s e s of e x a c t l y known  g e s t a t i o n a l age are r a r e l y a v a i l a b l e f o r a n a l y s i s , human s t u d i e s l i k e the present one must be content w i t h e x p r e s s i n g r e s u l t s a c c o r d i n g t o developmental  age  and thus  fetal  length. With i n c r e a s i n g developmental  age of the f e t u s e s  s t u d i e d , the l e n g t h , d r y weight and extent o f o s s i f i c a t i o n i n c r e a s e d i n both the humerus and  femur.  These f a c t o r s  showed a s t r o n g p o s i t i v e c o r r e l a t i o n with each o t h e r . The weights, were found weight.  r a t h e r than the lengths of the limb bones  to r e s u l t i n a more r e l i a b l e estimate of  T r o t t e r , i n h i s r e s e a r c h on o l d e r f e t u s e s (81),  d e s c r i b e d a s i g n i f i c a n t c o r r e l a t i o n between weights the t o t a l osseous s k e l e t o n t o b i r t h weight and of the osseous diaphyses o f the humerus and i n c r e a s e d with  c r i b i n g the developmental endochondral  of  to lengths  femur; each  age.  The many t a b l e s i n the l i t e r a t u r e  (61-68) des-  sequence of both membraneous and  o s s i f i c a t i o n have been concerned  w i t h the  o f appearance not the extent o r l e n g t h o f o s s i f i e d The  fetal  time  diaphyses.  present work has shown c o n c l u s i v e l y t h a t long bone  o s s i f i c a t i o n as detected from s i l v e r radiography i s a simple and accurate parameter of f e t a l age. s u b s t a n t i a t e d by performing  T h i s c o u l d be  the technique on a l a r g e backlog  71 o f t h e r a p e u t i c a l l y aborted f e t u s e s . age t a b l e , based  on the lengths o f the o s s i f i e d  o f femora and humeri, e o u s l y aborted  The r e s u l t i n g bone diaphyses  c o u l d then be used t o date  spontan-  specimens.  Bone composition r e s u l t s are i n agreement w i t h D i c k e r s o n ' s r e s e a r c h (86) on the human femur although the p r e s e n t study was  concerned w i t h both a younger, more  narrow age range, and a l a r g e r t o t a l sample s i z e . fundamental  The  change i n the composition of a bone d u r i n g  development i s an i n c r e a s e i n i t s degree o f o s s i f i c a t i o n . T h i s i s accompanied by a decrease water (85). study.  i n the percentage  Hammett's o b s e r v a t i o n was  I t was  substantiated in t h i s  found t h a t bone l e n g t h and o s s i f i c a t i o n b e s t  p r e d i c t e d water c o n t e n t .  However, because c l e a n i n g of bone  f o r a n a l y s i s takes c o n s i d e r a b l e time and c o n t r o l l e d d i t i o n s to determine it  of  con-  a c c u r a t e l y the percentage o f water,  i s customary to express composition of bone t i s s u e on  a dry f a t - f r e e The statement  basis.  r e s u l t s o f t h i s study seem t o c o n f i r m Dickerson's  (86) t h a t no f a t i s present i n the f e t a l  d u r i n g the 12-28  week age  range.  femur  However, the e f f e c t i v e n e s s  o f petroleum e t h e r to penetrate the bone and t o break  the  l i p o p r o t e i n complexes i n the marrow c o u l d be q u e s t i o n e d . m i c r o - s o x h l e t apparatus would have been a more s e n s i t i v e technique although problems i n d r y i n g and weighing o f such s i z e  a bone  (l-400mg) would s t i l l have to be s o l v e d .  A  Collagen  d i d not  femurs of f e t u s e s 9-20  i n c r e a s e s i g n i f i c a n t l y i n the  weeks developmental age.  s i m i l a r r e s u l t s were found by Dickerson  (86)  Although  in  femoral  c o r t i c a l bone, i t i s s u r p r i s i n g t h a t c o l l a g e n would i n c r e a s e when expressed as g/lOOg whole bone. c o l l a g e n was  Humeral c o l l a g e n was  femoral  not  at the 5% l e v e l of s i g n i f i c a n c e .  s i g n i f i c a n t l y higher  f e t u s e s than i n 9 - 10 week specimens. humeral and  Femoral  the o n l y v a r i a b l e examined t h a t d i d  p r e d i c t developmental age  not  c o l l a g e n content  i n 11-20  week  Differences in  are not r e a d i l y  explainable. Whereas c a l c i u m and  humeri o f 9-20  increased ratio  increased  l i n e a r l y i n both femora  week o l d f e t u s e s , i n o r g a n i c phosphorus  i n a n o n - l i n e a r manner.  Therefore  the  ( i n d i c a t o r of bone m i n e r a l i z a t i o n ) was  l e s s than 2.0  at 9-10  weeks, and  remaining age  range.  Dickerson  reported  r e l a t i v e l y constant  per lOOg dry f a t - f r e e s o l i d s .  constant (86)  Ca/P  and  Ca/P  significantly  at 2.0  i n the  Swanson (94,  95)  r a t i o s when expressed  However, f e t u s e s l e s s than  12 weeks were not s t u d i e d by e i t h e r r e s e a r c h e r .  The r e s u l t s  of the present work suggest t h a t e i t h e r the r a t i o o f  calcium  to i n o r g a n i c phosphate d e p o s i t i o n i s not constant w i t h bone growth, o r younger specimens have p r o p o r t i o n a t e l y l a r g e r amounts o f o r g a n i c phosphorus r e s u l t i n g i n  contamination.  Perhaps the r a t i o i n c r e a s e a f t e r 10 weeks was  due  to a  decrease i n the p r o p o r t i o n o f phosphate from e s t e r phos-  73 phates - a l a r g e p a r t o f the phosphorus i n the bones o f immature f e t u s e s b e i n g present  i n e s t e r form.  Because c r y s t a l s o f bone m i n e r a l  are  principally  l a i d down i n a s s o c i a t i o n with c o l l a g e n f i b r i l s , Ca/collagen  r a t i o g i v e s a measure o f the degree of s a t u r a -  tion of collagen f i b r i l s . (86) is  the  The  r a t i o was  found by  Dickerson  to change v e r y l i t t l e during growth i n humans.  i n agreement w i t h  collagen f i b r i l s  the c u r r e n t l y accepted  t h i s study fetuses.  view t h a t  are r a p i d l y m i n e r a l i z e d to about  s a t u r a t i o n soon a f t e r they are l a i d down.  This  The  80%  r e s u l t s of  i n d i c a t e a s i g n i f i c a n t l y lower r a t i o i n younger Again, bone composition  has not been r e p o r t e d .  of 9-10  week o l d f e t u s e s  Perhaps the c a l c i f i c a t i o n mechanism  i s not f u l l y developed to m i n e r a l i z e a s u r p l u s of c o l l a g e n fibrils  i n the c a r t i l a g i n o u s model.  reasonable  This explanation i s  because c a l c i f i c a t i o n o f long bones does not  begin u n t i l the f e t u s i s 8 weeks o l d Sodium content  (57) .  o f f e t a l bones, 9-10  weeks o l d  s i g n i f i c a n t l y h i g h e r than i n bones from f e t u s e s aged weeks. fluid,  Sodium i s found i n the bone i n the e x t r a i n the hydrated  l a y e r o f bone c r y s t a l s and  bone c r y s t a l s themselves.  Swanson and  lob  (94,  95).  11-20  cellular i n the  Although a dynamic process  o c c u r i n g , the trend seen here confirms  was  the f i n d i n g s of  is  Magnesium i s a l s o thought to be to f e t a l age found  (94, 95).  related  The c o n s t a n t value of bone magnesium  i n t h i s study, and  humeral and  inversely  the poor c o r r e l a t i o n between  femoral magnesium would suggest poor method  sensitivity. Some comments can be made concerning model evolved i n t h i s p r o j e c t .  the  fetal  Generally, physical  ables b e s t p r e d i c t e d o t h e r p h y s i c a l v a r i a b l e s .  vari-  Similarly,  biochemical v a r i a b l e s best predicted other biochemical variables.  With the e x c e p t i o n o f magnesium and c o l l a g e n ,  which remained constant, a l l b i o c h e m i c a l v a r i a b l e s c o r r e l a t e d s i g n i f i c a n t l y w i t h p h y s i c a l data a t b e t t e r than 5% l e v e l .  