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Illicit drug use during pregnancy and its relationship to neonatal outcomes among Hepatitis C positive… Cox, Michelle Byrne 2004

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ILLICIT DRUG USE DURING PREGNANCY AND ITS RELATIONSHIP TO NEONATAL OUTCOMES AMONG HEPATITIS C POSITIVE WOMEN TN BRITISH COLUMBIA by Michelle Byrne Cox B.Sc, Simon Fraser University, 1996 A THESIS SUBMITTED IN PARTIAL F U L F I L L M E N T OF T H E REQUIREMENTS FOR T H E D E G R E E OF M A S T E R OF SCIENCE in  T H E F A C U L T Y OF G R A D U A T E STUDIES ^Department of Health Care and Epidemiology) We accept this thesis as conforming to the required standard  T H E UNIVERSITY OF BRITISH C O L U M B I A December 2004 © Michelle Byrne Cox, 2004  ABSTRACT OBJECTIVES:  To investigate the relationship between stimulant and/or opiate drug use during  pregnancy, and adverse neonatal outcomes in Hepatitis C positive women.  METHODS:  HCV positive pregnant women in British Columbia who consented to participate  in a prospective, cohort study were enrolled in the HCV Vertical Transmission Study. A baseline questionnaire sought information on sociodemographic characteristics, substance use, obstetrical and medical history, and sexual behaviour. Follow-up questionnaires collected details on delivery and neonatal outcomes. The adverse neonatal outcomes of interest, for this analysis, were prematurity, low birth weight, low Apgar score, and admission to a neonatal intensive care unit. Required variables were extracted from the primary study dataset. The secondary analysis included descriptive, univariate, and multivariable statistical techniques to address the above stated objectives.  RESULTS:  Data from 136 women and their infants were analyzed for this study. Fifty-three  (39.0%) of the women gave birth to infants that suffered an adverse neonatal outcome. Approximately half (49.6%) of the cohort used stimulant drugs during their pregnancy, 35.9% used opiates, and 68.4%) smoked cigarettes. Concurrent substance use was very common among these women. Current stimulant use (p<0.01), current opiate use (pO.OOl) and current tobacco use (p<0.01) were associated with adverse neonatal outcome. Opiate use during pregnancy remained significant with adverse neonatal outcome after adjusting for stimulant use, tobacco use, age, aboriginal ethnicity, and gravidity. An odds ratio 5.52 (95% Confidence Interval: 1.82, 16.76) was determined through multi-variable analysis.  n  CONCLUSION:  Pregnant women living with HCV in British Columbia report high use of  stimulants, opiates, and tobacco during their pregnancies. The infants of these women also suffer high incidences of adverse neonatal outcomes. When a wide range of substances, obstetrical risk factors, and lifestyle characteristics were considered, the use of opiates during pregnancy was determined to be the strongest predictor of a poor neonatal outcome. Women who use opiates during their pregnancy are at increased risk of delivering an infant who will experience an adverse neonatal outcome.  iii  T A B L E OF CONTENTS ABSTRACT T A B L E OF CONTENTS LIST O F T A B L E S ACKNOWLEDGEMENTS CHAPTER 1 - INTRODUCTION 1.1  SIGNIFICANCE OF THESIS R E S E A R C H PROJECT  1.2  S T U D Y OBJECTIVES  2  1.3  SUMMARY  3  CHAPTER 2 - BACKGROUND  4  2.1  INTRODUCTION  4  2.2  NEONATAL OUTCOMES  5  2.1.1  Definitions  5  2.1.2  Prevalence of selected neonatal outcomes in British Columbia  7  2.3  2.4  ILLICIT DRUG USE A N D N E O N A T A L O U T C O M E S  .  7  2.3.1  Opiates: Opioid and heroin use A. Prevalence of use in pregnancy B. Mechanism of action C. Effects of use during pregnancy on neonatal outcomes  7 7 7 8  2.3.2  Stimulants: Cocaine and amphetamine use A. Prevalence of use in pregnancy B. Mechanism of action C. Effects of use during pregnancy on neonatal outcomes  10 Io 11 11  2.3.3  Multiple substance use  19  TOBACCO, ALCOHOL AND MARIJUANA  20  2.4.1  Illicit drug use and the use of other substances  20  2.4.2  Effects of use during pregnancy on neonatal outcomes A. Tobacco B. Alcohol C. Marijuana  20 20 20 21  iv  2.5  2.6  2.7  HEPATITIS C  21  2.5.1  A brief review of Hepatitis C A. Risk factors and disease transmission B. Viral agent, diagnosis and clinical manifestations C. HCV prevalence in Canada  21 21 22 23  2.5.2  Illicit drug users and Hepatitis C  23  2.5.3  Effects of Hepatitis C infection on neonatal outcomes A. Seroprevalence B. Vertical transmission C. Neonatal outcomes  24 24 25 25  S E X U A L L Y T R A N S M I T T E D INFECTIONS  25  2.6.1  Illicit drug use and sexually transmitted infections  25  2.6.2  Effects on obstetrical and neonatal outcomes A. Chlamydia B. Gonorrhea C. Genital herpes D. Genital warts E. Syphilis F. Trichomonias G. Hepatitis B virus H. Human immunodeficiency virus I. Summary  26 26 26 26 27 27 27 27 28 28  SUMMARY  28  CHAPTER 3 - METHODS  29  - The Hepatitis C Vertical Transmission Study  3.1  P R I M A R Y S T U D Y SETTING  3.2  S T U D Y S A M P L E SELECTION A N D S T U D Y ACTIVITIES  30  3.3  DATA MANAGEMENT  32  3.3.1 3.4  Statistical Software  29  32  V A R I A B L E S A N D V A R I A B L E DEFINITIONS  32  3.4.1  Main outcome variable  32  3.4.2  Main explanatory variables  33  3.4.3  Covariates  34  v  3.5  O V E R V I E W OF M E T H O D O L O G I C A L A P P R O A C H E S  37  3.5.1  Descriptive analyses  37  3.5.2  Univariate analyses  37  3.5.3  Multi-variable analyses  37  3.6  E T H I C A L CONSIDERATIONS  38  3.7  SUMMARY  38  CHAPTER 4 - RESULTS 4.1  4.2  4.3  39  DESCRIPTIVE A N D U N I V A R I A T E A N A L Y S E S  39  4.1.1  Neonatal outcomes  39  4.1.2  Sociodemographic characteristics  40  4.1.3  Substance use  41  4.1.4  Obstetrical history  45  4.1.5  Medical history  46  4.1.6  Sexual behaviour  47  4.1.7  Summary  48  MULTI-VARIABLE ANALYSES  49  4.2.1  Multi-variable logistic regression  50  4.2.2  Collinear variables A. Pregnancy complication B. Methadone use and opiate use C. Stimulant use and opiate use  50 50 52 52  4.2.3  Interaction terms  53  4.2.4  Final model  53  POWER  55  C H A P T E R 5 - DISCUSSION A N D I M P L I C A T I O N S  56  5.1  S U M M A R Y OF FINDINGS  56  5.2  UNIQUE CONTRIBUTIONS  60  vi  5.3  S T U D Y LIMITATIONS  61  5.3.1  Unavailable explanatory variables A. Substance use details B. Prenatal care and nutrition  61 61 62  5.3.2  External validity  62  5.3.3  Self-report and recall bias  63  5.3.4  Sample size  64  5.3.5  Collinearity  65  5.4  IMPLICATIONS  65  5.5  FURTHER R E S E A R C H  66  5.6  CONCLUSIONS  66  BIBLIOGRAPHY  68  APPENDICES  88  APPENDIX 1 -  88  APPENDIX 2  - Hepatitis C Vertical Transmission Study Maternal Follow-Up Questionnaire  APPENDIX 3 -  APPENDIX 4  Hepatitis C Vertical Transmission Study Baseline Questionnaire  98  Hepatitis C Vertical Transmission Study Delivery Follow-Up Questionnaire  105  - Hepatitis C Vertical Transmission Study Pediatric Follow-Up Questionnaire  112  APPENDIX 5 -  The Hepatitis C Vertical Transmission Study Group  vii  114  LIST OF T A B L E S  Table 2.1  Rates of selected neonatal outcomes in BC (2002)  Table 2.2  Summary of studies examining neonatal outcomes from in utero opiate exposure  Table 2.3  Summary of studies examining neonatal outcomes from in utero cocaine exposure  Table 2.4  Summary of studies that adjusted or matched for maternal factors, tobacco use, & alcohol use when examining neonatal outcomes from in utero cocaine exposure  Table 2.5  Summary of studies that adjusted for tobacco use & alcohol use as well as other illicit drugs when examining neonatal outcomes from in utero cocaine exposure  Table 3.1  Summary of baseline and follow-up questionnaire content  31  Table 3.2  Description of main outcome variable  33  Table 3.3  List of main study variables  JJ  Table 3.4  List of additional explanatory and descriptive variables  35  Table 4.1  Neonatal outcome details for the cohort (n=136)  40  Table 4.2  Univariate results for sociodemographic data for those women with an infant with an adverse outcome versus those whose infants had no adverse outcome  Table 4.3  Univariate results for substance use data for those women with an infant with an adverse outcome versus those whose infants had no adverse outcome  Table 4.4  Exclusive and concurrent stimulant and opiate use patterns for cohort  Table 4.5  Exclusive and concurrent opiate and methadone use patterns for cohort  Table 4.6  Univariate results for obstetrical history data for those women with an infant with an adverse outcome versus those whose infants had no adverse outcome  viii  15  41  43  44  44  46  Table 4.7  Univariate results for medical history data for those women with an infant with an adverse outcome versus those whose infants had no adverse outcome  47  Table 4.8  Univariate results.for sexual behaviour data for those women with an infant with an adverse outcome versus those whose infants had no adverse outcome  48  Table 4.9  List of variables considered for multi-variable analysis  49  Table 4.10  Multi-variable logistic regression results for Model 1  50  Table 4.11  Logistic regression results for model using pregnancy complication as outcome variable  51  Table 4.12  Univariate comparison of opiate use with methadone use  52  Table 4.13  Univariate comparison of opiate use with stimulant use  53  Table 4.14  Multi-variable logistic regression results for final model  54  Table 4.15  Multi-variable logistic regression results for alternate model  55  ix  ACKNOWLEDGEMENTS  I would like to extend my gratitude to the members of my thesis committee, Dr. Mark Tyndall, Dr. Deborah Money, Dr. Mel Krajden, and especially to my supervisor, Dr. David Patrick. I greatly appreciate all their support, guidance, and mentorship. I would like to acknowledge the Hepatitis C Vertical Transmission Study Group, especially those who gathered information from the participants for the primary study. Thank you to Lesley Cole and Vesna Popovska, your continual willingness to provide help was appreciated. I would like to recognize the HCV Vertical Transmission Study participants and their infants, who provided such detailed personal information in response to the initial questionnaires. I would like to acknowledge the staff in Epidemiology Services at the BC Centre for Disease Control for their support throughout the course of my program. 1 am appreciative of the statistical guidance provided by Mei Chong and Rick White with regard to my analysis. I am truly thankful to my mother, Toni. I deeply appreciate her support and the childcare she provided during the course of my degree. 1 would like to extend a special thank you to my husband, Wade. His continual support and encouragement made achieving this goal possible.  x  CHAPTER 1 - INTRODUCTION  Illicit drug use is recognized as a major epidemic that causes avoidable mortality and morbidity. It is a problem that persists despite education, law enforcement, and other anti-drug efforts. In the province of British Columbia alone there are between 170 and 200 deaths annually from injection drug overdose, making it among the leading causes of death for individuals aged 30-49 years. The burden of this problem does not end there. 1  Of more than 15,000 injection drug users in British Columbia, a substantial proportion will be women in their reproductive years. Due to the highly addictive nature of illicit 2  drugs, some of these women will continue to use drugs during their pregnancies. Most estimates report maternal drug use to be in the range of 3-4% of all pregnancies. " The 3  11  use of illicit drugs during pregnancy has the potential to harm both the pregnant woman and her baby.  1.1  SIGNIFICANCE OF THESIS RESEARCH PROJECT  This research examines the relationship between drug use during pregnancy and adverse neonatal health outcomes in HCV positive women. The research identifies additional risk factors for these adverse outcomes that include concurrent substance use, the use of other non-illicit substances, obstetrical history, and infectious diseases. The project also includes a component that describes the sociodemographic characteristics, medical history, and sexual behaviour of HCV positive pregnant women in this province. Various studies in the United States have previously examined the issue of drug use in pregnancy. To date no data related to this issue in British Columbia have been examined and, in fact, few Canadian studies exist. The differences between Canada and  1  the US, in their health care systems and approaches to illicit drugs, dictates the need for Canadian-based research to aid in the planning of health care, prevention and education in our country. The fact that the demographic profile of childbearing women in Canada, and more specifically in BC, is distinct from that of the US, further highlights that studies, specific to the women in this province, are necessary. In general, the components of this thesis will enhance the current body of knowledge and provide additional evidence to support or refute the association between drug use in pregnancy, and the effects of this behaviour on the health of newborns. More specifically, it will provide health related data that is representative of the situation and population in British Columbia. It is hoped that this research will direct the allocation of resources that will lead to effective interventions and improvements in the care of drugaddicted pregnant women in BC. The ultimate aim is the reduction of adverse health outcomes experienced by the infants born to these women.  