This i s a reasonable, but u n t i l now  the  undocumented,  find ing. In t h i s study, femoral and humeral data were found  to be comparable.  U n t i l now,  studies of s k e l e t a l  growth and development i n the human f e t u s have been to the femur.  limited  Data presented h e r e i n show t h a t the r a t e o f  growth between the humerus and the femur, as assessed p h y s i c a l and b i o c h e m i c a l v a r i a b l e s , i s s i m i l a r . i e n t s of Determination  Coeffic-  a s s o c i a t e d w i t h femur v a r i a b l e s were  g e n e r a l l y h i g h e r than those a s s o c i a t e d with  corresponding  humerus v a r i a b l e s when p l o t t e d a g a i n s t developmental ( l e s s s c a t t e r about the r e g r e s s i o n l i n e ) . r e s u l t s g e n e r a l l y had d i d femur r e s u l t s , and  by  age  However, humerus  a more s i g n i f i c a n t F p r o b a b i l i t y  than  therefore a greater separation into  75 age groups was  seen i n t h i s bone.  The reason f o r t h i s  p a t t e r n i s not r e a d i l y e x p l a i n a b l e . The study d i d not d e t e c t a c o n s i s t e n t sex d i f f e r ence among the f e t a l v a r i a b l e s a n a l y s e d . others have observed t h a t o s s i f i c a t i o n  Roche (84) and  i s more  advanced  i n the female than i n the male d u r i n g the l a s t three months p r e n a t a l and at b i r t h , whereas the b i r t h weights of males are g e n e r a l l y h i g h e r . . Perhaps  these e f f e c t s are not  d e t e c t a b l e u n t i l a f t e r 20 weeks developmental  age.  Caution must be e x e r c i s e d i n drawing c o n c l u s i o n s from the e f f e c t o f most maternal v a r i a b l e s on f e t a l  variables.  A s t a t i s t i c a l l y s i g n i f i c a n t c o r r e l a t i o n does not e s t a b l i s h a causal relationship. maternal v a r i a b l e s born v a r i a b l e s observed  A d i r e c t c o r r e l a t i o n found between  (e.g. age, p a r i t y , g r a v i d i t y ) and new-  (e.g. b i r t h weight and  (32, 48, 4 9 ) .  into e a r l i e r f e t a l l i f e .  length) has been  Apparently t h i s r e l a t i o n s h i p  extends  Previous s t u d i e s have shown that  maternal h e i g h t , weight and b i r t h weight  (33-38) are  d i r e c t l y c o r r e l a t e d w i t h c e r t a i n newborn growth  parameters.  The n e g a t i v e c o r r e l a t i o n found i n t h i s study c o n t r a d i c t s previous f i n d i n g s . unclear.  The reason f o r t h i s c o n t r a d i c t i o n i s  I t i s not i n c o n c e i v a b l e t h a t maternal age,  b i r t h weight,  weight,  p a r i t y and g r a v i d i t y c o u l d be c o r r e l a t e d i n  some way w i t h f e t a l s k e l e t a l growth, but f a c t o r s such as ethnic o r i g i n  (23, 24), maternal a n x i e t y (27, 28), smoking  (39, 40),  season  considered  (143)  and  p a t e r n a l v a r i a b l e s must a l s o be  i n the a n a l y s i s .  One  of these a d d i t i o n a l v a r i -  ables could be mediating the observed e f f e c t o f s o c i o economic s t a t u s on f e t a l weight The  (49-51).  p o t e n t i a l f o r undertaking  of the experimental  f e t u s e s was  s t u d i e s on the mothers  r a t h e r l i m i t e d because of  the emotional f a c t o r s a s s o c i a t e d w i t h the performance o f a therapeutic abortion. conducting  research  T e c h n i c a l problems a s s o c i a t e d  i n a h o s p i t a l manifested  through a t t i t u d e s of nursing available.  Accordingly,  personnel  i t was  amount of i n f o r m a t i o n obtained  and  with  themselves facilities  important to l i m i t  the  from the mother without  p r e j u d i c i n g the needs of the study. This  limitation curtailed  of the maternal d i e t a r y h i s t o r y . unique group o f women. had been granted  the scope and The  study concerned a  Seventy-three out of  seventy-six  t h e i r a b o r t i o n f o r p s y c h i a t r i c reasons.  They were e a s i l y upset, very g u i l t - r i d d e n , and reluctant volunteers.  I t was  not  generally  f e a s i b l e to v a l i d a t e  the q u e s t i o n n a i r e with blood or u r i n e samples, or 7-day d i e t a r y h i s t o r i e s questionnaire  accuracy  following discharge.  with  Whereas the  i t s e l f could have been v a l i d a t e d on normal  volunteers,  i t would have been o f d o u b t f u l s i g n i f i c a n c e to  extrapolate  from a normal s i t u a t i o n to the a b o r t i o n p a t i e n t s .  The  i n t e r v i e w placed emphasis on the q u a n t i t y  and  v a r i e t y o f the d i e t i n a r e l a t i v e sense. arranged  Scores were  on a continuum from low to h i g h .  Crump (45)  devised t h i s s c a l e from a study o f 483 pregnant women i n N a s h v i l l e , Tennessee.  He v a l i d a t e d the o r a l d i e t a r y  h i s t o r y u s i n g 7-day food records D i e t s were c l a s s i f i e d  from the same p a t i e n t s .  as "poor" (scores 24-33),  "fair"  (34-52), "good" (53-70) and " e x c e l l e n t " (71-133). his  c a l c u l a t i o n s a score o f 60 was found  From  t o r e p r e s e n t an  intake o f two-thirds the Recommended D a i l y Allowance during pregnancy. ard  N i n e t y - f i v e percent  (mean plus/minus two stand-  d e v i a t i o n s ) o f the n u t r i t i o n scores i n the present  fell  study  i n t o Crump's "good" o r " e x c e l l e n t " c l a s s i f i c a t i o n s .  Only 4 women c o u l d be considered pregnancy.  to have " f a i r " d i e t s  during  T h i s would i n d i c a t e that scores were taken  from  the upper range o f the normal p o p u l a t i o n d i s t r i b u t i o n ; not s u r p r i s i n g c o n s i d e r i n g t h a t the procedure and c o s t o f a t h e r a p e u t i c a b o r t i o n e f f e c t i v e l y l i m i t s the o p e r a t i o n to those  i n the middle-to-upper socio-economic Because the scores represented  fair  range.  a continuum from  t o e x c e l l e n t , i t was c o n s i d e r e d v a l i d t o regress  n u t r i t i o n a l data a g a i n s t f e t a l d a t a .  Perhaps egg,  cheese,  meat and milk content o f the maternal  d i e t gave an i n a c c u r a t e  p r o t e i n score, f o r t h i s v a r i a b l e showed no r e l a t i o n s h i p w i t h any o f the f e t a l parameters examined. n u t r i t i o n score and  On the other hand,  (a measure o f p r o t e i n , v i t a m i n s ,  minerals  c a l o r i e s ) d i r e c t l y c o r r e l a t e d w i t h length and dry weight  o f both humeri and was  femora.  In t u r n , dry weight of bones  the b e s t p r e d i c t o r o f f e t a l weight, and  b e s t p r e d i c t e d bone o s s i f i c a t i o n .  length of bone  Both bone l e n g t h  weight were s i g n i f i c a n t p r e d i c t o r s of f e t a l length developmental age,  and and  and good i n d i c a t o r s of bone c a l c i u m .  S k e l e t a l growth and maturation  are o b v i o u s l y under c o n t r o l  o f a fundamental b i o l o g i c a l growth mechanism ( 1 ) . data suggest t h a t n u t r i t i o n a l f a c t o r s may  affect  These the  e f f i c i e n c y w i t h which t h i s mechanism f u n c t i o n s . In c o n c l u s i o n , normal s k e l e t a l growth and opment of the human f e t u s can be d e s c r i b e d  devel-  i n terms o f a  c o r r e l a t i o n between whole f e t a l measurements, p h y s i c a l growth and b i o c h e m i c a l the humerus.  Using  composition  of e i t h e r the femur or  t h i s model, f u r t h e r n u t r i t i o n a l  r e s e a r c h could be conducted to e x p l o r e between f e t a l bone growth and  the r e l a t i o n s h i p  d i e t during  pregnancy.  Length and weight o f e i t h e r bone, as w e l l as being  signif-  i c a n t l y c o r r e l a t e d with maternal n u t r i t i o n  study,  are r e l a t i v e l y simple  and  accurate  and would allow c o n s i d e r a b l e a s i m i l a r time p e r i o d .  parameters to  analyse,  i n c r e a s e i n sample s i z e  Bone c a l c i u m would be the  p r e d i c t o r of bone composition  and  calcium.  with  Biochemical  r e l a t e d to maternal consumption o f  m i l k and o t h e r c a l c i u m - r i c h foods d u r i n g pregnancy. sibilities  during  best  could be compared  cord blood c a l c i u m and maternal blood f i n d i n g s c o u l d then be  in this  Pos-  are as numerous as the number o f dimensions  presented;  study i n t h i s area o f f e r s  an  interdisciplinary  b l e n d o f n u t r i t i o n , embryology, b i o c h e m i s t r y and  psychology.  80  R E F E R E C N E S 1.  Langman, J . : M e d i c a l Embryology. 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A . : Severe undern u t r i t i o n i n growing and a d u l t animals; dimensions and c h e m i s t r y o f long bones. B r i t . J . Nutr. 15:567-576 (1961).  171.  Widdowson, E . M., McCance, R. A.: Some e f f e c t s o f a c c e l e r a t i n g growth. Proc. Roy. Soc. B. 152:188-206 (1960).  172.  D i c k e r s o n , J . W. T., Widdowson, E . M.: Some e f f e c t s of a c c e l e r a t i n g growth. P r o c . Roy. Soc. B. 152:207-217 (1960).  173.  Hammond, J . : P h y s i o l o g i c a l f a c t o r s a f f e c t i n g b i r t h weight. P r o c . N u t r . Soc. 2:8-12 (1944).  174.  Wallace, R. R.: The growth o f lambs b e f o r e and a f t e r b i r t h i n r e l a t i o n to the l e v e l o f n u t r i t i o n . J . Agric. S c i . 38:367-376 (1948).  175.  Sherman, H. C , Booher, L . E.: The c a l c i u m content o f the body i n r e l a t i o n to that of the f o o l . J . B i o l . Chem. 93:93-103 (1931).  176.  Henry, K. M., Kon, S. K.: The e f f e c t of age and the supply o f phosphate on the a s s i m i l a t i o n o f c a l c i u m by the r a t . Biochem. J . 41:169-176 (1947).  177.  Warkany, J . : Appearance o f s k e l e t a l a b n o r m a l i t i e s i n o f f s p r i n g o f r a t s reared on d e f i c i e n t d i e t s . Anat. Rec. 79:83-100 (1941).  178.  Sherman, H. C : Calcium i n Foods and N u t r i t i o n . Columbia Univ. P r e s s , N. Y., 1948.  179.  Shaw, J . H.: M a r g i n a l p r o t e i n d e f i c i e n c y d u r i n g the reproductive cycle i n rats: I n f l u e n c e on body weight and development o f s k u l l s and teeth o f o f f s p r i n g . J . D e n t a l Res. 49:350-358 (1970).  180.  J h a , G. J . : Bone growth i n p r o t e i n Amer. J . P a t h . 53:1111-1121  181.  watchorn, E., McCance, R. A.: Subacute magnesium d e f i c i e n c y i n r a t s . Biochem. J . 31:1379-1390 (1937) .  182.  I r v i n g , J . T.: Calcium Metabolism N. Y., 1957, pg. 98) .  deficiency. (1968).  (Wiley & Sons,  94 183.  S t u a r t , H„ C : F i n d i n g s on the examination o f newborn i n f a n t s and i n f a n t s during the n e o n a t a l p e r i o d which appear to have a r e l a t i o n s h i p to the d i e t s o f t h e i r mothers d u r i n g pregnancy. Fed. Proc. 4:271-281 (1945).  184.  Berk, H.: Some f a c t o r s concerning the i n c i d e n c e o f d e n t a l c a r i e s i n c h i l d r e n . Amer. J . Dent. Assn. 30:1749-1754 (1943).  185.  M a s s l e r , M., Schour, I . , Poncher, H. G.: Developmental p a t t e r n s o f the c h i l d as r e f l e c t e d i n the c a l c i f i c a t i o n p a t t e r n of the t e e t h . Amer. J . D i s . C h i l d . 62:33-67 (1941).  186.  Booher, L. E., Hansmann, G. H.: S t u d i e s on the chemical composition o f the human s k e l e t o n . 1. C a l c i f i c a t i o n of the t i b i a o f the normal newborn i n f a n t . J . B i o l . Chem. (4:195-205 (1931) .  187.  Toverud, K. U.: 95:688-691  188.  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E.: E p i p h y s e a l development i n f e t a l maln u t r i t i o n syndrom. New. Eng. J . Med. 270:822824 (1964).  Norsk. Mag. (1934).  Laegevidenskap.  Prenatal influences in r i c k e t s . 6:161-166 (1935).  95 196.  Wedgewood, M., H o l t , K. S.: A l o n g i t u d i n a l study of the d e n t a l and p h y s i c a l development o f 2-3 year o l d c h i l d r e n who were underweight a t b i r t h . B i o l . Neonatorum. 12:214-232 (1967).  197.  Wilson, M., Meyers, H., P e t e r s , A.: P o s t n a t a l bone growth o f i n f a n t s with f e t a l growth r e t a r d a t i o n . P e d i a t r i c s . 40:213-223 (1967).  198.  Peck, W.: M a l n u t r i t i o n o f newborn secondary to p l a c e n t a l a b n o r m a l i t y . New. Eng. J . Med. 250:905-907 (1954) .  199.  Frances C : F a c t o r s i n f l u e n c i n g appearance o f c e n t e r s o f o s s i f i c a t i o n d u r i n g e a r l y c h i l d h o o l . Amer. J . Dis. Child. 57:817-830 (1939).  200.  Frances, C : F a c t o r s i n f l u e n c i n g the appearance o f centers of o s s i f i c a t i o n during e a r l y childhood. Amer. J . D i s . C h i l d . 59:1006-1012 (1940).  201.  D r i e z e n , S., Stone, R. E., S p i e s , T„: The i n f l u e n c e of c h r o n i c u n d e r n u t r i t i o n on bone growth i n c h i l d r e n . P o s t g r a d . Med. 29:182-193 (1961).  202.  Jones, P. R. M., Dean, R. F . A.: The e f f e c t o f kwashiorkor on the development o f the bones o f the knee. J . P e d i a t . 54:176-184 (1959).  203.  B e r r i d g e , F. R., P r i o r , K, M.: The s k e l e t a l development o f c h i l d r e n a t the b e g i n n i n g and end o f p e r i o d s o f supplemental f e e d i n g . Spec. Rep. S e r . Med. Res. C o u n c i l , London, no. 287, (1940).  204.  D i c k e r s o n , J . W. T., John, P. M. V.: The e f f e c t o f p r o t e i n c a l o r i e m a l n u t r i t i o n on the composition of the human femur. B r i t . J . 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A.: Notes on a m o d i f i c a t i o n o f the Neuman and Logan method f o r the d e t e r m i n a t i o n o f the hydroxyproline. Biochem. J . 74:70-71 (I960).  212.  Eastoe, J . E.: The amino a c i d composition o f mammalian c o l l a g e n and g e l a t i n . Biochem. J . 61:589-600 (1955).  213.  Burke, B,: The d i e t a r y h i s t o r y as a t o o l i n r e s e a r c h . J . Amer. D i e t . Assn. 23:1041-1046 (1947).  214.  Abramson, J„ H., Slome, C , Kosovsky, C : Food frequency i n t e r v i e w as an e p i d e m i o l o g i c a l t o o l . Amer. J . Pub. H e a l t h . 53:1093-1101 (1963).  215.  E p s t e i n , L„ M., Reshef, A., Abramson, J . H., B e a l i k , 0.: V a l i d i t y of a short d i e t a r y questionnaire. Israel J . Med. S c i . 6:589-597 (1970).  216.  Recommended D a i l y Allowances. N. R. C. P u b l i c a t i o n 1694, N a t i o n a l Academy o f Science, Washington, D. C , (1968) .  217.  D i e t a r y Standard f o r Canada. Canadian B u l l e t i n on N u t r i t i o n 6:1, Canadian C o u n c i l on N u t r i t i o n , March, (1964) .  218.  Duncan, D. B.: M u l t i p l e range and m u l t i p l e F Biometrics. 11:1-42 (1955).  219.  B a t t a g l i a , F. C : I n t r a - u t e r i n e growth. 1015 (1969) o  220.  Murphy, E . A., Abby, H.: The normal range - a common misuse. J . Chron. D i s . 20:79-88 (1967).  tests.  J . Pediat.  97  APPENDIX 1  98  Table X I .  