1.2  STUDY OBJECTIVES  The main objective of this research was to measure the impact of drug use on adverse pregnancy outcomes among women who are Hepatitis C positive. This thesis, therefore, was comprised of two primary objectives. The first objective was to investigate the relationship between stimulant drug use during pregnancy and adverse neonatal outcomes. The second objective was to investigate the relationship between opiate drug use during pregnancy and adverse neonatal outcomes. These objectives were carried out while controlling for other known risk factors such as concurrent substance use, obstetric history, and sociodemographic 2  characteristics. The main outcome considered for these objectives, adverse neonatal outcome, was determined by the incidence of the following indicators of neonatal health: premature birth; low infant birth weight; low Apgar score; or admission to a neonatal intensive care unit. Sub-analyses include describing the sociodemographic profile, obstetric and medical history, and sexual behaviour of those HCV positive pregnant women who report drug use during their current pregnancy.  1.3  SUMMARY  The Hepatitis C Vertical Transmission Study, based at the Children's and Women's Health Centre of British Columbia, was initiated to study specific objectives related to HCV infection during pregnancy and disease transmission to the infant, it has provided a unique opportunity to study illicit drug use during pregnancy and the effect of this behaviour on neonatal outcomes. This thesis project was undertaken to study this issue in BC by addressing the above stated objectives.  3  CHAPTER 2 - BACKGROUND  2.1  INTRODUCTION  The issue of drug use during pregnancy and its effect on the neonate is a complicated one. There are many factors, outside of maternal drug use, that may influence an infant's health; these include obstetrical history, infectious diseases, and genetic factors. In addition, women who use drugs have complex issues. Their illicit drug use often goes hand-in-hand with the use of other substances such as alcohol and tobacco that, if used during pregnancy, are known to have detrimental effects on the fetus. Drug users are also at increased risk of acquiring sexually transmitted infections, which may put their infants at increased risk of poor neonatal outcomes. This chapter will review the current literature related to drug use during pregnancy and the effects on the neonate. It will also provide the relevant background related to the use of other substances, and infectious diseases that may also lead to adverse pregnancy outcomes. The first section in this chapter will define, and then present rates of selected obstetric and neonatal outcomes. The second section will review studies that have examined the issue of drug use in pregnancy and its effect on the neonates. The third section is related to tobacco, alcohol, and marijuana use, and in particular the effects of these substances on neonatal outcomes. The fourth section will focus specifically on hepatitis C. It will provide a brief review of this infection, its' relation to drug users, and how it affects pregnancy outcomes. Finally, the fifth section focuses on the effect of various sexually transmitted infections on neonatal health.  4  2.2  NEONATAL OUTCOMES  2.2.1  DEFINITIONS  The brief glossary below provides definitions for some relevant obstetrical and neonatal terms: Abruptio placentae  A disorder of pregnancy in which the placenta prematurely separates from attachment to the wall of the uterus; marked by hemorrhage, pain, and fetal distress.  12  Apgar score  The infant is evaluated at 1, 5 and 10 minutes post-delivery and is assigned a score out of two for each of the following: heart rate, respiratory effort, muscle tone, reflex irritability, and colour. A score of 10 is the highest possible and indicates an infant in the best condition. The Apgar score is the standard method of assessing a baby at delivery. In 13  general, a total score below 7 indicates distress.  12  Gravidity  The number of pregnancies a woman has ever had, including her current pregnancy.  Low Apgar score  Infant receives a score of less than 7 at 5 minutes post-delivery.  13  Low infant birth weight (LBW)  Infant is born with a weight of less than 2500 g, irrespective of the gestation period.  5  14  Intrauterine growth restriction (IUGR)  Fetal size is less than 10 percentile, by ultrasound measurement. th  Neonate  An infant from birth to four weeks (birth to 28 days). Neonatal intensive care unit (NICU)  Hospital unit designed for special care of the seriously ill, premature, or very low birth weight newborn.  12  Oligohydramnios  Abnormality of pregnancy characterized by an insufficient or decreased volume of amniotic fluid surrounding the fetus. '  Less than 10 percentile of amniotic fluid  12 14  th  index. Polyhydramnios  Abnormality of pregnancy characterized by an excess volume of amniotic fluid surrounding the fetus. '  12 14  More than 90 percentile of amniotic fluid index. th  Preterm birth or prematurity  Infant is born prior to 37 weeks gestational age; that is 36 weeks 6 days, or less.  1314  A  premature infant is usually of low birth weight.  Special nursery hospitalization  Premature infants often require special care that is provided in the neonatal intensive care unit.  12  6  2.2.2  PREVALENCE OF SELECTED NEONATAL OUTCOMES IN BRITISH COLUMBIA  Table 2.1 provides the rates of selected neonatal outcomes for British Columbia. Table 2.1: Rates of selected neonatal outcomes in B C ( 2 0 0 2 )  1 5 1 6  British Columbia  Neonatal outcome  Percent (%)  Prematurity  7.0 , 9 . 1  16  Low birth weight  5.3 , 5 . 5  16  Low Apgar score  1.3  NICU admission*  11.0**  15  15  16  16  l e v e l II & III NICU admissions **# of admissions/total # births; not # of newborns admitted/total # births  2.3  2.3.1  A.  ILLICIT DRUG USE AND NEONATAL OUTCOMES  OPIATES: OPIOID AND HEROIN USE  PREVALENCE OF USE IN PREGNANCY  With the rise of the drug epidemic in the 1960s prenatal care providers began to see an increase in the number of women that used illicit drugs during their pregnancies. Years before the rise of cocaine use, heroin addiction in pregnancy was identified as a matter of concern. In the subsequent decades, studies have estimated that the use of opioids by expectant women ranges from 0.3% to 3.9%). " B.  MECHANISM OF ACTION  Opioids are natural or synthetic derivatives of the poppy plant. Opium is the actual resin from poppies, heroin a semisynthetic derivative, and methadone a completely synthetic opioid. Although they differ in chemical structure the pharmacological 17  7  properties of these opiates are the same.  Most opioids can be ingested; however, opium  and heroin are also smoked, and morphine and heroin can be injected. Opioids act by binding to endogenous opioid receptors in the central nervous system, autonomic nervous system, smooth muscle and vasculature.  18,19  The effect is to decrease  the release of noradrenalin producing a euphoric effect. Opioids also cause a release of dopamine providing added positive reinforcement.  18  In addition to euphoria, opiates  cause respiratory depression, and peripheral vasodilation. Heroin, like all opiates 17  including methadone, rapidly crosses the placenta and, therefore, illicit use results in both 18 20  maternal and fetal addiction. '  Any subsequent withdrawal of the drug by the mother 18 20  then causes the fetus to undergo simultaneous withdrawal. '  Reported maternal effects  of withdrawal include uterine irritability, and preterm labour and delivery. C.  18 2 0 2 1  EFFECTS OF USE DURING PREGNANCY ON NEONATAL OUTCOMES  There are many studies reporting neonatal outcomes from opiate exposure in utero but the usefulness of their results is often limited by the shortcomings of the study. Several early studies related to fetal opiate exposure were conducted without the use of a drug-free control group while other authors failed to include a statistical analysis of their data. " 22  26  A number of later studies did carry out statistical analyses and they have been  summarized in Table 2.2.  8  Table 2.2: Summary of studies examining neonatal outcomes from in utero opiate exposure A d v e r s e neonatal o u t c o m e studied  Studies finding statistically significant difference  Lam e t a l 1 9 9 2 O r o e t a l 1987  Gillogley e t a l 1 9 9 0  28  Little e t a l 1 9 9 0  Prematurity  Keith e t a l 1989  29  Lam e t a l 1 9 9 2  Ostrea e t a l 1 9 7 9  Keith e t a l 1989  33  Connaughton et al 1 9 7 7 Stimmel e t a l 1 9 7 6  34  36  Fulroth e t a l 1 9 8 9  33  Keith e t a l 1989 Lam et al 1 9 9 2  31  37  Ostrea et al 1 9 7 9  Special nursery hospitalization  27  36  *Stimmel e t a l 1 9 7 6  Low Apgar score  35  Gillogley et al 1 9 9 0  28  Naeye e t a l 1 9 7 3  35  *Kandall e t a l 1 9 7 7  33  27  31  Kandall et al 1977  32  Ostrea e t a l 1 9 7 9  Low birth weight  Studies finding no difference  30  31  28  *Methadone exposure  In addition to narcotic withdrawal syndrome, among the most commonly recognized neonatal complications are prematurity, and low birth weight. " ' In terms of 18  21 40  prematurity, the results are equivocal. Many studies found significant differences between their groups ' ' ' while equally as many studies did not. '  For low birth  weight, the majority of studies did report significant differences between study and 27 11  28 33 34 36 37  comparison groups ' ' '  while only a few found no differences. '" It is important  to note, however, that of those finding significant differences most did not consider or control for other factors that might have affected the outcome, such as maternal tobacco 27  or alcohol use, or the use of other drugs.  In the study by Gillogley et al, when they  controlled for prenatal care, smoking and prior preterm delivery, the authors did not find any significant differences for prematurity or low birth weight.  9  With regard to Apgar scores, two studies found a significant difference between opiate exposed infants and the control group, while Ostrea et al were not in agreement with this finding. " '  Again, the analyses of these studies did not control for other risk  factors. In summary, a number of studies examining opiate exposure during pregnancy have been conducted. However, most of the research regarding adverse neonatal outcomes, such as prematurity and low birth weight, employed only a univariate approach. The authors of these studies often concluded their research by recognizing that the relationship between opiate use and neonatal outcomes was confounded by other socioeconomic and behavioural risk factors, in particular the concurrent use of tobacco and/or other illicit drugs. Unfortunately, when researchers recognized the need for multivariable analysis a rise in cocaine use and its subsequent use during pregnancy took the forefront. Thus, the need for multi-variable approaches to examine the neonatal effects of in utero opiate exposure still remains. 2.3.2  A.  STIMULANTS: COCAINE AND AMPHETAMINE USE  PREVALENCE OF USE IN PREGNANCY  A sharp reduction in the price of cocaine in the 1980s saw a shift in popularity toward this drug. The use of cocaine to produce a state of euphoria continues, and its highly 39  addictive properties mean women often fail to discontinue use even after learning they are pregnant. Various studies in the United States have estimated maternal cocaine use during pregnancy to be between 0.7% and 18%>."" The prevalence of cocaine use during 3  pregnancy in Canada is not known but a Toronto study, that included three hospitals, 39  found the overall incidence of cocaine exposure to be 6.25%. The prevalence of 10  amphetamine use during pregnancy has not been as well studied; estimates of 0.2% and 37  0.66%) have been reported. ' B.  MECHANISM OF ACTION  Cocaine can be snorted, injected or smoked as freebase or crack.  '  21,38 41  Its' effect is to  block the reuptake of norephinephrine and dopamine resulting in a euphoric state. This inhibition of reuptake results in vasoconstriction, hypertension and tachycardia because of rising norepinephrine levels and activation of the sympathetic nervous system. " 1941  44  Vasoconstriction in a pregnant woman will lead to a decrease in placental blood flow and a subsequent decline in oxygen transfer to the fetus. Increased uterine tone can result from the elevated sympathetic output. '  21 41  Since cocaine readily crosses the placenta,  fetal effects of the drug are often observed in addition to the maternal effects. ' ' The 41 42 44  more commonly reported maternal and fetal effects of prenatal cocaine use include premature labour and delivery, low birth weight, fetal distress, fetal growth retardation, and fetal death. ' ' " 19 38 42  44  Amphetamines, like cocaine, can be taken orally, sniffed, or injected, and have a stimulatory affect on the central nervous system.  38,45  There are limited studies on the  effects of amphetamine use on the neonate, and any poor outcomes observed may be due to other lifestyle factors. C.  38,45  EFFECTS OF USE DURING PREGNANCY ON NEONATAL OUTCOMES  With the rise in the use of cocaine as a recreational drug came a rise in the number of studies examining adverse neonatal outcomes from in utero cocaine exposure. The majority of the studies in the 1980s and early 1990s found differences between study and  11  comparison groups for prematurity ' ' - and low birth weight. ' ' ' ' ' ' ' The 2730 32 46  56  11 27 47 49 51 52 56 57  results, however, are equivocal with some studies reporting contrary results for these outcomes. ' ' '  31 46 58 59  A summary of these studies is presented in Table 2.3. The table also  shows there are studies that have reported conflicting results for low Apgar score and special nursery hospitalization. As with the studies related to opiate exposure during pregnancy, however, most of these studies failed to control for confounders. The influence of other risk factors already known to be associated with these outcomes, such as smoking with low birth weight, were not considered and an independent association cannot be established.  12  Table 2.3: Summary of studies examining neonatal outcomes from in utero cocaine exposure  Studies finding statistically significant difference  Neonatal outcome  Datta-Bhutada e t a l 1 9 9 8 Rosengren e t a l 1 9 9 3 Calhoun e t a l 1 9 9 1 Cohen e t a l 1 9 9 1  Keith e t a l 1989  47  50  52  27  Mastrogiannis et al 1 9 9 0 Fulroth et al 1 9 8 9 54  55  Chouteau et al 1 9 8 8  56  32  Singer et al 1994  Richardson e t a l 1 9 9 9  57  Rosengren e t a l 1 9 9 3 Cohen e t a l 1 9 9 1 Kelley e t a l 1 9 9 1  Low birth weight  59  31  27  56  40  Calhoun e t a l 1 9 9 1 Cohen et al 1 9 9 1  48  Little e t a l 1 9 8 9  31  Phibbs et al 1 9 9 1  Chazotteetal 1991  59  Mastrogiannis et al 1 9 9 0  49  Calhoun et al 1 9 9 1 Special nursery hospitalization  46  52  Chouteau et al 1 9 8 8  Keith e t a l 1989  58  Datta-Bhutada e t a l 1 9 9 8 Keith e t a l 1989  51  Gillogley e t a l 1 9 9 0 Frank e t a l 1 9 8 8  47  Chazotteetal 1991  49  Phibbs e t a l 1 9 9 1  Low Apgar score  53  30  Neerhof e t a l 1 9 8 9 O r o e t al 1 9 8 7  31  51  Gillogley e t a l 1990  Little et al 1 9 8 9  58  49  Phibbs e t a l 1 9 9 1  Prematurity  Richardson e t a l 1999  48  Dombrowski et al 1 9 9 1 Kelley et al 1 9 9 1  46  Studies finding no difference  48  53  54  Chazotte e t a l 1 9 9 1  59  52  Neerhof e t a l 1989  51  There are a number of studies that have attempted to control for the influence of maternal risk factors, as well as prenatal alcohol and tobacco use, through matched or 10 2158  multi-variable analyses. ' ' "  62  They are improvements on the univariate approach to in  utero cocaine exposure employed by the studies mentioned above; these studies are  13  summarized in Table 2.4. Of the studies presented here, two that used multi-variable analyses found an association between prematurity and cocaine use (OR 13.40, 95% CI 1.23-145.0; RR 3.4, 95% CI 2.9-4.0) ' while two others, that matched for various 62 63  confounders, found significant differences between their groups (p<.05 and p<.0005). '  61 64  Similarly, two studies using multi-variable analyses reported associations with low birth weight (RR 1.59, 95% CI 1.03-2.43; RR 4.4, 95% CI 3.7-5.2) , and two others, that 6062  matched for certain risk factors, found significant differences between exposure groups (p<05 and p<.005). " Of note, a meta-analysis, that included results from six studies 61  64  examining low birth weight, reported a pooled estimate of the random effects relative risk of 1.77 (95% CI 1.15-2.71). The studies included in this meta-analysis had adjusted for 65  tobacco use and presented results for 'any' prenatal cocaine exposure. Two studies examining low Apgar score that reported no significant findings are also presented in Table 2.4.  60-61  Although the studies in Table 2.4 considered maternal factors as well as  tobacco and alcohol use, the difficulty in determining an independent association between the adverse neonatal outcomes and prenatal cocaine use still persists. These studies did not consider the influence of other illicit drugs that could potentially have effects on neonatal outcomes. In fact, the number of studies that have considered illicit drug use in addition to other risk factors are few.  14  Table 2.4: Summary of studies that adjusted or matched for maternal factors, tobacco use & alcohol use when examining neonatal outcomes from in utero cocaine exposure Neonatal o u t c o m e  Results  Studies  R R / O R (95%CI) or p-value  Shiono et al 1 9 9 5 * E y l e r e t a l 1994 Prematurity  10  Handler e t a l 1 9 9 1  62  63  ' M a c G r e g o r et al 1 9 8 7 Sprauve e t a l 1 9 9 7 Shiono e t a l 1 9 9 5 Low birth weight  *Eyler e t a l 1994  10  p<05  Matched for T, A , G , M A , M R  OR 13.40(1.23-145.0)  T, A , P C , P, M A , M R , Preterm  RR 3.4 (2.9-4.0)  T, P C , G, M A , M R , hospital  p<0005  Matched for T, P, M A , S E S  OR 1.59(1.03-2.43)  T, A , P C , M W , M A , P C , Preterm  O R 0.7(0.4-1.3)  T, A , M, P, M A , M R , income, BMI, L B W . - S T I s , age 1st  p<05  Matched for T, A , G , M A , M R  OR 9.90 (0.53-184.0)  T, A , P C , P, M A , M R , Preterm  R R 4 . 4 (3.7-5.2)  T, P C , G, M A , M R , hospital  p<005  Matched for T, P, M A , S E S  OR 1.34 (0.57-2.30)  hypertension, abruption, F G R  NS  Matched for T, A , G , M A , M R  61  Handler e t a l 1 9 9 1  62  63  *MacGregor e t a l 1 9 8 7 Sprauve e t a l 1 9 9 7 *Eyleret al 1994  T, A , M, P, M A , M R , income, BMI, L B W , STIs, age 1st  64  60  Kliegman et al 1 9 9 4  Low Apgar score  O R 1.3(0.9-2.0)  61  Kliegman et al 1 9 9 4  60  Controlled or matched variables  64  61  T=tobacco; A=alcohol; M=marijuana; PC=prenatal care: P=parity; G=gravidity; MA=maternal age; MR=maternal race or ethnicity; SES=socioeconomic status; BMI=body m a s s Index; LBW=prior low birth weight baby; Preterm=prior preterm birth; age 1st=age at 1st intercourse; hospital=location of delivery hospital; FGR=fetal growth restriction NS=not significant "no multi-variable analysis  15  The 1994 study by Richardson et al controlled for other illicit drug use, as well as tobacco and alcohol, and reported that cocaine use was not associated with either prematurity or low birth weight.  66  These results confirmed those from an earlier study  by Hadeed et al who found no significant difference between groups for prematurity.  67  However, even though these latter researchers excluded subjects that had used other illicit drugs and/or alcohol, they did not consider tobacco use. A study by Miller et al in 1999 did adjust for both tobacco and alcohol use as well as opiate use. The results of this 69  later study, therefore, were able to support the lack of association found by Richardson et al for prematurity, and low birth weight with maternal cocaine use. Miller et al reported odds ratios and 95% confidence intervals of 0.6 (0.2 - 1.9) for prematurity and 1.2 (0.4, 3.6) for low birth weight. In contrast, Kistin et al found relative risks (95%> CI) for prematurity, and low birth weight of RR 4.0 (2.3-7.0), and RR 5.3 (3.0-9.3) respectively. They dealt with the confounding effects of other illicit and non-illicit substance use by excluding any mother that was a user of heroin, amphetamines, marijuana, tobacco and/or alcohol. This 68  association between maternal cocaine use, and prematurity and low birth weight is supported by the results of another study. Bateman et al found that the risk of both prematurity and low birth weight were almost doubled in the cocaine exposed group with odds ratios and 95% confidence intervals of 1.94 (1.21-3.11) and 2.10 (1.23-3.67) respectively. The results of these studies are summarized in Table 2.5. 70  Studies by Eyler et al and Cherukuri et al also reported significant results for prematurity and low birth weight from maternal cocaine use. '  71 72  16  Although both of these  studies excluded concurrent users of other illicit drugs neither considered tobacco use. Similarly, Forsyth et al examined NICU admissions as a result of cocaine use during pregnancy, but failed to account for maternal tobacco use.  73  Therefore, the usefulness  the results from these studies is limited and they are not included in Table 2.5.  17  Table 2.5: Summary of studies that adjusted for tobacco and alcohol use as well as other illicit drugs when examining neonatal outcomes from in utero cocaine exposure Neonatal o u t c o m e  Prematurity  Results  Studies  R R / O R (95%CI)  Miller e t a l 1 9 9 9  69  Kistin e t a l 1 9 9 6  68  Richardson et al 1 9 9 4 Bateman e t a l 1 9 9 3  Low birth weight  OR = 0.6 (0.2,1.9)  Op, T, A , M, P C , P, MA, M R , L B W , STIs, A b u s e  RR = 4.0 (2.3,7.0)  G, M A , M R ; excluded heroin, A m p h , T, A , M  NA  T, A, M, other illicit drugs; excluded <18 yrs, no P C  O R = 1.94(1.21,3.11)  Op, P C P , T, A , M, P C , G , M A , M R , Syp, infant sex  66  70  Controlled variables  Miller et al 1 9 9 9  69  O R = 1.2 (0.4,3.6)  Op, T, A, M, P C , P, MA, M R , L B W , STIs, A b u s e  Kistin e t a l 1 9 9 6  68  RR = 5.3 (3.0,9.3)  G, M A , M R ; excluded heroin, A m p h , T, A , M  NA  T, A , M, other illicit drugs; excluded <18 yrs, no P C  O R = 2.10 (1.23,3.67)  Op, P C P , T, A , M, P C , G , M A , M R , S y p , infant sex  Richardson etal 1994 Bateman etal 1 9 9 3  70  66  Op=opiates; Amph=amphetamines; T=tobacco; A=alcohol; M=marijuana; PC=prenatal care; P=parity; G=gravidity; MA=maternal age; MR=maternal race or ethnicity; LBW=prior low birth weight baby; STIs=sexually transmitted infections; Syp=syphilis; Abuse=physical and/or sexual abuse NA=no association  18  In summary, there are some studies that have employed a multi-variable approach to maternal cocaine use and the neonatal outcomes prematurity, low birth weight, low Apgar score and special nursery hospitalization. Of those that have attempted to adjust for confounders, however, few have considered the influence of concurrent drug use and the results from these studies remain equivocal. Additional research that controls for other illicit drug use, and tobacco use as well as obstetric and maternal factors is required to support or refute the association between in utero cocaine exposure and neonatal outcomes.  2.3.3  MULTIPLE SUBSTANCE USE  The above review mentioned that abusers of one illicit drug are often multiple substance users, concurrently indulging in more than one other licit or illicit substance. These substances may include cigarettes, alcohol and/or other drugs of abuse. This polydrug use holds true for pregnant users as well, with several studies finding that pregnant women who use one illicit drug are also using one or more other substances. "' ' ' 4,6  2930 55 74  For example, a study by Frank et al found that 14% of pregnant cocaine users were also opiate users and that 9% of pregnant cocaine users were found to be using 'other illicit drugs'.  11  In another study, Zuckerman et al found that 22% of those using cocaine during  pregnancy also used opiates. Hence, the need to consider concurrent drug use in any 6  analysis that examines the effects of a specific drug on an outcome.  19  2.4  TOBACCO, A L C O H O L AND MARIJUANA  2.4.1  ILLICIT DRUG USE AND THE USE OF OTHER SUBSTANCES  As discussed above, the concurrent use of other substances by pregnant drug users is not uncommon. In fact, many pregnant users continue to consume alcohol, smoke tobacco and use marijuana. One study found that 9% of cocaine users consumed two or more alcoholic drinks per day whereas only 2% of the non-users consumed the same number of drinks. Similarly, 31 % and 28% of cocaine users smoked more than one 11  pack of cigarettes per day and smoked marijuana three or more times per week, respectively. This was compared to 7% smoking more than one pack of cigarettes per day and 5% smoking marijuana three or more times per week, in the non users group.'  1  2.4.2  A.  EFFECTS OF USE DURING PREGNANCY ON NEONATAL OUTCOMES  TOBACCO  It is estimated that between 12% and 20% of pregnant women smoke and the adverse outcomes related to this behaviour are well documented. ' " Among the maternal 16 75  77  complications associated with smoking during pregnancy are spontaneous abortion, premature rupture of membranes and preterm delivery. ' " 1216 76  78  In addition, there are  many complications faced by the neonates who have been exposed to tobacco in utero. These include increased incidence of intrauterine growth restriction, low birth weight, and stillbirth or perinatal death. B.  ' ' "  1216 21 76  78  ALCOHOL  Although alcohol is a well-recognized teratogen, it is still estimated that approximately 15% of pregnant women drink alcohol. ' ' '  16 21 79 80  20  Of those, between 1% and  3% are frequent or binge drinkers consuming more than 7 drinks per week. '  21 79  Alcohol  abuse during pregnancy can result in birth defects and mental retardation as well as spontaneous abortion, preterm labour, and growth deficiencies. ' ' C.  MARIJUANA  Data from the Ottawa Prenatal Prospective Study estimated that 20% of women use marijuana during the year prior to their pregnancy with only about half of them discontinuing use after learning they were pregnant. Other studies confirm the 84  percentage of women using marijuana during pregnancy may be in the range of 106 85 89  30%. ' '  _  The effects of marijuana use during pregnancy are not as well studied or  reported as other illegal substances. There are, however, some studies that have linked intrauterine growth retardation, preterm labour and preterm birth with marijuana use during pregnancy while others have found no association. '  6 79,85  2.5  2.5.1  A.  " '  87 89-91  HEPATITIS C  A BRIEF REVIEW OF HEPATITIS C  RISK FACTORS AND DISEASE TRANSMISSION  Infection with hepatitis C is contracted through contact with infected blood or body 92  fluids." The virus is communicated from an infected host to a susceptible host via direct contact with body fluids, or indirect contact via biological products including blood, serum, or organs.  92,93  Modes of direct contact include sexual transmission and vertical  transmission. Transmission via sexual contact represents a fairly low-risk route of infection and accounts for only approximately 2.5% of cases. ' The risk of perinatal 94 95  21  infection is also relatively low. " Higher rates of both sexual and vertical transmission have been observed in individuals who are co-infected with H I V . ' ' 94  95  97100  The highest rates of infection for hepatitis C via indirect contact are associated with individuals that receive contaminated blood, blood products or organs, and individuals exposed to contaminated needles and medical equipment. '  94 97101102  In countries such as  Canada, however, the implementation of modern blood screening techniques have now virtually eliminated the risk of acquiring HCV via blood/blood product transfusion.  94103  Sharing needles or drug paraphernalia is now the most common route of infection in Canada and many other developed countries.  103104  Other modes of transmission via contaminated objects include tattoo or piercing equipment, or personal hygiene items that could have traces of contaminated blood, such as razors or dental  floss. ' ' ' '  94 97 98 102 103  Indirect contact via breastfeeding has also been  implicated as a mode of transmission; however, the evidence regarding this route, as a means of communicating the virus, is unresolved.  95  B.  VIRAL AGENT, DIAGNOSIS AND CLINICAL MANIFESTATIONS  Hepatitis C infection is caused by an enveloped RNA virus in the Flaviviridae family.  92104  It was first recognized in 1989, and therefore, identification of the virus is  relatively recent. Since widespread screening is not currently recommended in Canada, 105  diagnosis of hepatitis C infection may be suspected from presentation of symptoms, physical examination, or a history of risk taking behaviour. Such suspicions may be confirmed by serologic assays since antibodies to the proteins of HCV permit diagnosis 92  of infection.  22  Within its human host, the hepatitis C virus may manifest itself in two stages of disease progression: acute and chronic.  106  Acute disease is not usually symptomatic but  may be characterized by anorexia, vague abdominal discomfort, nausea, vomiting, and jaundice in 5-25% of newly infected individuals.  '  92,101 106  Only about 20% of individuals,  asymptomatic or symptomatic, will spontaneously clear the virus. This means that 7592  85%o of infected individuals will suffer long-term infection and progress to a chronic disease state.  100106  Of those individuals with chronic infection, a large proportion (10-  25%) will develop chronic liver disease, which may progress to cirrhosis or sometimes even carcinoma over multiple decades. ' ' '  94 100 102 103  C.  HCV PREVALENCE IN CANADA  Since many HCV infected individuals experience no symptoms of disease, and widespread screening does not exist, there is a proportion of individuals in the population who are unaware of their infection. Therefore, even though hepatitis C has been deemed a nationally reportable disease in Canada, the prevalence of this illness in our country is not known. It has been estimated, however, that the prevalence in the general Canadian population is 0.81% or approximately 251,000 people.  107  Twenty to twenty-five percent  of the reported cases of hepatitis C in Canada occur in BC.  2.5.2  ILLICIT DRUG USERS AND HEPATITIS C  The tie between illicit drug use and hepatitis C infection is evident. In developed countries where blood product screening exists, injection drug use is the primary route of HCV transmission. In Canada, approximately 75% of prevalent infections and the majority of new cases are now attributed to injection drug use.  23  107  Therefore, it is not  surprising that intravenous drug users, as a group, have the highest prevalence of HCV infection.  108  Long-term surveys of adult injection drug users have consistently shown HCV prevalences in the range of 70-90%.  109-114  Some studies have even reported that six  months after initiating injection drug use, the prevalence rate of infection exceeds 75%." '" More specifically, in a cohort of Vancouver injection drug users the 4  5  prevalence of HCV was found to be 87%> and the annual incidence to be 26%.  98,I04J16  The prevalence of HCV among non-intravenous drug users is far less frequently reported. Woodfield et al reported the prevalence of anti-HCV antibodies among those who administer drugs via oral and/or nasal routes to be approximately 5%; considerably lower than that of intravenous users.  117118  This lower rate is consistent with the fact that  intranasal cocaine use cannot be unequivocally implicated as an independent risk factor. '  97 114  2.5.3  EFFECTS OF HEPATITIS C INFECTION ON NEONATAL OUTCOMES  A. SEROPREVALENCE  The seroprevalence of hepatitis C in pregnancy has been reported to be between 14%; however, higher rates have been observed for women in high-risk categories, including intravenous drug users." " 9  124  In British Columbia, the overall HCV rate,  determined by an anonymous seroprevalence study, was found to be 1.17% while the rate among women residing in the Lower Mainland was as high as 1.9%.  125  24  B.  VERTICAL TRANSMISSION  Although the reported rates are varied, it is recognized that vertical transmission of the hepatitis C virus from mother to infant does occur. Transmission rates from zero to 36 percent have been reported; however, the average rate in healthy women is between 5 and 6 percent. ' ' ' " 97 99 121 126  The unpublished rate of transmission from the HCV Vertical  133  Transmission Study is 2.7%. C.  NEONATAL OUTCOMES  There are limited studies that have considered obstetrical and/or neonatal complications in HCV-infected women. From the available data, however, there is no indication that HCV infection during pregnancy causes an increased risk of adverse outcome other than vertical transmission of the virus. - < - ' 119  121  129  131 134  136  More  specifically, studies have found no differences in mean birth weight, gestational age at delivery, or mean Apgar score."  2.6  2.6.1  9,135  SEXUALLY TRANSMITTED INFECTIONS  ILLICIT DRUG USE AND SEXUALLY TRANSMITTED INFECTIONS  It is well recognized that there is a link between illicit drug use and the incidence of sexually transmitted infections (STIs). " 137  141  Individuals who use drugs, whether they are  injection or non-injection drugs, are at increased risk of acquiring STIs through high-risk sexual behaviours. " 137  139,141  "  143  The tendency of drug-using individuals to engage in this  type of high risk behaviour can be largely explained by the addictive nature of illicit drugs. Most individuals quickly become addicted and also soon lack the economic means to sustain such a habit. Consequently, they resort to the exchange of sex for money or  25  drugs.'  In addition, some illicit drugs may have more direct influence on  40141144  behaviour including sexual disinhibition.  140  Regardless of the reasoning, illicit drug use  often results in the participation of risky sexual behaviours, including an increased number of sexual partners, and thereby leads to an increased risk of STIs. ' ' -' ' 138 139 141  2.6.2  145 146  EFFECTS ON OBSTETRIC AND NEONATAL OUTCOMES  There are many sexually transmitted infections (STIs) that are recognized to have an affect on pregnancy and/or neonatal outcomes. Some of the most common are considered below. A. CHLAMYDIA  The organism responsible for chlamydia infection is Chlamydia trachomatis.,  Any  147  infant exposed to chlamydia during a vaginal delivery is at a 5-15% risk of pneumonitis, as well as a 15-25%) risk for conjunctivitis, an eye infection which can to lead to blindness. " 147  150  Other conditions possibly associated with prenatal chlamydia infection  include spontaneous abortion, premature rupture of membranes, preterm labour and low birth weight.  149  B. GONORRHEA  Pregnant women infected with Neisseria gonorrhoeae, are at an increased risk for spontaneous abortions, premature rupture of membranes, preterm labour and delivery. ' 147 150  153  C. GENITAL HERPES  The herpes simplex virus (HSV-2) is the organism responsible for genital herpes.  148  Spontaneous abortion, birth anomalies, or intrauterine growth restriction can occur if  26  intrauterine HSV infection occurs during pregnancy. '  147 154157  The neonates of infected  mothers are also at risk of acquiring the infection during a vaginal delivery; therefore, delivery by caesarean section is usually recommended for mothers with symptomatic genital herpes. ' ' '  12 147 156 157  Without antiviral therapy, infection in the neonate is associated  with infant morbidity as well as mortality. ' '  147 156 158  D. GENITAL WARTS  Human papillomavirus (HPV) infection, in the genital area, is characterized by visible single or multiple warty growths.  147  Infants exposed to HPV during delivery are at risk of  acquiring laryngeal papillomatosis. ' '  147 150 159  E.  SYPHILIS  The syphilis bacterium, Treponema pallidum, is the cause of syphilis and untreated infection has well-recognized adverse effects on pregnancy outcome. Congenital syphilis can cause spontaneous abortion, prematurity, stillbirth, growth restriction, neonatal morbidity and mortality. - ' ' ' 12  147 150 160 161  F. TRICHOMONIASIS  Trichomoniasis is caused by infection with the Trichomonas vaginalis protozoan. '  147 162  Maternal trichomoniasis infection is a recognized cause of premature  rupture of membranes, preterm delivery and low birth weight. ' '  147 157 163  G.  HEPATITIS B VIRUS  The most prevalent adverse pregnancy outcome associated with hepatitis B virus infection is the vertical transmission of HBV to the neonate. ' '  147 164 165  27  There is also some  evidence to indicate that if the acute severe phase of HBV infection occurs during the third trimester of pregnancy, then there is an increased risk of preterm delivery.  147  H. HUMAN IMMUNODEFICIENCY VIRUS  Like HBV infection, the primary risk to a neonate of an HIV infected mother is vertical transmission of the virus, and its' associated morbidity and mortality.  147166167  Evidence related to the effect of infection on pregnancy outcome is varied; some results show that mothers with advanced HIV may have higher incidences of prematurity, low birth weight, and still-births. I.  161166  "  168  SUMMARY  A number of sexually transmitted infections have been implicated as risk factors for various obstetrical and neonatal complications including prematurity, preterm labour/delivery, and low birth weight.  