CR length (mm) 1.0 1.5 1.8 2.0 2 .8 3.0 3 .5 4.0 4.5 5.0 6.0 6.5 7.0 7 .5 8.0 9.5 10.0 11.0 12 .0 13.0 14.0 15.0 16.0 17.0 18.5 20.0 21.0 22.0 23 .0 24 .0 25.0 26.0 2 7.0 28-29 30-31 32-34 35-36 37 38-39  Crown-rump l e n g t h versus fetus  days after ovu1'n 18 20 22 22 24 25 26 27 28 28 29 29 30 31.5 32 33 33 34 35 35 36 37 37 38 39 40 41 41 43 43 44 45 51 52 53 54 55 56 57  CR length (mm) 40-41 42 43-44 45-46 47-48 49 50-51 52-53 54 55-56 57-58 59-60 61-62 63-64 65 66-67 68-69 70-71 72-73 74 75 76-78 79-80 81 82 83-86 87-89 90-91 92-93 94 95-97 98-99 100-101 102-103 104 105-106 107-108 109-110 111-112  developmental age o f  days after ovul'n 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96  CR length (mm) 113-114 115-116 117-118 119-120 121-122 123-124 125-126 127-128 129 130-131 132-134 135-136 137-138 139 140-141 142-143 144-145 146-147 148-149 150 151-152 153 154-155 156-157 158 159-160 161-162 163-164 165 166 167 168 169 170-172 173-174 175-177 178-179 180  days after ovul'n 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 121 122 124 125 128 130 131 132 133 134 135 136 137  99  Plate  1.  Specimen  in i n t a c t s*c  100  2.  Placenta Female:  and f e t n s Crown-rumD l e n g t h D e v e l o p m e n t a l aoe -  114mm 97 rlavs  Plate 3.  Eviscerated fetus with and leer removed  riant  arm  102  Plate  4.  S i x f e t a l lone? b o n e s ; c l e a n e d (femur, t i b i a , f i b u l a , humerus. rad i u s , u l n a )  103  P l a t e 6.  Fetus nreoared ^or r a d i o a r a p h y a f t e r s i l v e r n i t r a t e treatment  Plate  7.  Radnoaraphr f o r 1 day  fetus  in  formalin  Plate  8.  Radioqraphr f o r 6 days  fetus  in silver  nitrate  107  Piste  9.  Radioaraoh; fetus f o r 10 d a y s  in silver  nitrate  108  Table  XII.  Minimum graphy  Crown-rump mm  formalin  length  treatment  for silver  Formalin Treatment days  60 75  2  90 90-110 110-130 o v e r 130  4 5  40-  6075-  radio-  3 6 7  Table X I I I .  Optimum s i l v e r n i t r a t e radiography  Crown-rump l e n g t h mm 40- 60 60- 70 70- 80 80- 90 90-100 100-110 110-120 120-130 1.30-140 over 140  Silver  treatment  nitrate days 2 3 4 5 6 7 8 9 10 11  for fetal  treatment  110  Table XIV.  Exposure time f o r f e t a l radiographs on G. E . Model F u n i t (58kv., lOma)  Crown-rump mm  length  40- 60 60- 90 90-130 130 and over  Exposure time sec 1 2 3 4  Ill  F i g u r e (o.  Measurement o f o s s i f i e d  s h a f t o f f e t a l bone  a.  Length o f o s s i f i c a t i o n o f long bone (femur, t i b i a , f i b u l a , humerus, r a d i u s , ulna)  b.  Width of o s s i f i c a t i o n a t proximal metaphysis o f each long bone  c.  Width of o s s i f i c a t i o n a t d i s t a l metaphysis o f each long bone  I f necessary, a bone was d i v i d e d i n t o two o r three p a r t s by p e n c i l l i n e s p e r p e n d i c u l a r to the plane o f the bone; length o f each s e c t i o n was measured and t o t a l length found by add i t i o n . Measurements were recorded  in millimeters.  112 Form 1.  Dietary History Specimen Number  A.  D a i l y pattern time Breakfast  Mid-Morning  Lunch  Mid-Afternoon  Dinner  Mid-Evening  1  recall: food  amount  0  J  '  113 B.  Food Frequency Q u e s t i o n n a i r e  How o f t e n and how much do you e a t o f the f o l l o w i n g of foods? J  Mi l k  types  1 .^J^!L^r7 JeJ\  Cheese s-J"^-/-V-^^>.  ^^vyi**^  a.  —  ^/ j^e^-^r^T^^j  j^/>cj  Je,  F i s h — T *e^*^*n^*prT*l.<rrTt*tKrzXJi.  Poultry  j j s L .  /  Bread — ^ ^ / ^ J J ^ * * ^ e . s ^ > * * J * ^ - t J s t / ^ > j ^ > C e r e a l products  Vegetables:  Jr^»'**<*^^aJ^^  green j/hs<<ajr,  potatoes  Swe  citrus  e ts  Fats  d?«m*«a~£i*, .  4.s-f^ y  J. t  —<d*xJ<«4*i^.  *rsi*  .£><Jhfaf£4,  Arrzrr?*aisr?s*A+,  /H*«<t'4f«  •fJjp.  J>-rs77*^, ^r~x> Jarr^^sL^J^ v C y ^ ^  Beverages  ^,  jluj^Pj  <n(  N u t r i t i o n a l Supplements  Cigarettes  -r^*-^-*-  ^*^t^t»Jpa^  Si*»J*a*<£n  <t-t t w >t ?  *m*tarrr^s*L, .^rt^x^i^.  non-citrus  y%^u^tjrj  J. ,j  ye 11 ow .^<ast*4*&?Jk<i, *(wn^r2f,.  y^^je^u-JoLci^.  Fruit:  „<L-e*asr7  ^^r^/JJ-^  A**^*/^.  114 L i k e s and D i s l i k e s  D.  G e n e r a l Comments  115 Form 2.  Nutritional  Status Specimen Number_  Dietary  Intake bv S n e c i f i c  /03 7  Food Groups (Crump e t a l . Am . J . O b s t e t . Gynec. 77:562, 1959)  Food Group (number s e r v i n g s per week)  5 4 3 2 1  Excellent Good Fair Poor V e r y Poor  Food group Milk Meat, eggs, cheese Cereal Vegetables Fru i t Butter  Milk  Meat Eggs Cheese  Cereal  2 8+ 21-2 7 14-20 7-13 3- 6  21+ 16-20 11-15 6-10 3- 5  2 8+ 14+ 21-27 . 11-13 8-10 14-2 0 5- 7 7-13 3- 4 3- 6  no. s e r v i n g s per week  Fruit  Butter  14+ 11-1.3 8-10 5- 7 3- 4  2 8+ 21.-2 7 14-20 7-13 3- 6  rating  /6 >JP9  -*  >w >/v  J?  >j*  s  Total Nutrition Score (133)  Comments:  Veg.  Weighted Nu t r i t i o n Score (3 0)  Protein Score ( 4 9 )  Nutrition Index (5)  Form 3.  Socio-economic  Status Specimen Nnmhgr 1031  Short Form Socio-economic Score 9 8 7 6 5 4 3 2 1 0  Occupation o f F a t h e r (or mother) professional, semi-professiona1 official,propriet. manager, c o l . student clerical skilled semi-skilled protective service high school student s e r v i c e (except p r o t e c t or domestic) domestic s e r v i c e farm l a b o u r e r u n s k i l l e d labourer  Socio-economic  Group  Group I Group I I Group I I I Group IV  Index Occupation  Index (Crump e t a l . J . P e d i a t . 51:678, 1957) Education o f Father  Education o f Mo the r college 4  college 4  college 3 college 2 college 1 grade 12  college 3 college 2 college 1 grade 12  grade 11  grade 11  grade 10 grade 9 grade 8 l e s s than 8  grade 10 grade 9 grade 8 l e s s than 8  Score X 2  Range  0-14 15-29 30 - 49 50 - 72  low  Answer  |  1 high  Given  of Father  Score 7  Education , o f Mother  S  Education o f F a t h e r  7  Marital  7  Status TOTAL SCORE (X2) SOCIO-ECONOMIC GROUP  s z  Marital Status g i v e average o f known values f o r "married" (4 - 8) divorce, sep. desert., widow (average 1-3) single  117  APPENDIX 2  OEP VAR DE A G E THE  INO VAR CRLEN AND  H  CONST A 36.34 * " ARE USED  COEFF B 0.5418 TO P L O T T H E  F R A T 10 (B) 0. 1 1 8 5 0 REGRESSION  FPROB (B) 05 0.0 L I M E ; THE  STD E R R (A.) 0.5446 I S U S E D WHEN  »*"  STD ERR STD ERR IB) < Y) 0 .49760-02 1 .283 A P L O T POINT COVERS DATA  RSQ //? 0.9953 POINTS  140.0  / I / / / / / / /  124.0 / /  11 / /  / / /  . 5  1 0 8 .0 / / /  . 1 2 21 .11  / / /  92.00  •  / / / / / / / / / / / /  1*2 1 * 11 2. 1 1 1 . 212 4* 122 111. j_2 "" ~  "  "1  76.00  «  / / /  1 2 1*1  /_ / / /  "  1  *  *1 1  6 0 . 00  //!////777////////////I 45.00 ExHib'iT  A//////////////////|///////////////////I///////////////////1//////////////7////T  73.00 \.  T)e  we to ( 3 « e n t o \ cuje (V)  101 . 0 uersu5  crown-rump  C  )  rnrn  129.0  157.0  185.0  DEP VAR HEADC THE  I NO VAR DEAGE AND  CONST A  COEF F  -72.47 «•*" ARE  USED  FR A T 10 (B)  8 1.919 TO  PLOT  FPROB { B)  1355.  STD ERR (A)  0.0  THE R E G R E S S I O N  LINE;  THE  S T D ERR (B)  4.927 »*"  IS  USED  WHEN  STD ERR (Y )  0. 52120-01  7.299  A PLOT POINT  COVERS  RSO //?  0.9603 DATA  POINTS  2 00. 0 t / / / / / /  170.0 / / / / / /  3  / /  140 .0 (mm)  / / / / / _/ /  -  / / 110.0  80.00  1  "  1  1  1  11 1. .  *  1  / / / / / / / / / -  1 1 1  1 .  1  11  . 1  1 1  1  1  1 1 * 1 1 41 . 1 11 111  7 / / / / / 50. 00  1  1  I 1 . 1 12 1 *  1  . 1  1  1  //!///////////////////I///////////////////|///////////////////1///////////////////1///7 60. 00 Exh'ibirrf.  76.00  92.00  ( 4) dai  s  108.0  T)e.\je.\c>pmef\-tcL\ £>_e (X) versus head. c\rcurr&e.re.nee. (V)  ///////////////1  124.0  140.0  DEP VAR FOOTL THE  CONST A -20.93 ARE USED  i NO VAR OEAGE " . « ' AND  CQEFF F R A T 10 8 (B) 0.4-236 1080. TO PLOT T H E R E G R E S S I O N  FPR08 STD E R R < B) (A) 0.0 1.218 L I N E ; THE ••*" I S U S E D WHEN  STO E R R S T D ERR (B ) ( Y) 0.12890-01 1.805 A PLOT POINT COVERS DATA  37. 00  1  RSQ 0.9507 POINTS  J  1  / /  .  / /  1 1 1  • 1  / /  *  /  1  / /  31 .00  *  / /  • 1  / /  *  1  / / /  1  1 . 1  1  /  1 •  1 1  /  2.5. 0 0 _  -  1  7  1  /  (mm ] V J  1  / / /  •  .  1 1  1 *  1  /  1  *  1 1 1 1 .  / / /  1 1  •  19. 00 1  / / /  .1 • 11 1  /  1  / /  1 1 1  11  •V  1  / /  22 2 #11  /  13. 00  * / / /  1  / / /  1  12 1  .1 11 1 *  11 1 ^  / /  1  1  /  7. 0 0 0  . 1  1 i  -  1  .  11  //I / / / / / / / / / / / / / / / / / / / I / / / / / / / / / / / / / / / / / / / I / / / / / / / / / / / / / / / / / / / i / / / / / / / / / / / / / / / / / / / i / / / / / / / / / / / / / / / / / / / i 60.00  £xhibit  76.00 3.  l)e\/e.lcpmemTa.\ aqe.  92.00 versus  -fooT leogTh (Y)  (da us) 3  y  108.0  124.0  140.0  J  DEP VAR WEIGH THE  440.  INO VAR DEAGE " . " AND  CONST A -338.4 « * " ARE USED  COEFF B 4.613 TO P L O T T H E  FRATIO <B) 402.6 REGRESSION  FPROB (B) 0.0 L I N E ; THE  " * "  STD ERR S T D ERR STD ERR (A) <B) 1Y } 21.74 0.2299 32.20 IS U S E D WHEN A P L O T P O I N T C O V E R S  RSQ  /Al DATA  0.8779 POINTS  0 / / / / /  / / /  3 50 .0 / / / / /  2 6 0 .0  4 ^  / / / / /  / / /  170.0  ~ / /  3 1 . 1  / /  80.00  / / / / / / / / / / / / /  . 1 1 1 1 .  1  1 . 1 1  .1  211 . 1 12 11  2  121  1  11 .1111 3311  1  1  1 1  1 11  1  1  1  1  /  -10.00  //I / / ? / / / / / / ? / / / / / / / / / ! / - / / / / / / / / / / / / / / / / / / I / / / / / / / / / / / / / / / / / / / I / / / / / / / / / / / / / / / / / / / I / / / / / / / / / / / / / / / / / / / J 60.00 Exh'ibiT  76.00  -V.  De.\zciaf>ona<\ta.\  a g e (x)  92. 00 versus,  ^ 6^ a<  -petal we'ighr _V)  108.0  124.0  L40.0  DEP VAR  DRUWP  THE  32.00  TND VAR DEAGE " . « AND  CONST  A -1.278  ARE USED  CD E P F B  FRATI 0  F PROB (B)  (B) 173.0  0.2541 TO P L O T T H E R E G R E S S I O N  LINE;  S T D ERR {A)  0.0000 THE  »«*»  IS  1.826 USED  S T D ERR (B)  0.19320-01 PLOT POINT  WHEN A  STD  ERR  RSQ  /HA  {Y)  2.706 0.7555 COVERS DATA POINTS  1  / _/ / / /  T  1 1  / / /  T 27 .00 / /  /_ /  /  l  /  l  ll  l .  i  / /  22.00  l l in  7 / /  ii  / / / / / /  17.00 / / / / /  1 1 1  / / /  12.00 / /  ± / / / /  /  7. 000  //I///////////////////I///////////////////i///////////////////i///////////////////I///////////////////I 6 0. 00  76.00  92.00  (days)  108.0  124. 0  140.0  DEP  VAR  GEAGE THE  IND  CONST  VAR  COEFF  A  OEAGE AND  «*"  FRATIO  B  1.940 ARE USED  FPROB  (8)  0.9971 TO P L 3 T T H E  (B)  114.3 REGRESSION  LINE;  0.0000 THE "*••  STD  ERR  (A)  STD  ERR  STD  ERR  R SQ  (B) <Y) 0.9325D-01 13.06 0.6712 WHEN A PLOT POINT COVERS DATA POINTS  8.815 IS USED  fJt3  143.0  t /_ / /  1 .1  J_ / /  L /  1  1 2 5 .0  .  / /  /_ / / /  T 107  1  .0  1  .  / /  J_ / / _l  89.00  1 .  / / /  1  /  ii  l_ l  1  1 *  1  l . 12  / / / /  71 . 0 0  f 1 1 2  /  1 1  .1  /  1  /  7 / / /  53.00  76  60.00 Exhibit  6.  .00  Leo&\oprr>cntaL\ aqc  ///////////////////i///////////////////I///////////////////I (day*) 108 .0 140.0 92. 00 124.0 versus ^esta.ti'or>ek.l duje  DEP VAR FOOTL THE  IND VAR GEAGE " . " AND  CONST COEF F FRATIO A B (B) -9.780 0.2979 128 .6 A R E U S E D TO P L O T T H E - R E G R E S S I O N  FPROB (8) 0.0000 L I N E ; THE « * «  STD ERR S T D ERR STD ERR (A) (B) (Y) 2.548 0.2627D-01 4.477 I S U S E D WHEN A P L O T P O I N T C O V E R S  37 .00  R SQ  /jW  0.6967 POINTS  DATA  1  1  1  / /  1 1  / / /  1  / / / /  • 1  31.00  •  / /  •  /  1  /  •  / / /  1  1  1 2 1  /  1  1  /  2 5.00  1 / /  1 1  *  2  /  • 1  /  1  •  / / / /  1  1  2  1  19 . 0 0  •  1  /  1  / /  . 1 1  /  •  1  / / / / /  13.00  1  1 1  1 . 1 -  1 1  1  2  1  1 11 11 1  1  1  1  1  1  /  1  / /  *  / / / /  1  2  1 1 1 11  /  .  1  1  /  1  1  7.000  2  1  1  //|///////////////////I///////////////////]///////////////////I///////////////////I///////////////////I 53.00  71.00  89.00  Exhibit y. Gestatic/)a[ age (X) versus foot length [ Y)  107.0  125.0  143.0  J  OEP VAR GEAGE THE  INO VAR  CONST A  COEFF  F PROB (B)  FRATIO  B (B) CRLFN 38.04 0.5414 114.3 A N D " * • • A R E U S E D TO PLOT T H E R E G R E S S I O N  LINE;  0.0000 THE  STD ERR (A)  5.544 IS  USED  STO  ERR  <B)  0.5065D-01 WHEN A P L O T P O I N T  STD  ERR  RSQ  (Y) 13.06 COVERS  DATA  0.6711 POINTS  143 .0 / / /  1  /  1  /  / / /  1  125 .0  .  / / /  / / /  T  /  .107 .0  .1  / / /  / / / / /  1  .1  1 1  1  89.00 / / / / /  1 1 1.  12 1 1  / / -f  71 .00  11  11  / /  _/ / / / / /  53.00  /?)///////////////////1 ///////////////////!///////////////////I///////////////////I7//7///A/////////// I (m/n) 129 . 0 185.0 157.0 4 5 . 00 7 3. 0 0 101 .0 E/hibir 9. Gestational age (,V) versus cro*J*-ru/np lertc^Pi (x)  OEP IND CONST COEFF FRATIO FPR08 STO ERR STO ERR STO ERR RSO VAR VAR A B (B) (8) <A) (B) (Y) HEADC GEAGE -18.48 1.313 111.7 0.0000 12. 05 0. 1243 21.17 0.6660 THE ".» AND "*« ARE USED TO PLOT THE REGRESSION L I N E ; THE «*" IS USED WHEN A PLOT POINT COVERS DATA POINTS 200. 0 / / / / / / /  170.0 / / / /  / /  1 1  /  I  /  140.0  / / /  , ,  1  1 1  1  •  1 1 .  /  / /  .  1 1 1  / / /  110.0  8  0  / / / / / / / / .  0  0  1 1  1 1  1  1  1  1 1 . 1 1 1 1  1 -  1  11 .  1  1  1  /  50.00  / / / / / / /  . .  .  1  .  1  . 1 1_1 1 1 211 1  1  //| / ///////A/////////71 // 77/7/////////////!///////////////////1//////////////////?1///////////////////1 53 .00  Exhibit  71.00  <?. &e&tcktiona.l a<ye  89.00  versus  ( i^ dat  s  head c'ircu/*rfere>nce- £V_)  107.0  125.0  143.0  DEP VAR WEIGH THE  440.0  IND VAR GE A G E AND  CONST A *****  COEE F B  -200 .7 ARE  USED  3 .074  TO P L O T  FRATIO ( 8)  76.44  FPROB JBJ  THE R E G R E S S I O N  LINE;  0.0000  THE » * "  S T D ERR (A) IS  34.10 USED  S T D ERR STD ERR (B ) <Y ) 0. 3 5 1 6 59.91 WHEN A P L O T P O I N T . C O V E R S  RSQ  DATA  0.5772 POINTS  / / / / / /  / 35  0.0 / / / / / /  /  260 .0  4>-  I t f T /  7  /  / /  170.0 /  L / /  / / / / /  80.00  T / /  1 2  / / /  2  -10 .00  1  21311 .1 1  11 21 1  //j///////////////////I///////////////////! 5  3.00  gxh'bir 10.  71. 00  89. 00  G-ettational age (x) versus fetal weight ( Y j  107.0  125.0  143 . 0  OEP VAR  ORUWP  THE  I NO CONST VAR A GEAGE 6.439 AND " * » • A R E USED  COEFF B  0.1679  TO P L O T  FPROB -(B)  FRATIO (B )  53.45  THE R E G R E S S I O N  LINE;  STD ERR { A)  0.0000 THE  STD ERR CB)  STD ERR (Y)  RSQ  2.228 0.2296D-Q1 3.913 0.4884 IS U S E D W H E N A PLOT POINT COVERS DATA POINTS  3 2.00 / / /  / / / /  27 .00 / /  1  / / /  11  / /  22 .00  T / /  i  / /  i i . i  j_ / / /  I  I  1 7. 00  1 . /  (_  111 11  / / / /  / / /  12.00 / / / / / /  /  7. 000  //I///////////////////I///////////////////I///////////////////I///////////////////I///////////////////I 53.00 ExHtb'ir II.  71.00 Gestational  ac^c, (_x) versus  89.00 ske\e.ta.\ iocL*x £ v )  107.0  12 5. 0  143.0  OFP VAP F-DPY THE  I NO VAR OF AG F AND  CONST A - 4 1 2 .2 ARE USED  COEFF B 5 .191 TO P L O T THE  FRATIO  FPROB ( B) 0.0 L I N E ; THE  (B) 3 1 9 .9 REGRESSION  S T O FRR S T D ERR STD ERR (A) (B) <Y ) 2 7 . 44 0. 2902 40. 64 I S U S E D WHEN A P L O T P O I N T C O V E R S  "*"  RSO  DATA  0. 8510 POINTS  450.0 / / / / / / / / /  360.0 / / / / / /  / / / 270  .0  I /  / / / / / I 180.0 / / / / / / / / /  1 .  1  1  90. 00 / /  .  /.  -0.0  / / / / / t -  1  1  1  1 .  1 1  1  1 1  ... 11  1 1 2 2 1 2 1 1 1  1 111 *422 1 1 1 1 1 .  1 . .  .  .  .  .  //!///////////////////I///////////////////I///////////////////I///////////////////I///////////////////I (riau*,) 60.00  E*h)b\r ML.  76 .00  Dcve-lepsyiental  ctqe. _>0  9 2 . 00  ^  108.0  versus femora-i d r q weiqMr _V_  124. 0  140.0  DEP VAR H ~ DRY THE  IND VAR DEAGE • ' . « ' AND  CONST A  COEFF B  -269.4 ARE  FRAUD (B)  3.472  USED  TO  PLOT  FPROB (B)  482.4  THE  STD E R R (A)  0.0  REGRESSION  LINE;  THE  14.94 "*«  IS  USED  STD E R R <B)  STD  0.1581 WHEN A  PLOT  RSQ  ERR  <Y) 22.14 POINT  COVERS  )30  0.8960 DATA  POINTS  270. 0 / / / / / / / /  210.0 / / / / /  l  / /  l  150.0 T / / /  i  /  /  * 2  / / /  90. 00  1  / /  1  1  1  /  / / /  1 1  1.  1  / /  30.00  / / 7 / / /  . :  11  1 11 111  121 2  1  1*11 I ~ T 322T 1 2 . 