2.7  SUMMARY  In summary, when one considers studying neonatal outcomes the task is always a complicated one. There are many variables, such as obstetrical history, that must be taken into account. Furthermore, when examining a study population such as illicit drug users the task becomes all the more complex. Illicit drug use is linked to other behaviours and health issues that potentially pose an increased risk to the infant. It is necessary, therefore, to consider these additional factors when studying illicit drug users and outcomes in their neonates. This thesis will examine the effects of stimulant as well as opiate drug use on specific neonatal outcomes while controlling.for concurrent tobacco and/or other illicit drug use.  28  CHAPTER 3 - METHODS 3.1  PRIMARY STUDY SETTING -  The Hepatitis C Vertical Transmission Study  Of 141,000 HCV infections that have been reported in Canada, British Columbia 107  accounts for 20-25% of these reported infections.  Our province, therefore, provides a  unique opportunity to study Hepatitis C infection. The seroprevalence in pregnant women in BC is estimated at 1-2%.  125  Hepatitis C is the most common blood-borne infection complicating pregnancy in Canadian women. Yet there remain many unanswered questions regarding this infection in pregnancy, and the factors affecting vertical transmission. The objectives of the Hepatitis C Vertical Transmission Study, therefore, were to determine the vertical transmission rate of hepatitis C in British Columbia and to identify the specific maternal, virologic, and pre, peri, and post partum factors associated with the vertical transmission of this infection. The Children's and Women's Health Centre of British Columbia is the largest obstetrical facility in Canada and provides an ideal setting for a large, prospective cohort study on perinatal hepatitis C infection. The Hepatitis C Vertical Transmission Study was funded by Health Canada and based at the C&W Health Centre of BC. It enrolled HCV positive pregnant women from throughout the province, beginning in September 2000 until September 2003. Due to the high seroprevalence of HCV positivity among intravenous drug-users, this cohort included a large sub-group of drug-users from the downtown Eastside of Vancouver.  104  Thus, identification of HCV positive pregnant  women led to the enrollment of a sub-sample of women who admitted using drugs during  29  their current pregnancy. Therefore, while addressing the needs of the primary study, this cohort also provided the opportunity to study this sub-population and the objectives outlined for this thesis. 3.2  STUDY SAMPLE SELECTION AND STUDY ACTIVITIES  HCV positive women were identified through a linked database system between Canadian Blood Services (CBS) and the Public Health Information System (PHIS) at the British Columbia Centre for Disease Control (BCCDC). The database linkage identified 547 women with reported, confirmed HCV infection who were or became pregnant over the study period. Hepatitis seropositivity was determined by two sequential enzyme immune assays (EIA). The physicians, of acknowledged HCV positive pregnant women, were sent a package containing study information, including a letter of invitation and consent form for the patient. Other recruitment methods included physician referrals and in-person recruitment as well as a website and posters. Those women who consented to participate were enrolled in the Hepatitis C Vertical Transmission Study and contacted by the study coordinator. A detailed questionnaire, administered by the study nurse, collected information on demographics, obstetrical/gynaecological and medical history, behavioural/risk factor history, and sexual history. This baseline questionnaire was administered antenatally and the subjects were followed through delivery and for 18 months post-partum. Post-partum follow-up questionnaires gathered information related to delivery, neonatal and pediatric details. Chart reviews were used to collect data when necessary. A summary of the four questionnaires utilized is provided in Table 3.1 and the full questionnaires are included in the Appendices.  30  Table 3.1: Summary of baseline and fo low-up questionnaire content Section  #of Questions  T y p e of Q u e s t i o n s  Baseline Questionnaire  Demographics  14  Age, marital status, ethnicity, education, employment, income  Obstetrical/ Gynaecological History  22  Early/late pregnancy complications, STI during pregnancy, previous pregnancy outcome/mode  Medical History  20  Medical problems, HCV/HIV/Other hepatitis diagnoses, liver disease diagnoses  Behavioural/Risk Factors  40  Blood/blood product exposure, injection drug use history, occupational/household exposure  Sexual History  39  Sexual partner history, S T D history, sexual relations for drugs/money, high risk sexual practices Maternal Data Questionnaire  Baseline Characteristics  6  Gravity, parity, L M P , date of H C V diagnosis  Prenatal Tests  7  Rh status, amniocentesis, HBV, HIV, Syphilis, Varicella  Antenatal Infections  5  Candida, bacterial vaginosis, C M V , genital herpes  Prescription medications  2  Antiretroviral therapy, other medications  Substance Use  2  Tobacco/alcohol, other drugs  Laboratory Results  17  HIV RNA, C D 4 count, H C V R N A , H C V P C R , A L T  Antenatal Complications  12  Hypertension, weight gain, antepartum hemorrhage, Delivery Data Questionnaire  Pregnancy Outcome  4  Delivery date, outcome, gestational duration  Delivery Information  12  Labour details, mode of delivery, delivery complications  Postpartum Follow-up  3  Length of hospital stay, complications  Neonatal Information  13  Birth weight, cord blood gases, Apgar scores, defects  Medical Problems  3  Prematurity, jaundice, sepsis, viral infection  Breastfeeding  1  Breastfeeding infant, maternal medications Pediatric Data Questionnaire  Infant Health  4  Skin problems, E N T problems, G l problems  Virology  4  HIV culture, HIV P C R , H C V P C R , H C V Ab  Laboratory Results  6  A S T , ALT, PTT, PT, Bilirubin, Albumin  31  3.3  DATA MANAGEMENT  Data collected for the Hepatitis C Vertical Transmission Study was verified, coded, entered, and stored in a relational database created using Microsoft Access software. All personal identifying information of each mother and infant was removed from this database. This thesis analysis utilized the data collected for the primary study. For the purposes of data preparation and cleaning, the dataset was imported into Microsoft Excel. Subjects with non-singleton pregnancies were excluded from the analysis. As well, some mothers had more than one pregnancy during the study period and enrolled twice. In order to maintain an independent sample, data for only the second pregnancy was included in this thesis study. Variables were chosen based on the literature review for this project. Many variables were used directly from the database while it was necessary to modify or combine others to produce a needed variable. Newly created variables and those requiring further definition are included in Section 3.4. 3.3.1  STATISTICAL SOFTWARE  All data analysis for this thesis was carried out using S-Plus 6.1 Statistical Software.  3.4 VARIABLES AND VARIABLE DEFINITIONS  3.4.1  MAIN O U T C O M E VARIABLE  The main outcome variable and its response categories are presented in Table 3.2.  32  Table 3.2: Description of main outcome variable Variable  Response Categories  A d v e r s e neonatal o u t c o m e  YES  NO  Premature delivery  Yes  No  Low birth weight  Yes  No  Low Apgar score  Yes  No  NICU admission  Yes  No  summary measure based on the following outcomes:  ADVERSE NEONATAL OUTCOME:  positive response for this summary measure was  determined by a positive response for any of the following outcomes: infant is born prior to 37 weeks gestational age  •  Premature delivery:  •  Low birth weight:  infant is born with a weight of less than 2500 g  •  Low Apgar score:  infant receives a score of less than 7 at 5 minutes post-  delivery •  3.4.2  N I C U admission:  infant is admitted to neonatal intensive care unit post-delivery  MAIN EXPLANATORY VARIABLES  Table 3.3 presents the main explanatory variables with their corresponding response categories. Table 3.3: List of main study variables Variables  Response Categories  DRUG USE VARIABLES Current stimulant use  Yes  No  Current opiate use  Yes  No  33  Definitions for the main explanatory variables are presented here. CURRENT STIMULANT USE:  mother reported use of any of the following after the date of  her last menstrual period (LMP): • Crack cocaine  • Nasal cocaine  • Crystal meth  • Amphetamines (Speed)  CURRENT OPIATE USE:  • Ecstasy (MDMA)  mother reported use of any of the following after the date of her  LMP: • Heroin  • Morphine  • Opium  • Talwin/Ritalin 3.4.3  COVARIATES  Table 3.4 presents other explanatory and descriptive variables and their corresponding response categories.  34  Table 3.4: List of additional explanatory and descriptive variables Variables  R e s p o n s e Categories  OTHER SUBSTANCE USE Current methadone use  Yes  No  Current marijuana use  Yes  No  Current other illicit drug use  Yes  No  Current tobacco use  Yes  No  Average # cigarettes/day  Continuous  Alcohol use over past year  Yes  No  SOCIODEMOGRAPHIC CHARACTERISTICS Continuous  Age Aboriginal ethnicity  Yes  No  Less than high school education  Yes  No  Yearly gross household income <$30,000  Yes  No  REPRODUCTIVE/OBSTETRIC HISTORY 1  >2  Prior preterm birth (< 37 weeks)  Yes  No  Pregnancy complication in current pregnancy  Yes  No  Sexually transmitted infection during current pregnancy  Yes  No  Vaginal  C-section  HBV diagnosed  Yes  No  HIV diagnosed  Yes  No  H C V P C R positive  Yes  No  Gravidity  Type of delivery MEDICAL HISTORY  SEXUAL BEHAVIOUR Age at first intercourse  Continuous  # partners in past year  Continuous  # partners in lifetime  Continuous Yes  Engaged in high risk sexual behaviour  Explanatory variables needing further definition and definitions for newly created explanatory variables are presented here.  35  No  CURRENT OTHER ILLICIT DRUG USE: mother  reported use of any of the following after  the date of her LMP: • Acid/LSD  • PCP  • Mescaline  • Mushrooms CURRENT METHADONE USE: mother  reported use of methadone after the date of her  LMP. PREGNANCY COMPLICATION IN CURRENT PREGNANCY:  includes occurrence of any of  the following during the pregnancy: • Oligohydramnios  • Abruptio placentae  • Polyhydramnios  • Hypertension  • Intrauterine growth restriction SEXUALLY TRANSMITTED INFECTION DURING CURRENT PREGNANCY:  includes any  of the following: • Syphilis  • Gonorrhea  • Genital herpes  • Chlamydia  • Genital warts  • Trichomonas  • Other STI ENGAGED IN HIGH RISK SEXUAL BEHAVIOUR:  one or more of the following were  reported: • Sexual contact with gay/bisexual men • Sex with someone with genital herpes or who had genital sores • Sex with a male or female prostitute • Ever been paid or received money for having sex • Ever given or received sex for drugs  36  3.5  OVERVIEW OF METHODOLOGICAL APPROACHES  3.5.1  DESCRIPTIVE ANALYSES  Frequencies and percentages are used to describe the cohort as a whole as well as for the two groups: mothers with infants who suffered an adverse outcome versus mothers whose infants had no adverse outcome. Summary statistics and appropriate graphical representations were produced for descriptive and exploratory purposes. 3.5.2  UNIVARIATE ANALYSES  Explanatory variables were compared for those with infants who suffered an adverse outcome versus those with infants who had no adverse outcome. As appropriate, t-tests or Wilcoxon Rank Sum were used to compare continuous variables. Chi-square or Fisher's exact test were used for categorical variables. Crude odds ratios and 95% confidence intervals were computed for all categorical variables. 3.5.3  MULTI-VARIABLE ANALYSES  Multi-variable logistic regression was used to investigate the association between current stimulant  and/or current opiate drug use during pregnancy and the likelihood  of an adverse neonatal outcome. Other explanatory variables found significant in the univariate analyses as well as potential confounders and interaction terms were also considered in the regression analysis. Significance of individual regression estimates was tested by Wald statistics. A critical value of 3.84 at ct=0.05 was used. Where appropriate, the likelihood ratio test was used was used for the comparison of regression models, and the change in the log odds ratio was compared when considering the influence of potential confounders. Beta coefficients, standard error, and Wald statistics  37  as well as odds ratios with their 95% confidence intervals were reported for the regression models. The odds ratio is the measure of the association between the independent variables and the dependent variable. The assumptions made for the model to be valid were that all observations are independent, observations are measured without error, inclusion of all higher order terms, and variance is predicted by the model.  