12  1  1  1  /  / / /  -30.00  //I///////////////////I///////////////////I///////////////////I///////////////////|///////////////////I 60.00  7 6.00  9 2. 00  f x A i b i f /_. Dcv<si'of>mer)-t<a.l ex^e. 0 0 versus.  108.0  hume.ra.\ ctrtj we.ia^ht iv)  124.0  140.0  DEP IND VAR VAR F-H20 DEAGE THE «.»* AND  CONST COEF F FRATIO F PROB STD ERR STD ERR STD ERR RSQ A 8 (Bl ( B) (A) (B) (Y) 102.3 "0.2224 256.2 0.0 1.314 0.1390D-01 1.946 0.8206 ARE USED TO PLOT THE REGRESSION L I N E ; THE «*•• I S USED WHEN A PLOT POINT COVERS DATA POINTS  /SI  89.80 / /  11  / / / / / /  86 .40  11 /  i  /  _  /_  7 / /  i. . 1  /  83 .00  1 /  12 1 11  / /  / /  79.60  11  ± / / /  1 1 1  / / / / /  .1  1  / / /  1  76. 20  1  /  *1  / / /  1  / / /  72. 80  .  //I///////////////////I 60. 00  £xhtb»r /<y.  92.00  76 .00 Developmental  a^e  versus  femora.!  (day*) wafer  108.0 content  (.YJ  124. 0  1 140.0  DEP VAR H-H2 0 THE  IND CONST VAR A DEAGE 100.1 « . » AND " * » ARE USED  COEFF FRATIO B (B) -0.2359 186.4 TO P L O T T H E R E G R E S S I O N  / / / / /  STD ERR <B)  (A) 1.633  0.0000  0. 1728D-01 T H E " * « I S U S E D WHEN A P L O T P O I N T  STD ERR  <Y) 2.419  COVERS  RSO  /SJt  DATA  0.7690  POINTS  j  <,  1  / /  LINE;  S T D ERR  1  88. 50  /  FPROB (B)  1  1  1  ..  1  / 84 . 6 0  •  / /  80. 70.  1 .1  J  lb. 8 0  72.90  1  1  / / / / / / /  •  1 •  1 1 1  /  \  1  1  . 1 1  .  1  / / / / / / / /  1 1 1 «  1  1 1 1 1 1  1 1  1 1  / / / / / / / / /  1 1 1  1  1  .  1  2  1 1 1 1 1 1 1  / / / / / / / / /  . 1 1 .  1 2  1 1  .  1 2  69.00  //I / / / / / / / / / / / / / / / / / / / I 60.00  Exh'ib'ir  i ///////////////////I///////////////////I///////////////////I///////////////////|  76.00  s (if!) Versus  92.00  ^ i^  humeral  Mater  dai  S  108.0  contenT (VJ  124.0  140.0  J  DEP VAR F-LEN THE  I NO VAR DEAGE '«." AND  CONST CO EPF FRATIO F PROB A B (B) (B) -27.65 0.57 64 1044. 0.0 "*•» ARE USED TO PLOT THE REGRESSION L I N E ; THE  STD ERR STD ERR STD ERR RS Q {A) IB) IY) 1.687 0.1784D-01 2.498 0.9491 I S USED WHEN A PLOT POINT COVERS DATA POINTS  /33  51 .00 / /  1  / / /  / / /  42.00 / /  2  /  3 3.00 (mm)  1  / /  7 / /  l  i  l  i  l l  / /  l  / / /  l  24. 00 /  11  / / / /  l  2 1 1 2 * 1 1  /  _/  15. 00  7  2. 1  1.1 1  / / / / /  6. 000  11  ///////////////////I  //I///////////////////I 60.00 Exhib'if  92.00  76.00 lk.  Dsv&lopmenTcti  aqe. £*)  versus  femoral  (daus) len^Th  108.0 (Y)  124.0  140.0  DEP VAR H-LEN THE  46 .00  IND VAR DE A G E AND  "*•»  CONST A  CO E E F B  - 2 2 . 25  0. 5OO2  ARE  USED  TO  PLOT  FRATIO <BI  F PROB (B)  966.6 THE  0.0  REGRESSION  LINE;  THE  STO  ERR  STD  ERR  STD  ERR  (A) (BJ {Y) 1 .521 0.1609D-01 2.253 •»*" I S USED VI HE N A PLOT POINT COVERS  RSQ  /SV  0.9452 DATA POINTS  / /  7" / / / / /  ii  38.00 / / /  1  / / / / /  30. 00  T /  I  / /  22.00  / / / / / / / /  1 1  1  1  .  1 I 1 1 1 . 1 2 1  1 1 1 1  / /  14.00  / / / / 7  1 *  1 1 n*"  11 .1 1  / / /  6. 000 7/I  ///////////////////I///////////////////]///////////////////I///////////////////1///////////////////1  60.00 Bjfh'ib'iT 17,  76.00 De\ze)opn?eryT<zl ct^e. (x) versus  92.00 humeral  108.0 /enajh  (Y)  124.0  140.0  DEP VAR F-OSS THE  IND CONST VAR A DEAGE -26.37 « . " AND " * « ARE USED  3 8 .00  COEFF  FRATIO  FPROB  8  <B)  <B)  0.4574 1391. TO P L O T T H E R E G R E S S I O N  LINE;  STO ERR STD ERR S T O ERR (A) iB) <Y) 1.160 0.1227D-01 1.718 I S U S E D WHEN A P L O T P O I N T C O V E R S  0.0 THE  RSO  „ ^  0.9613 DATA POINTS 1  / / /  •  •  /  1  / /  •  1  /  1  / /  31.00  1 / /  1.  1  / / /  1  /  /  I  /  1  2 4 . 00  I 1  1  /  1  /  1  1  / /  1  .1  •  1 1 .  1 7 . 00 /  1 1 1  1  /  I  1  / / /  1  1 1  •  1  / / /  l i i .  /  .  / /  l  1  .2 2  21 1 111 1 1  i  .I  / /  n i l  I  .  /  i  I  /  u . i  /  3 . 000  1 . 1  1  /  /  •  »  / /  /  1  1  /  10.00  .  •  /  /  1  2  /  V  1  1 1  11 . 1 2  //]///////////////////1///////////////////1///////////////////I///////////////////|///////////////////| 60.00  76.00 Dei/<slopmenTcx\  aqe. (x)  92.00  ^  d a  _ ^  108.0  s  versus •femorexi ossification  £v)  124.0  140.0  I NO OEP VAR VAR DE AGE H-OSS THE ".»' AND 37 .00  CONST COEFF FRATIO F PROB A B (B) (B) -24.15 0.4366 1579. 0.0 ARE USED TO PLOT THE REGRESSION L I N E ; THE " i * "  STD ERR STD ERR STD ERR RSQ (A) (B) (Y) /^-» 1.039 0.1099D-01 1.539 0.9658 I S USED WHEN A PLOT POINT COVERS DATA POINTS  -  •  1  /  )  \  / / /  •  /  •  /  / / /  30 .00  • 2 1  -  1  /  .1  1  1  / / / /  /  1  /  1  / /  2 3.00  -  1 11 . 1 1  / /  ( rrtm\ \. J  11  / /  1 2 .  / /  /  1  / / /  1 .1 1 1211 . 11 111 • 1 1 1 1  / /  / /  /  9. 000  1.  . 3 •  *  / / /  16.00  1 1 1  1  -  1  1  *  11  1  1  1  1  . 1 1 1  1. 1  / /  1  *1  I  / / / / /  1* •  /  1 1. 1 1 . 2 1  /  2 . 000  //I///////////////////I///////////////////I///////////////////I///////////////////I///////////////////| 60 .00  Exnibir  76.00 /9.  Dc-ue\oprnenTa.{  age. (X.) versus  92.00 hurnestxt  108.0 ossification  124.0  140.0  J  DEP VAR F-COL THE  IND CONST COEFF FRATIO VAR A B (B> DEAGE 17.08 0.36230-01 2.019 «.» AND «*« ARE USED TO PLOT THE REGRESSION  FPROB STO ERR STO ERR STD ERR (B) iA) (B> (Y, 0.1571 2.410 0.25490-01 3.570 L I N E ; THE '•*» I S USED WHEN A PLOT POINT COVERS DATA  RSQ 0.0348 POINTS  *Sr  30 .70 /  / / / / / /  26.90 / / /  / /  1 1  7 23.10  ($/jOO$ bone)  19 .30  1  I  IT  /  7"~ /  ~  t  1  / / / / /  1  2  1  1  1  1 1  . 1  1 1  1  1  1  1  1  1 l  / _/_.„  / / /  15.50  / / / /  l  l l  n l  1  1  1  1  1 i  "  l  l  / /  / /  1  1  1  / / /  11 .70 //I///////////////////I ///////////////////I / //////////////////I///////////////////|///////////////////I 60.00 Exh'ib'iT #C.  76.00 Develop merfta.1. Q.a&- (XJ versus  92.00 Peroral  (dtaus}3  collagen  108.0  124.0  140.0  DEP IND CONST COEFF FRATIO FPROB STD ERR STD ERR STD ERR RSQ VAR VAR A 8 (B) ( B) (A* <B) <Y) H-COL DEAGE 14.20 0.6403D-Q1 6.499 0.0130 2.374 0.2512D-01 3.517 0.1040 THE " AND "•*» ARE USED TO PLOT THE REGRESSION L I N E ; THE »•*" IS USED WHEN A PLOT POINT COVERS DATA POINTS  J3S  32 .00 / / / /  / /  27. 00  L / / /  /  ,  _  /  22. 00  / / / / / / /  11  1  1  1 1  1 11 2  1 1  1 111 1 1  1  1  1 1  .  1 1  .1 1  /  / / /  . 1 .  1  1  1  1  /  17.00  /  1  -  / / / / /  1 I 2  1 1 1  1 _  I  1_ 1  1  / / /  12.00  T / / / / /  7.000  . . //i///////////////////!///////////////////I///////////////////I///////////////////]///////////////////I t  60.00 £jth'ibir  76. 00 £).  3>e\jelopnnenT<xl a^e  92.00 _X) versus  humer<x\ collagen  108.0 £Vj  124.0  140.0  DEP IND VAR VAR F-CAL DEAGE THE "." AND  CONST COEFF FRATIO FPROB A B {B) (8) -0.6499 0.1595 102.8 0.0000 »*" ARE USED TO PLOT THE REGRESSION L I N E ; THE  STD ERR STD ERR STD ERR RSQ {A) (B) CY} 1.487 0.15730-01 2.202 0.6474 IS USED WHEN A PLOT POINT COVERS DATA POINTS  /S?  21. 40 / /_ / / / /  /  1  /  1  18. 40 / /  1  J  1  '  1.  /  /  1  21  / / /  1 5.40  T / /  / /  u i  /  I  / / /  12.40  l u l l  / / / / / "7  1  .  1  . 1 1  1 1  1  1  1  11  1  1  / /  9.400  -  .  1 1 I  / / /  / / /  6 .400  //I///////////////////1///////////////////1///////////////////I///////////////////17//7///////////////1 60 .00 £xh'ibiran.  76.00 Developmental  age  92.00 versus  fen^oro.!  ^  d  a  ^  calcium  108.0 i?)  124.0  140.0  >  DEP VAR H-CAL THE  IND VAR DEAGE AND  CONST COEF F FRATIO FPROB STD ERR STD ERR STD ERR RSQ A B ( B) (B) (A) (B) (Y> -0.1232 0.16 16 69.53 0.0000 1. 832 0. 19380-01 2.713 0.5539 ARE USED TO PLOT THE REGRESSION L I N E ; THE «*»• IS USED WHEN A PLOT POINT COVERS DATA POINTS  /to  22. 20 / / / / / /  ,1  /_  18. 50  1  /  1 / / / / / /  1 1 1  / /  1.  14. 80 2 1 1 1 * 1  / / / / /  jL  I  1  1.  /  1 1 1 . 10 .1 1  / /_  1  11  / / / / / / /  7.400 / / /  7 / / 3 .700  7/17/////////// ///////T/7//7/////////7/7//I 7/77//////////////71///////////// />//// f 77/77////////////// I (days) 140.0 1 08.0 92. 