3.6  169  ETHICAL CONSIDERATIONS  Ethical approval was received from the University of British Columbia Clinical Ethical Review Board, and Children's and Women's Health Centre of BC for the primary study. An amendment, submitted for the secondary analysis comprising this thesis, was also approved by both review boards.  3.7  SUMMARY  The Hepatitis C Vertical Transmission Study database offers an appropriate data source for the analyses described in this thesis. It is an excellent data source providing detailed histories for a challenging cohort of pregnant drug users and non-users. As well, it is a source of prospectively collected data related to the pregnancies, deliveries and post-partum health of infants born to these women.  38  CHAPTER 4 -  4.1  RESULTS  DESCRIPTIVE AND UNIVARIATE ANALYSES The Hepatitis C Vertical Transmission Study enrolled 154 patients. Five subjects  were not included in the primary dataset because o f early withdrawal from the study or refusal to sign the consent form. This thesis study then excluded two patients with nonsingleton pregnancies as well as the data for six subjects that corresponded to patients with double enrollment. Neonatal outcome data was not available for 5 additional entries. Data from 136 women and their infants were analyzed.  4.1.1 NEONATAL OUTCOMES Fifty-three (39.0%) o f the infants born to women in the study cohort had an adverse outcome, as defined for this study. Eighty-three (61.0%) o f the infants had no adverse outcome. The results for the neonatal outcome data are presented in Table 4.1. There were three stillborn births (2.2%) and one intrauterine death (0.7%). A m o n g the women in the cohort, 17.6%, 13.2%, 5.9%>, and 26.5%> had infants born prematurely, infants born with low birth weight, infants receiving a low Apgar score at 5 minutes, and infants admitted to the neonatal intensive care unit, respectively. O f those infants admitted to N I C U , the median length o f stay was 5.5 days (range 1.0 - 69.0). Fourteen infants (10.3%o o f the cohort) were born small-for-gestational-age ( S G A ) . The adverse neonatal outcome group had nine S G A babies while the group with no adverse outcomes had five S G A babies. In addition, twenty-one infants that had an adverse outcome suffered from substance withdrawal syndrome; that is 15.4% o f the cohort. Interestingly, thirteen (9.6%>) o f those infants without an adverse outcome also experienced some level o f substance withdrawal syndrome.  39  Table 4.1: Neonatal outcome details for the cohort (n=136) Adverse Outcome O u t c o m e Variable  n (% of cohort)  Adverse Outcome  53  (39.0)  Stillborn  3  (2.2)  Intrauterine death  1  (0.7)  Prematurity  24  (17.6)  Low Birth Weight  18  (13.2)  Small for Gestational A g e  14  (10.3)  8  (5.9)  Neonatal Intensive Care Unit Admission  36  (26.5)  Of those admitted to NICU, median (days) length of stay in NICU  5.5  Low Apgar Score  Range (days)  (1.0-69.0)  Substance withdrawal syndrome  21  (15.4)  4.1.2 SOCIODEMOGRAPHIC CHARACTERISTICS The mean age o f this cohort o f women was 30.2 + 5.54 years. The mean age for the adverse outcome group was 30.2 + 5.44 years while the mean age for the group with no adverse neonatal outcome was 30.1 + 5.63 years. There was no significant difference in age between the two groups. Comparisons between the groups for other sociodemographic characteristics revealed no significant differences in aboriginal ethnicity, education level or yearly household income less than $30,000/year. The frequencies and percentages for the sociodemographic characteristics o f the cohort, as well as the two groups o f interested are presented in Table 4.2. Crude odds ratios and 95% confidence intervals are also found in this table.  40  Table 4.2: Univariate results for sociodemographic data for those women with an infant with an adverse outcome versus those whose infants had no adverse outcome Adverse Outcome  No A d v e r s e Outcome  n (%)  n (%)  n(%)  Mean (years)  30.2  30.2  30.1  Std deviation  5.5  5.4  5.6  Characteristic  Cohort  Crude Odds Ratio  Lower  Upper  9 5 % CI 9 5 % CI  p-value  Age 0.932  Aboriginal Yes  33(25.4)  15(30.0)  18(22.5)  No  97(74.6)  35(70.0)  62(77.5)  Yes  47(41.2)  20(47.0)  27(38.0)  No  67(58.8)  23(53.5)  44(62.0)  Yes  83(74.8)  33(85.0)  50(69.0)  No  28(25.2)  6(15.4)  22(30.6)  1.5  0.66  3.29  0.339  1.4  0.66  3.05  0.372  2.4  0.89  6.60  0.079  < High school education  < $30,000 yearly income  Percentages based on valid data. Range of missing values (0.0 -18.4%)  4.1.3 S U B S T A N C E USE  Illicit and non-illicit substance use among this group of women was common. In fact, 49.6%, 35.9%o, and 19.5% admitted use, during their pregnancy, of stimulants, opiates,  and other illicit drugs, respectively. While a large proportion of women continued to smoke during their pregnancy (68.4%>), prenatal use of marijuana (22.6%>) and alcohol (23.9%o) were not as heavy. Table 4.3 summarizes substance use among the cohort as  well as for the two groups of interest: those women whose infants experienced an adverse outcome versus those whose infants did not. Significant differences were found between those women whose infants had an adverse outcome and those whose infants did not for stimulant use (p<0.01), opiate use  41  (p<0.001)  as well as methadone use (p<0.001). Almost two-thirds (64.0%) of the  mothers of infants with an adverse outcome admitted to the use of stimulants during their pregnancy while only 40.0% of the mothers of the infants without an adverse outcome reported such use. With respect to opiate use, 57.1% of the adverse neonatal outcome mothers admitted use compared to 22.8%) of the no adverse neonatal outcome mothers. A significant difference  (p<0.01)  was also found between the two groups for tobacco use,  83.0%o versus 59.0%.  However, there was no significant difference for the average  number of cigarettes smoked per day by the women in each group. No significant differences were found between the groups for other illicit drug use, marijuana use, or alcohol use. Crude odds ratios and 95% confidence levels for this data are presented in Table 4.3.  42  Table 4.3: Univariate results for substance use data for those women with an infant with an adverse outcome versus those whose infants had no adverse outcome Substance Used  Cohort n (%)  Adverse  No A d v e r s e  Outcome  Outcome  n (%)  n (%)  Crude Odds Ratio  Lower Upper 95% CI 95% CI  p-value  Current stimulant use Yes  62(49.6)  32(64.0)  30(40.0)  No  63(50.4)  18(36.0)  45(60.0)  Yes  '46(35.9)  28(57.1)  18(22.8)  No  82(64.1)  21 (42.9)  61 (77.2)  Yes  45(33.3)  28(53.9)  17(20.5)  No  90(66.7)  24(46.2)  66(79.5)  Yes  25(19.5)  12(23.5)  13(16.9)  No  103(80.5)  39(76.5)  64(83.1)  Yes  28(23.1)  12(25.5)  16(21.6)  No  93(76.9)  35(74.5)  58(78.4)  Yes  32(23.9)  12(23.5)  20(24.1)  No  102(76.1)  39(76.5)  63(75.9)  Yes  93(68.4)  44(83.0)  49(59.0)  No  43(31.6)  9(17.0)  34(41.0)  2.7  1.27  5.59  <0.01  4.5  2.09  9.78  <0.001  4.5  2.11  9.71  <0.001  1.5  0.63  3.65  0.353  1.2  0.53  2.93  0.619  1.0  0.43  2.20  0.940  3.4  1.46  7.86  <0.01  Current opiate u s e  Current methadone u s e  Current other illicit drug use  Current marijuana use  Use of alcohol over past year  Current t o b a c c o u s e  Avg # cigarettes/day among those currently using tobacco Median (# cigarettes)  10  15  10  Range (# cigarettes)  1.0-40.0  1.0-30.0  1.0-40.0  Percentages based on valid data. Range of missing values (0.0-11.0%)  43  0.122  Table 4.4 provides further detail regarding the substance use patterns of the women in this cohort. It highlights the exclusive and concurrent use of stimulants and opiates. The groups that used both stimulants and opiates, or neither stimulants nor opiates represent the two largest groups in the cohort. In fact, very few individuals, only four, restricted their drug use to opiates during their pregnancy. Table 4.4: Exclusive and concurrent stimulant and opiate use patterns for cohort Substance used  Cohort  Adverse Outcome  No A d v e r s e Outcome  n(%)  n(%)  n(%)  Stimulants only (No opiates)  20(16.4)  5(4.1)  15(12.3)  Opiates only (No stimulants)  4(3.3)  3(2.5)  1 (0.8)  Both stimulants & opiates  39(32.0)  24(19.7)  15(12.3)  Neither stimulants nor opiates  59(48.4)  15(12.3)  44(36.1)  Percentages are for valid data. Missing values 10.3%.  Similarly, there are few individuals who used opiates without the use of methadone, and even fewer who were exclusively maintained on methadone. A larger percentage of the cohort reported the use of both opiates and methadone during their pregnancy. The data for the exclusive and concurrent patterns of opiate and methadone use in this population are presented in Table 4.5. Table 4.5: Exclusive and concurrent opiate and methadone use patterns for cohort uonorc  Adverse Outcome  No A d v e r s e Outcome  n(%)  n(%)  n(%)  «*\ I t «^ >•+  Substance used  Opiates only (No methadone)  12(9.4)  5(3.9)  7(5.5)  Methadone only (No opiates)  9(7.1)  4(3.2)  5(8.2)  Both opiates & methadone  33(26.0)  22(17.3)  11 (8.7)  Neither opiates nor methadone  73(57.5)  17(13.4)  56(44.1)  Percentages are for valid data. Missing values 6.6%.  44  4.1.4 OBSTETRICAL HISTORY  The obstetrical history for the two groups of women was considered in the univariate analysis. There were no statistically significant differences in the gravidity of women in the groups. Similarly, there was no difference in the number of prior preterm births the women in the adverse neonatal outcome group had experienced compared to the women in the no adverse neonatal outcome group. With regard to the current pregnancy of the women, there were no statistically significant differences between the comparison groups for incidence of a pregnancy complication. Comparisons between the two groups for other obstetrical variables, including incidence of a sexually transmitted infection during the current pregnancy and type of delivery also found no statistically significant differences. These results as well as crude odds ratios and 95% confidence intervals are presented in Table 4.6.  45  Table 4.6: Univariate results for obstetrical history data for those women with an infant with an adverse outcome versus those whose infants had no adverse outcome  (%)  Crude Odds Ratio  47(90.4)  70(85.4)  1.6  0.53  4.87  0.395  17(12.7)  5(9.6)  12(14.6)  Yes  12(9.8)  7(15.2)  2.5  0.76  8.57  0.208  No  110(90.2)  39(84.8)  71 (93.4)  Yes  26(19.4)  14(27.5)  12(14.5)  2.2  0.94  5.33  0.065  No  108(80.6)  37(72.6)  71(85.5)  Yes  33(25.6)  16(32.0)  17(21.5)  1.7  0.77  3.82  0.184  No  96(74.4)  34 (68.0)  62(78.5)  Vaginal  91 (67.4)  38(73.1)  53(63.9)  1.5  0.72  3.28  0.266  C-section  44(32.6)  14(26.9)  30(36.1)  Obstetric History  Cohort n  (%)  Adverse  No A d v e r s e  Outcome  Outcome  n  (%)  n  Lower Upper 95% CI 95% CI  p-value  Gravida 117(87.3)  >2 1 Prior preterm birth (< 37 wks)  5(6.6)  Pregnancy complication in current pregnancy  STI during current pregnancy  Type of Delivery  Percentages based on valid data. Range of missing values (0.7 - 1 0 . 3 % )  4.1.5 MEDICAL HISTORY  The data analyzed included medical history variables that could potentially have some influence on the outcome of infants born to women in the cohort. This data included the number and percentage of women that had been diagnosed with HIV, whether the women were HCV PCR positive, and if they had been diagnosed with HBV. No statistically significant differences were found for any of these variables. The univariate results for the medical history data are presented in Table 4.7.  46  Table 4.7: Univariate results for medical history data for those women with an infant with an adverse outcome versus those whose infants had no adverse outcome Medical History  Cohort  Adverse Outcome  No A d v e r s e Outcome  n (%)  n (%)  n (%)  Crude Odds Ratio  Lower Upper 95% CI 95% CI  p-value  HIV diagnosed Yes  19(14.0)  10(18.9)  9(10.8)  No  117(86.0)  43(81.1)  74(89.2)  Yes  102(76.1)  39(75.0)  63(76.8)  No  32(23.9)  13(25.0)  19(23.2)  19(14.3)  9(17.3)  10(12.4)  114(85.7)  43(82.7)  71(87.7)  1.9  0.72  5.07  0.188  0.9  0.40  2.04  0.809  1.5  0.56  3.95  0.425  H C V P C R positive  HBV diagnosed Yes No  Percentages based on valid data. Range of missing values (1.5 - 4.4%)  4.1.6 S E X U A L B E H A V I O U R  The sexual behaviour of the women was compared for those with an infant with an adverse outcome versus those whose infants had no adverse outcomes. The median age at first sexual intercourse was the same for both groups of women, 15.0 years. There were no significant differences found, between the two groups of interest, for the number of sexual partners in the past year or in a subject's lifetime. The data and comparisons presented for these two "number of sexual partner" variables was computed after removal of an extreme outlier from the dataset; one individual answered 500 to 2000 partners in an 18 month period. Similarly, there was no significant difference between the adverse outcome group and the no adverse outcome group for the number of individuals that reported engaging in high risk sexual behaviour. The data for these sexual history  47  variables are summarized in Table 4.8. The crude odds ratio for the variable engaged in high risk sexual behaviour was 2.0 (95% C I : 0.89, 4.73).  