00 124.0 60 .00 76. 00 EixhibiT  H3.  Dcvelopryj<sA-t<a.l ctge [*) versus  humero.1  calcium  DEP IND CONST COEFF FRATIO FPROB STD ERR STD ERR STD ERR RSQ VAR VAR A B (B) (B) (A) IB) <Y) F-PHO DEAGE 2.708 0.46420-01 44.77 0.0000 0.6558 0.6937D-02 0.9714 0.4443 THE " AND ••*«' ARE USED TO PLOT THE REGRESSION L I N E ; THE «»*« IS USED WHEN A PLOT POINT COVERS DATA POINTS 9.600 / / /  / /  8 .300  *1 / /  / / /  7.000  I / (q/JOu'gbQne)/ /  /  jul_ _.  /  1  1 .  1  /  2* 2 1  J_ 1  / /  5 .700 /  L / / / / /  L. 4 .400 / / / / /  3. 100  //1 / // // // // // /A///7//1//////77///////////1 60. 00 £xhib)TDcvc\opmenTa.\  92.00  76. 00 age  versus  femora\  Ldaus)  inorganic  108 .0 phosphorus  124.0  140. 0  DEP IND CONST COEFF FRATIO FPROB VAR VAR A B ( B) ( B) H-PHO DEAGE 2.902 0.4666D-01 31.17 0.0000 THE ».•• AND •'*» ARE USED TO PLOT THE REGRESSION L I N E ; THE  STD ERR STD ERR STD ERR RSQ (A) (B) (Y) 0.7900 0.8358D-02 1.170 0.3576 IS USED WHEN A PLOT POINT COVERS DATA POINTS -<  9. 800 / / / /  / / /  8. 200  7 1  1 1  1  /  1 1 1 1 1  / / /  6 .600  (QJIOOQ  11  111 . 11  f / bone) /  I / /  5.000 /  /_ / / / / / / /  3. 400 /  T / / / / / / /  1 .800  / / i / / / / / / / / / / / / / / / / / / / ! 6 0 .00 Exhibit  jf£.  ///////////////////I///////////////////I///////////////////J///////////////////i 76.00  Developmenta-l  aae (x)uersus  92. 00 humeral  (days)  108. 0  morqaiiic. phosphorus  (y)  124.0  140.0  DEP I NO CONST COEFF, FRATIO FPROB STD ERR STD ERR STO ERR RSQ VAR VAR A 8 {B) (B) (A) <8) { Y* F-MAG DEAGE 0.6585 -0. 14460-02 3.965 0.0487 0. 68640-01 0.72620-03 0.1017 0.0661 THE »«.» AND "*« ARE USED TO PLOT THE REGRESSION L I N E ; THE «*" I S USED WHEN A PLOT POINT COVERS DATA POINTS 0. 9 200 / / / / / / /  L  0.8000  1 / /  __ / / / /  0. 6800  / / /  0.b600 l  L /  u  i  l  /  l  /  i  l  1  2  l  1  l  u i  l  l  i  1 1  1  1 1  1  1 1  .  0.4400 /  T / / / /  / /  0.3200  i ///////////////////j///////////////////i///////////////////Mill 60. 00 £xh'ibir  76. 00 T>e\J<°lo amenta!  92.00 aae, C%) versus, -femora,! /naqnesi  108 .0 um  124.0  n n  / / / / / / / / / / / i 140. 0  DEP IND VAR V AR H- MAG DEAGE THE " .»' AND  CONST COEFF FRATIO FPROB A 8 < B) ( B) 0.6890 -0.1542D-02 4.217 0.0424 ARE USED TO PLOT THE REGRESSION L I N E ; THE  STD ERR STD ERR STD ERR RSQ (A) (B) (Y J 0.7097D-01 0. 7508D-03 0.1051 0.0700 IS USED WHEN A PLOT POINT COVERS DATA POINTS -<  0.9100 / / / /  / / /  0. 7700 /  / / _/ / / / /  0. 6300 /  1 .  1  1 1 1 1. 1 1  / / /  0. 4900  1  /  1  1 1  1  / / / /  / / /  0.3500 / /  L / / / 0.2100  //i///////////////////i77/////////////////i///////////////////\ 76.00  60 .00 Exhibit  J?7.  DevelopnneiTa.1  a  -^  92. CO e  £x*_) versus, humeral  (days) magnediuryn  ///////////////////I///////////////////I 108. 0  (* V)  124.0  140 .0  IND VAR DEAGE AND  DEP VAR F-SOD THE 8. 300  6 .700  5_.iQ0_  \j  CONST A 7.603 »•*•» A  -/  1  R  E  U  S  1  E  D  COEFF FRATIO FPROB STD ERR STD ERR STD ERR RSQ B (8) IB) IA) IB) (Y) -0. 6025D-01 29. 72 0.0000 1.045 0.1105D-01 1.548 0.3467 TO PLOT THE REGRESSION L I N E ; THE «*" I S USED WHEN A PLOT POINT COVERS DATA POINTS )  1  / / / / / / / /  -/  / / / / / / / /  1  1  1  -  / / taste ) f  1  J  / 1  3 .500  / / /  .  1 •  1  -/  / / / / / / / /  1 .900  »  1  1  1  1  «  -/  1  / / / / / / / / 0.3000  1  •  1  21  2 1  1 21 11 22 1  . 1  1  1  1  1 2  1 1  1 1  11  1 1 1  . 1  1 1  1 1 1  .  1  1 1  1  -  //I///////////////////I///////////////////I///////////////////\///////////////////I/////////////////// 1 60 .00 Exh'ibiT  76.00 AS. Jtevel&pmeitcil  aae (x) versus  92.00  (• - U J d a  femoral sodiiino  108 .0  s  if)  124.0  140.0  )  DEP VAR H-SOD THE  IND VAR DEAGE AND  CONST COEFF FRATIO FPROB A B (B ) (3) 6.424 -0.5045D-01 25.48 0.0000 ARE USED TO PLOT THE REGRESSION L I N E ; THE  STD ERR STD ERR STO ERR R SQ (A) (B) (Y) 0.9448 0.99940-02 1.399 0.3127 IS USED WHEN A PLOT POINT COVERS DATA POINTS  7.400 /  _  / / / /  / /  (_  6.000  t /  /_ / /  / T /  4 _600  -_ / /  / /_  / / /  3.200 / / /" / _/_  / / /  1.800  0.4000  f  1 1  "7 / / / / / 7 •/  1  2 1 1 1  1 1  12 21 1 21 i i  1  1  .  11 11  i  1  1 1_ 1  1  i  1  i  / / I / / / / / / / / / / / / / / / / / / / I / / / / / / / / / / / / / / / / / / / I / //////////////////I 60 .00 Exhibit  49.  76.00 Developmental  <zoe _*) versus.  92. 00 humeroS  ^  a  .1  r i  ° ^ ^  sodiiunn  _ V)  ///////////////////I///////////////////I 108.0  124.0  140.0  DEP VAR FCACO THE 1. 000  IND VAR DEAGE AND  CONST COEFF FRATIO FPROB STD ERR STD ERR STD ERR A B ( B) (B) (A) (B) (Y) 0.9567E-01 0.64790-02 68.47 0. 0000 0. 7402D-01 0.7830D-03 0.1096 «*•» ARE USED TO PLOT THE REGRESSION L I N E ; THE «*" IS USED WHEN A PLOT POINT COVERS DATA  RSQ 0.5501 POINTS  / I 7 / /  / / j  0. 8700  7  / / /  1 1  /  /  1  U 1  /  0.7400 (ratio)  I / /  / / /  1  1  1 11  1  /  /  1  .  1  1  1  /  0.6100 /  1  .  /  / / /  .  1  1  .1  1  /  /  .  l  l  1  0.4800 / / / /  /  0. 3500  L . . / / I / / / / / / / / / / / / / / / / / / / I / / / / / / / / / / / / / / / / / / / I / / / / / / / / / / / / / / / / / / / I / / / / / / / / / / / / / / / / / / / I I III i l l HI III11 III l\ 60.00 Exhibit  76.00 30.  Developmental  age  92.00 (*) versus  femoral  ^  d < a  _ 3 r  calcium  108.0 jcotlaqen  ratio  124.0 C^)  140.0  DEP I NO VAR VAR HCACO DEAGE THE » .« AND 1 .140  CONST COEFF FRATIO FPR08 A 8 (8) iB, 0.1894 0.5872D-02 52.88 0.0000 ARE USED TO PLOT THE REGRESSION L I N E ; THE  STD ERR ' STD ERR STD ERR RSQ (A) IB) (Y) 0.76330-01 0.8075D-03 0.1131 0.4857 IS USED WHEN A PLOT POINT COVERS DATA POINTS  / / / / /  0.9900 /  / / /  0.8400  f f 11  / /  11  /  1  1 1 1  / /  1  /  1  0.6900 / / / / /  11  / / /  0.5400 / /  J. f / / 0. 3900  1 //! 77777777///////////!///////////////////1 60.00 £xh'ih>'rf SI.  76.00 T)e\/elopnte.nt<x\ cxge (_X) versus  92.00 humera.\  108.0 ca\c\umlcoHcxqer\  ract'io  124. 0  140.0  DEP I NO CONST COEFF FRATIO FPROB STD ERR STD ERR STD ERR RS Q VAR VAR A 8 (B) (B) (A) (8) {Y) FCAPH OE AGE 1. 129 0.93840-02 38.14 0.0000 0.1.436 0.1519D-02 0.2128 0.4052 THE ". " AND "*«• ARE USED TO PLOT THE REGRESSION L I N E ; THE ••*« I S USED WHEN A PLOT POINT COVERS DATA POINTS 2.410  1  /  1  /  _  /  / / / . / / / / / / _/_ / /  2.170  1 1  1 _ _ '  /  / / 1.930. _ _ _ _ _ / / /fatia) I V  '  1_  1  1  "  1  I  .  1  1  .  1  1  1  • ~""  1  .  1 _  _  1  1  1  1  1  .  2  1  1  .  i  1  .1  1  .  /  1  . 1 .  1  .  111 1  1 _  _/  1.690  1  1  __  1 1  1  1 11_ _ 1  /*?  ;  . i  / / /  * .  1  1  1  1  I /  / / /  1  / /  1.450  /  1 1 1  __  _  1  1  / / .  /___  .  /  / /  1.210  / 1 , _ _ _ / / i / // // / / / / / / / / / / / / / / i ////77 7/ I'/i i II II i in ii II II/in 60.00 Exhibit  76.00 3&.  Develop  me*nta.l exqe C*) versus  11 II II 11 I\II  92.00  ( d)  femoral  calcium  dal  s  _  a  II  it  II  ii ii7iii/\  108.0 / phos/ohajte:  i fin 124.0  ratio  _V)  II HI/HI  in  II i  140.0  DEP VAR  IND  CONST  VAR  .CO EPF  A  FRATIO  B  F PROB  < B)  STD ERR  < B)  STD ERR  { A)  IB)  STD ERR  RS Q  (Y)  JSt>  HCAPH DEAGE 1. 131 0.96 770-02' 51.62 0.0000 0 .1273 0.1347D-Q2 0.1886 0.4796 THE «.« AND »*« ARE USED TO PLOT THE REGRESSION L I N E ; THE »*« I S USED WHEN A PLOT POINT COVERS DATA POINTS 2 .400  ~~/ /  I 1  1  1  1  I  ~. 1  / / /  / /  1  1  1  1  11  / /  2.180  /  1.960  / / / / / / 7 / -  gratia)  / /  1  :  /  1  1 11  1  . 1  2 1  1__ "TT i i 1  . 1  /  /  1  1  .  _  /_  7 " / / 1 .740  i  1  ~  ~ .  / •  .  1 1  /  F /  ~  i n  /  /  1 . 520 / / / / / / /  1 .300  //I///////////////////!///////////////7/7/177777//////////////I 60.00 &th~ib'.T 33.  