Table 4.8: Univariate results for sexual behaviour data for those women with an infant with an adverse outcome versus those whose infants had no adverse outcome Sexual History  Cohort n  (%)  Adverse  No A d v e r s e  Outcome  Outcome  n  (%)  n  (%)  Crude Odds Ratio  Lower Upper 95% CI 95% CI  p-value  Age at first sexual intercourse Median (years)  15.0  15.0  15.0  Range (years)  4.0-25.0  4.0-19.0  7.0-25.0  Median  2.0  2.0  2.0  Range  1.0-6.0  2.0-6.0  1.0-6.0  Median  15.0  20.0  10.5  Range  2.0-100.0  3.0-100.0  2.0-100.0  Yes  70  (63.1)  30  (73.2)  40  (57.1)  No  41  (36.9)  11  (26.8)  30  (42.9)  0.111  # partners in past year 0.057*  # partners in lifetime 0.170*  Engaged in high risk sexual Behaviour 2.0  0.89  4.73  Percentages based on valid data. Range of missing values (0.0 -18.4%) *p-value with extreme outlier removed  4.1.7  SUMMARY  The univariate analyses identified four variables with significant results. The variables current stimulant use, current opiate use, current methadone use, and current tobacco use all yielded significant p-values from chi-square analyses.  48  0.091  4.2  MULTI-VARIABLE ANALYSES  All the variables that were significant in the univariate analyses were initially considered for the multi-variable analysis. In addition, other variables of interest considered for the multi-variable analysis included: age, aboriginal ethnicity, gravidity, and incidence of a pregnancy complication. The inclusion of these variables was dictated by those considered in other studies, as presented in the literature review of this thesis, or by their clinical significance. Aboriginal ethnicity was of particular interest since this study and its' data reflected a study population with a different ethnic distribution than that of past studies. The pregnancy complication variable was considered because of its' potential influence on an adverse outcome as well as the fact that its' p-value (p=0.065) approached significance. The variables to be considered for the multi-variable analysis are listed in Table 4.9.  Table 4.9: List of variables considered for multi-variable analysis Significant Variables  p-value  Current stimulant use  <0.01  Current opiate use  <0.001  Current methadone use  <0.001  Current tobacco use  <0.01  Other Variables of Interest  p-value  Pregnancy complication  0.065  Gravidity  0.395  Age  0.932  Aboriginal ethnicity  0.339  49  4.2.1  MULTI-VARIABLE LOGISTIC REGRESSION  Multi-variable logistic regression was carried out to identify risk factors associated with an adverse neonatal outcome. The logistic regression model (Model 1) included all the variables from Table 4.9 as predictor variables, and the summary measure adverse neonatal outcome as the dependent variable. Univariate Wald test statistics were considered to determine the significant variables in the model. A critical value of 3.84 at a=0.05 was used. The coefficient estimates, Wald statistics, and odds ratios with 95% confidence intervals, for Model 1, are presented in Table 4.10.  Table 4.10. Multi-variable logistic regression results for Model 1 Wald Test Statistic  Adjusted Odds Ratio  Lower 95% CI  Upper 95% CI  0.596  0.02  0.92  0.29  2.97  1.105  0.663  2.78  3.02  0.82  11.07  Current methadone use  0.835  0.559  2.24  2.31  0.77  6.89  Current tobacco use  0.456  0.587  0.60  1.58  0.50  4.99  Pregnancy complication  0.681  0.543  1.57  1.98  0.68  5.73  Age  0.027  0.045  0.35  1.03  0.94  1.12  Aboriginal ethnicity  0.166  0.497  0.11  1.18  0.45  3.13  Gravidity  1.140  0.843  1.83  3.13  0.60  16.31  peta Coefficient  Standard Error  (Intercept)  -3.573  1.546  Current stimulant use  -0.080  Current opiate use  Variable  4.2.2  A.  COLLINEAR VARIABLES  PREGNANCY COMPLICATION  Of interest in Model 1 is the variable pregnancy complication and its' potential relationship to substance use. It was suspected that this variable may represent an  50  intermediary variable between substance use and adverse neonatal outcome, and thus, its' inclusion as an explanatory variable may be inappropriate. To investigate this further a sub-analysis was carried out. The potential relationship between pregnancy complication and substance use was confirmed by the results of an additional univariate analysis. Opiate use was associated (p<0.05) with pregnancy complication in a chi-square analysis. The results of a logistic regression model using pregnancy complication as the dependent or outcome variable support this finding and are presented in Table 4.11 below. Table 4.11: Logistic regression results for model using pregnancy complication as outcome variable Variable  (3eta  Standard Error Coefficient  (Intercept)  -1.836  0.325  Current opiate use  0.905  0.461  Wald Test Statistic  Adjusted Odds Ratio  Lower 95% CI  Upper 95% CI  3.85  2.47  1.00  6.10  The results of this sub-analysis and the relationship between pregnancy complication and opiate use, suggest that pregnancy complication should be excluded from the final model. In a decision to exclude this variable, a comparison of the full model (Model 1) to a reduced model (excluding pregnancy complication) was carried out. Using the likelihood ratio test, it was determined there was no advantage to including pregnancy complication in the model. The reduced model was as good as the full model (p>0.001). A comparison of the log odds ratio for the adjusted and unadjusted models also suggests that excluding this variable results in a better model. The log odds ratio comparison revealed that inclusion of the variable pregnancy complication led to a greater than 10% change for all other explanatory variables.  51  B. METHADONE USE AND OPIATE USE  The relationship between opiate use and methadone use was also considered. It is clear from Table 4.12, that opiate use and methadone use are associated in univariate analysis. It is also evident from this data that the majority of women in this study that used methadone had also used opiates at some point during their pregnancy. Since the data for the timing of opiate versus methadone use was not available, what is important is the fact that they 'currently' used opiates or used opiates during their pregnancy. This may mean that the association of methadone with adverse neonatal outcome in the univariate analysis is actually driven by the subjects' opiate use. The highly correlated relationship between current opiate use and current methadone use dictated that methadone use be removed from the model. The likelihood ratio test (p>0.001) and a comparison of the log odds ratio for the adjusted and unadjusted model (>10% change in predictor variables) supported this decision.  Table 4.12: Univariate comparison of opiate use with methadone use  Current methadone use  Opiate vs. Methadone Use  Current opiate use  YES  NO  YES  33  12  NO  9  73  p<0.001  C. STIMULANT USE AND OPIATE USE  It is evident from Table 4.4, and Table 4.13 below that the variables opiate use and stimulant use are also highly correlated. Based on the a priori objectives of this study, however, it was determined that neither of these variables should be excluded from the  52  logistic regression model. Excluding one of these substance use variables would have meant the omission of a main explanatory variable, and that a key risk factor remained unexplained.  Table 4.13: Univariate comparison of opiate use with stimulant use  Current stimulant use  Opiate vs. Stimulant U s e  Current opiate use  YES  NO  YES  39  4  NO  20  59  p<0.001  4.2.3 INTERACTION TERMS  As previously discussed, a number of substances included in this model may have been used concurrently. In fact, as suggested by the data in Table 4.4, concurrent use of stimulants and opiates is especially prevalent among the women in this cohort. For these reasons, it was necessary to investigate the relationship between the substance use variables further. To this end, a number of interaction terms were introduced into the model. All possible two-way interaction terms for current stimulant use, current opiate use, and current tobacco use as well as a three-way interaction term were considered. None of the interaction terms were found to be significant and therefore, none were included in the model. 4.2.4 FINAL MODEL  The final model for predicting neonatal outcome is as presented in Table 4.14. Current stimulant use, current opiate use, current tobacco use, age, aboriginal ethnicity, and gravidity are included as explanatory variables for the dependent variable adverse  53  neonatal outcome. The regression coefficients obtained through the logistic regression "indicate the effect of an individual variable on the log odds of the outcome event with all the remaining variables held constant. The coefficient denotes the magnitude of the increase or decrease in the log odds produced by one unit change in the value of the regressor variable".  170  From the model, current opiate use is independently associated with adverse neonatal outcome, odds ratio 5.52 (95% CI: 1.82, 16.76). For tobacco use during pregnancy, an odds ratio of 2.27 (95%> CI: 0.79, 6.58) was observed; however, this association was not statistically significant. A non-significant result was also observed for current stimulant use. Moreover, the effect of stimulant use during pregnancy appears to be protective OR 0.69 (95%>CI: 0,23, 2.08). Age, aboriginal ethnicity, and gravidity were not significant in the final model. The number of events per variable for this model was 7.5 EPV.  Table 4.14: Multi-variable logistic regression results for final model Variable  Standard peta Error Coefficient  Wald Test Statistic  Adjusted Odds Ratio  Lower 95% CI  Upper 95% CI  (Intercept)  -3.745  1.460  Current stimulant use  -0.369  0.562  0.43  0.69  0.23  2.08  Current opiate use  1.708  0.567  9.08  5.52  1.82  16.76  Current tobacco use  0.822  0.542  2.30  2.27  0.79  6.58  Age  0.047  0.043  1.18  1.05  0.96  1.14  Aboriginal ethnicity  0.180  0.451  0.16  1.20  0.49  2.89  Gravidity  0.830  0.767  1.17  2.29  0.51  10.32  A regression model using the alternate explanatory variables, # partners in past year, HIV diagnosis, and STI during current pregnancy is also included here for comparative purposes. As with the model presented above, opiate use remained 54  significant in the model with a similar odds ratio. There was little change in the odds ratios for the variables stimulant use and tobacco use. See Table 4.15.  Table 4.15: Multi-variable logistic regression results for alternate model Wald Adjusted Standard Beta Lower Variable Test Odds Error Coefficient 95% CI Statistic Ratio  Upper 95% CI  (Intercept)  -1.812  0.742  Current stimulant use  -0.849  0.686  1.54  0.43  0.11  1.64  Current opiate use  1.698  0.687  6.11  5.46  1.42  21.00  Current tobacco use  0.959  0.550  3.04  2.61  0.89 .  7.67  # of partners in past year  0.142  0.279  0.26  1.15  0.67  1.99  HIV diagnosed  0.634  0.696  0.83  1.89  0.48  7.38  STI during current pregnancy  -0.155  0.565  0.08  0.86  0.28  2.59  4.3  POWER  Power is the probability of rejecting the null hypothesis when H o is false.  171  Or in  other words, the ability of a study to demonstrate an association if one exists. The 93  observed power for this study for current stimulant use and adverse outcome was computed to be 0.69. The observed power for current opiate use was computed to be 0.97. In order to achieve a power of 0.80 for stimulant use and adverse outcome, and based on the proportions observed in this study, one would need a sample size of at least 61 subjects in the adverse neonatal outcome group. This thesis study was limited by the sample size available from the primary study.  