76.00 Develop ry>enta\l age  92.00 £>0 versus  humeral  t***^)  7/777 /77///////////I//7/////7////////771~~ 108.0  CO Icium j phasphatez  124.0 rectio  _V)  140.0  DEP VAR M-WEI THE  IND CONST COEFF FRATIO FPROB STD ERR STD ERR STD ERR RSQ VAR A B (B) (B) (A) (B) (Y) M-HEI -233.0 3.127 17.45 0.0001 122.6 0.7486 35.01 0.2376 AND * « ARE USED TO PLOT THE REGRESSION L I N E ; THE «*'• I S USED WHEN A PLOT POINT COVERS OATA POINTS M  392 .0 /  L  / t I / / / /  355. 0 / / / /  / / / / /  318.0  7 /  4*9)-  /  / t / / /  2 81.0  1  / / / /  I  1.  / / /  244.0  11  / / / / / / / /  207.0  / / I / / / / / / / / / / / / ///////I / / / / / / / / / / / / / / / / / / / j - / / / / / / / / / / / / / / / / / / / I / / / / / / / / / / / / / / / / / / / | / / / / / / / / / / / / / / / / / / / I 146.0 Exhibit  153.0 2*1.  Nare.fn<x\. height  160.0 (v) u_r__s rnaYema.\  u/eighT _Y)  167.0  174.0  181.0  DEP VAR M-PAR THE  IND VAR M-AGE AND  CONST COEFF FRATIO FPROB A B «B) (B) -2.860 0.1641 50.04 0.0000 ARE USED TO PLOT THE REGRESSION L I N E ; THE »*«  STD ERR STD ERR STD ERR RSQ (A) (B) (Y) 0.6952 0.2320D-01 1.463 0.4719 IS USED WHEN A PLOT POINT COVERS DATA POINTS  9. 000 / / /  / / / / /  7 .200 / /  A / / / 5. 400 / /  (r>r> ch'tleLten) / / / / / /  3.600 / / / / / / /  /  1. 800  /  _  f I /  "  '" 1 2  1  /  1  1  .  1  / / / /  0. 19 07E-05 - 1 1 2 3. 4 4 2 1 2 2 //I///////////////////I///////////////////I///////////////////)///////////////////!///////////////////I 14.00 JExh'ib'iT 3S-  21.00 Na.ferr>aA aae. C*} versus.  28.00 matema.\  par.Tu  / ciears.) 3  _Y^)  35.00  42.00  49.00  DEP IND VAR VAR M-GRA M-AGE THE " ." AND  CONST COEFF FRATIO FPROB STO ERR STD ERR STD ERR R SQ A B (B) (B) (A) <B. (Y) -2.213 0.1912 55.40 0.0000 0.7698 0.2569D-01 1.620 0.4973 ARE USED TO PLOT THE REGRESSION L I N E ; THE »*" IS USED WHEN A PLOT POINT COVERS DATA POINTS  ^  s  10. 00 / / / / / / /  8. 200 / /  / / / / /  6 .400  7  l  ,  J_ /  4.600  l  :  "  / /  1  /  1  1  2  1  1  1 1 . 2  1  2  1  1  2  / / / /  /  2 .800  .  7  1  2  _____  1  1  1  1  2  / /  _/ / / / / /  1.000  - 1 1 2 .2 4 4 2 1 1 2 2 1 1 //I///////////////////I///////////////////I///////////////////I///////////////////I///////////////////I 14.00 Exh'ih'iT 34>.  2 1. 00 /iat-ema.\ aqe (Lfecws) versus  2 8.00  ^  mexterrto.i Cfr&uidiTcf _V_)  35.00  42.00  49.00  DEP IND CONST COEFF FRATIO FPROB STD ERR STD ERR STD ERR RSO VAR VAR A B (B) {B) (A) (BJ IY) M-GRA M-PAR 1.406 1.011 215.4 0.0000 0.1874 0.68890-01 1.038 0.7937 THE AND «*« ARE USED TO PLOT THE REGRESSION L I N E ; THE «*" IS USED WHEN A PLOT POINT COVERS DATA POINTS "A" REPRESENTS 10 OR MORE DATA POINTS  'SV  10.00 / / / / / /  _/_  8. 200  /  / /  /_ / /  /  6. 400 / /  4. 6 00  / / t / /  / 2 / / / /  _/ /  2. 800 / /  / 3 / / /  / . /  1 .000  - A //I///////////////////j///////////////////I///////////////////I///////////////////|///////////////////I -0.0 Exhibit  1.800 £7.  Na.tetna.1 par'tfy (*)  3.600 Versus  (no.  children)  rna+erna.1 arai/ictitij ( V)  5.400  7.200  9.000  DEP V AR SESGP THE  CONST COEFF FRATIO FPROB I NO A. B ( B) (B) V AR 0.9613 0.5070D-O1 202.2 0.0000 SESSC AND »*" ARE USED TO PLOT THE REGRESSION L I N E ; THE  STD ERR STD ERR STD ERR RSQ (A) (BJ <YI 0. 1274 0. 3566D-02 0.3467 0.7831 IS USED WHEN A PLOT POINT COVERS DATA POINTS ~z  4.000  r  / / / / / /  J_ 3 .300  I  / /  /_  1  6  1  3  2  2  4.  3 1 1  / / /  / /  2.600 / / / / J_  / /  1  /  1  *  3  2  8  4  1.900 / / / / /  1. 200 / / / > / / / /  0.5000  //!/////////////7///7/1 /'////////1 ///////// 5.000 Exhih'iT JS.  18.00 Socio-economic*  Score  \ ///////////////////!///////////////////!////////////////// 31.00  (x) Versus  socio-econoryiicj  44.00 group  _V)  57.00  /I 70.00  DEP VAR N-WSC THE  IND CONST COEFF FRATIO VAR A B (8) N-TOT 6.160 0.1670 342.0 AND "*•» ARE USED TO PLOT THE REGRESSION  FPR08 <B) 0.0 LINE," THE  STD ERR STD ERR STD ERR (A) <B) ( Y) 0.8297 0.9027D-02 1.364 I S USED WHEN A PLOT POINT COVERS DATA  RSQ 0.8593 POINTS  29. 00 /  1  / / /  11  / /  25 .60 / / /  / /  11  1  /  _ 22 .20  j_ j  j  /  —  1* 1 1 *  /  / _  ^2  j  / /  I.  /  /  1  1 1  i  n  i  i n I  1111 1 1  18 .80 /  _/  *_2  11_  / /  /  1  1  / /  /  15.40 / / / / / / /  12.00 //I / ////////////7//"///1 30. 00 ExhibiT  nn ftu//////nun ///////f///////////1///////////////////I/  5 0. 00 39.  Total  nutrir,on  score, i*) versus  70.00 weighted  90 .00 nutrition  score C V)  //////////////////1 110. 0  130.0  DEP VAR N-IDX THE 4. 800  IND VAR N-TOT AND  CONST COEFF FRATIO FPROB A B IB} (B) 1.050 0.2762D-01 328.5 0. 0 »*" ARE USED TO PLOT THE REGRESSION L I N E ; THE «*»  STD ERR STD ERR STD ERR RSQ (A) IB) (Y) 0.1401 0.1524D-02 0.2303 0.8544 I S USED WHEN A PLOT POINT COVERS DATA POINTS  / /_ / /  /S?  1 1 1  _/_ / /  4.200  t_ /  1  1  / /  2.2  11  1  / / /  i  J_ / 3 .600  i  2  *1  2  1 1  /  T  i j_ / / j  .2  1 1 1  111 1 1 1  / /  3.000  i  j_  1111 1 1 .2 2  1  1  TT  / / / /  ]_ / / _/_  2. 400  /  / / _/_  1 .  1  /  /  1 .800  j_ / /  30 .00 £:xniJb/T */0 •  50 .00 ToTa.1 nut'rit-/on  score  90. 00  70.00 _V) uersus  nutrition  'index.  _W  110.0  130.0  DEP IND VAR VAR N-IDX N-WSC THE ANO "A" REPRESENTS  STD ERR STO ERR RSQ CONST COEFF FRATIO FPROB STD E*R (B) ( Y) A B ( B) (B) (A) 0.1055 0-02 0.28710-01 0.9977 0.2448E-01 0 .1657 0. 2469D 05 0. 0 0.2262D-01 ARE USED TO PLOT THE REGRESSION L I N E ; THE »* , I S USED WHEN A PLOT POINT COVERS DATA POINTS 10 OR MORE DATA POINTS M  TT  4.800 / /  3.  7 /  4.200  J_ / / j_ / / /  f_ / /  3.600  . 7  _/_ / /  T /  . 7  j_ / i j_ /  t 3. 000  ]__ /  j_ / / j_ t / _/  7  2. 400  j  f f  2.  7  j_ / / 1 .800 15.40  12 .00 Exhibit  47.  Nutrition  index. ( V*) ver&us  22. 20  1 8. 80 ivemhtecL nutrition  score  _ X)  25.60  29.00  DEP VAR N-PRO THE  IND VAR N- TOT ".« AND  CONST A - 7 . 749 ARE USED  FRATIO FPROB STD ERR STD ERR STD ERR < B) < B) (A) IB) (Y, 0.3947 43.59 0.0000 5.495 0. 5 9 7 8 0 - 0 1 9.033 TO PLOT THE R E G R E S S I O N L I N E ; THE " * « • I S USED WHEN A P L O T P O I N T C O V E R S D A T A COEFF B  R SQ  /S?  0.4377 POINTS  48 .00  L t I  T  /  IT  /  39.00  J_ / / /  11  /  1  / / / / /  3 0 .00  7 / /  l  l  / /  l  /  l  /  i  l l  l  l  /  i  21 .00  r  / __ /  u  /  /  i  /  I I  / /  I 2; oo  7 / / / / / /  3.000  //| ////'////////////// / I / / / / / / / / / / / / / / / / / / / j / ////////////////// I / / / / / / / / / / / / / / / / / / / j / / / / / / / / / / / / / / / / / / / " I 30.00 Ejth\b\r  50.00 .  ToTal nutrition  score (X} versus  70.00 protein  90.00 score  110.0  130.0  DEP VAR N-WSC THE  I NO CONST COEF F FRATIO VAR A 8 (B) N-PRO 16.39 0 .17.18 26.83 AND •»*" ARE USED TO PLOT THE REGRESSION  FPROB STD ERR STD ERR STD ERR (B) (A) (B) if) 0.0000 0.9983 0. 3317D-01 2.990 L I N E ; THE "*« IS USED WHEN A PLOT POINT COVERS DATA  RSQ  /60  0.3239 POINTS  29.00 /  J f / I / /  2 5. 60 / / / /  1 1  / /  "i  r  22.20  1 1 1  / / /  1  /  1  1 .  /  1 1  / / / /  18. 80 / / / / /  1 1  1 1  T I JL 15. AO  /  / / /  r  / f / /  12.00  - 1 . //j///////////////////I///////////////////|///////////////////I///////////////////I///////////////////I 3.000 Exhibit  12.00 43.  Protein  score  _X) versus  21.00 lAie'iqhtecL nutrTrion  30.00 score, (j?)  39.00  48.00  DEP VAR N-IDX THE  IND VAR N-PRQ AND  CONST COEFF FRATIO FPROB A 8 (B) (B) 2.733 0.2876D-01 27.54 0.0000 ARE USED TO PLOT THE REGRESSION L I N E ; THE  STD ERR STD ERR STO ERR RSQ {A) (B) ( Y) 0.1649 0.5480D-02 0.4941 0.3296 I S USED WHEN A PLOT POINT COVERS DATA POINTS  4 .800 /  L / / / / t f  4.200 /  1 1  / / /  11  1  1  1 i l l  / /  3.600  T  f f /  / /  i  i  / / /  3.000  -  . 1  11  1  1  1  / / / / / / / /  2.400 / / / / /  / 1 1. 800  //I///////////////////i///////////////////i7//////////////////i///////////////////i///////////////////j 3.000  jZxhibir*/?.  12.00 Protein  score,  (x) versus  21.00 nutrition  index.  30.00 ^V}  39.00  48.00  

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