55  C H A P T E R 5 - DISCUSSION A N D I M P L I C A T I O N S 5.1  S U M M A R Y O F FINDINGS  The HCV Vertical Transmission study database has provided detailed insight regarding substance use, obstetrical and medical history, and a wide range of lifestyle characteristics among a group of hepatitis C positive pregnant women. In particular, this data highlights the fact that these pregnant women, living in British Columbia, report high use of stimulants, opiates, methadone, and tobacco during their pregnancies as well as high levels of concurrent substance use. The data also reveals that the infants of this group of women suffer high incidences of adverse neonatal outcomes. When comparing those women with an infant with an adverse outcome versus those with no adverse neonatal outcome, it is clear that substance use is an important risk factor for poor outcome in neonates. In fact, the crude odds ratios (95% CI) for stimulant use, opiate use, methadone use, and tobacco use are 2.7 (1.27, 5.59), 4.5 (2.09, 9.78), 4.5 (2.11, 9,71), and 3.4 (1.46, 7.86) respectively. In interpreting these univariate results it is important to recognize that concurrent use of these substances is extensive among this group of women. Employing a multi-variable approach is necessary. Such an approach is, however, complicated by the number of variables that may influence adverse neonatal outcomes as well as the relationships between these various explanatory variables. Of interest in this analysis, was the role of the variable pregnancy complication. In the univariate analysis this variable approached significance as a risk factor for an adverse neonatal outcome and thus, this variable was originally included as an explanatory variable. However, the potential link between opiate use and various  56  pregnancy complications raised the question of whether this variable could possibly be an intermediary or alternate outcome variable. An analysis of the association of opiate use with pregnancy complication confirmed the relationship between these two variables and the variable pregnancy complication was excluded from the final model. The methadone use variable was also of particular interest in determining the final model. Efforts are often made to prescribe methadone to opiate users. These efforts are particularly important during pregnancy since regular methadone maintenance may help stabilize the often-chaotic lifestyles of drug users. In the case of pregnant women, this may lead to more regular prenatal care. However, for this study the timing of methadone use was not recorded and therefore, one cannot confidently separate those individuals that may have achieved a less chaotic lifestyle. Furthermore, since the majority of methadone users had admitted use of opiates during their pregnancy it is possible that the association of methadone and adverse outcome is in fact, driven by the use of opiates. Since methadone use and opiate use were potentially measures of the same risk, methadone use was excluded from the final model. In interpreting the association of opiate use with adverse neonatal outcome, however, one must still be aware of the potential influence of methadone. Since a substantial number of opiate users were prescribed methadone in efforts to ensure more regular prenatal care and better outcomes for their infants, the odds ratio observed for opiate use may in fact, underestimate the true association with adverse neonatal outcome.  57  Perhaps the most notable finding of this study is the fact that current opiate use remained independently associated with adverse neonatal outcome in the multi-variable analysis, OR 5.52 (95% CI: 1.82, 16.76). That is, women who continue to use opiates during their pregnancy are at a 5.52 increased odds of delivering a baby who will experience an adverse neonatal outcome. These results support the findings of past researchers who have found statistically significant differences in adverse neonatal outcomes between their study and comparison groups.  ' " These past studies did  28,29-32-34 36  37  not, however, employ multi-variable approaches. Therefore, this analysis offers additional insight by providing a measure of the association between opiate use and adverse neonatal outcome. Clearly the effects of opiate use during pregnancy are of grave concern to the neonates of these women. The results of this study establish that opiate use is clearly predictive of adverse outcome, however, the review provided in this thesis and the univariate analysis led to the a priori  expectation that stimulant use and tobacco use would also prove independently  associated in a multi-variable model. Bearing in mind that the result is non-significant, the odds ratio for stimulant use is counter-intuitive and suggests a protective effect OR 0.69 (95%> CI: 0.23, 2.08). This is consistent with the results of Richardson et al and Miller et al who reported no association of cocaine use with prematurity or low birth weight.  66,69  In fact, Miller et al report results of similar magnitude which are also non-  significant. They present an odds ratio for cocaine use and prematurity of OR 0.6 (95%> CI 0.2, 1.9), and for cocaine use and low birth weight of 1.2 (0.4, 3.6), both adjusted for other risk factors including opiates, tobacco, maternal race, maternal age, and parity. In 69  contrast, Bateman et al adjusted for a similar list of risk factors and found odds ratios  58  (95% CI) of 1.94 (1.21, 3.11) and 2.10 (1.23, 3.67) for prematurity and low birth weight respectively. Kistin et al reported considerably higher relative risks (95%CI) of 4.0 70  (2.3, 7.0) for prematurity and 5.3 (3.0, 9.3) for low birth weight. These latter two studies adjusted for maternal race, maternal age, and gravidity, and excluded all subjects that had used heroin or tobacco.  68  One possible explanation for the results of this thesis analysis is that there were too few subjects reporting exclusive use of stimulants or opiates to appropriately control for the separate effects of these substances. In fact, there were only 4 subjects that reported using opiates without the concurrent use of stimulants. This extensive overlap in stimulant use and opiate use may have resulted in a model that is able to estimate the overall effect on adverse neonatal outcome but is not able to accurately determine the contribution made by each individual substance variable. Furthermore, although the collinearity of the stimulant and opiate use variables presented challenges for this analysis, it is an important finding that such a large proportion of women used both substances during their pregnancy. High rates of concurrent drug use are recognized throughout the literature and this study confirms this behaviour among pregnant women in the province of British Columbia. In light of this, it is clear that concurrent use must be appropriately accounted for when educating female drug-users as well as in detoxification efforts. It should also be a consideration for future research.  The odds ratio (95%CI) observed for tobacco use and adverse neonatal outcome was 2.27 (0.79, 6.58). This indicates that women who smoke during pregnancy are at  59  increased odds of having an infant with an adverse neonatal outcome; however, the result is not statistically significant. This finding is consistent with the well-documented increased risk of prematurity and low birth weight among smokers. " 172  178  The non-  significance of the result is likely related to insufficient power.  5.2  UNIQUE CONTRIBUTIONS  There are several studies using a multi-variable approach to determine the association between cocaine use during pregnancy and adverse neonatal outcomes. However, none of these studies published results for opiate use during pregnancy and such outcomes. Consequently, this study makes a very unique contribution by presenting a measure of the association between opiate use and adverse neonatal outcome. This thesis study has also provided several other unique contributions. Among the studies related to maternal drug use during pregnancy and adverse neonatal outcomes, there are few studies that have been conducted in Canada and, at the time of this thesis literature review, none in British Columbia. Most studies have been conducted in the USA. When one considers the differences the health care systems and approaches to illicit drug use it is evident that a study conducted in Canada will provide our health care workers with additional insight when caring for their patients. It will also provide policy makers with a Canadian perspective of this health care issue so they can be confident their decisions are appropriate for our nation's population. Not only is this study unique in its study setting, but the study population is distinct from that of past studies. The HCV Vertical Transmission Study offered the opportunity  60  to study neonatal outcomes in a population of pregnant women living with Hepatitis C; a population that may have special medical concerns during pregnancy. This thesis is also unique with respect to the extensive list of patient characteristics that were considered as risk factors for adverse neonatal outcomes. Few studies have considered such a comprehensive set of patient attributes. Inclusion of all these factors clearly illustrates that the complexity associated with this outcome measure has been recognized by this study. A neonate's health can be affected by a variety of exposures and maternal characteristics and thus, the need to account for multiple substance use in addition to demographic and obstetrical characteristics.  5.3  5.3.1  STUDY LIMITATIONS  UNAVAILABLE EXPLANATORY VARIABLES  The secondary analysis for this thesis project was limited to the data collected by the primary study questionnaire. Although the Hepatitis C Vertical Transmission Study provided a rich data source, some additional explanatory variables would have enhanced the analyses described above.  A.  S U B S T A N C E USE DETAILS  A measure to assess the amount and frequency of drug use throughout pregnancy would be particularly useful in enhancing this analysis. Detail of this level would allow a doseresponse relationship to be established. Demonstrating such a relationship, that as the dose of drug exposure increases the risk of adverse outcome increases, would provide 180  very strong evidence for a causal relationship.  In addition, timing of drug use, for  example identifying the trimester of use, would also be informative. The developmental 61  stage at which the drugs were used may play an important role in the outcomes observed. As well, timing of use would allow a distinction to be made between women who continued their drug-using habits, versus those who ceased using or successfully maintained a methadone program. B. PRENATAL CARE AND NUTRITION  Prenatal care and adequate nutrition during pregnancy are both important factors that may have some influence on neonatal outcomes. Therefore, questions to establish that adequate care and nutrition were received would also provide valuable data and useful additions to the list of explanatory variables. 5.3.2  EXTERNAL VALIDITY  The primary study was designed to capture the population of HCV positive pregnant women in our province. It is from this population that the sub-population of current drug-using women was identified. Since a proportion of drug-using women may not seek any prenatal care until the on-set of labour, this cohort likely represents more stable drugusing pregnant women. It is reasonable to assume that the sub-group in this study would be comprised of those women with less extreme drug-using habits who have at least sought some health care during their pregnancy as opposed to some women who have such chaotic lifestyles that they would not be able to access any health care or this study. Therefore, any estimates of association between drug use and outcomes presented in this thesis are more likely to underestimate rather than overestimate the association. It is also important to note that this cohort captures only those women who are concurrently HCV infected. For this reason, the studies comprising this thesis may not be  62  generalizable to the entire population of drug-using pregnant women. However, the prevalence of HCV positivity among (intravenous) drug-users is approximately 80% and therefore, identification of HCV positive pregnant women is likely to capture a large proportion of those women who use drugs during their pregnancy.  104  Nonetheless, this  study will be biased to include women who have been involved in injection drug use, while drug using women who have never injected may not be represented. 5.3.3  SELF-REPORT AND R E C A L L BIAS  A large proportion of the information collected for this study was ascertained by selfreport and therefore, is subject to the honesty of the participants in reporting their answers. Of particular concern is the truthfulness of participants regarding their drug use history during pregnancy. The potential for these types of untrue responses have, however, been minimized by efforts to ensure confidentiality and anonymity, and by the nature of the relationship between the study nurse and the women. In addition to collecting data, the study nurse acts as a counselor and advocate, and thus promotes a strong relationship of trust with the participants. This relationship is demonstrated by the high retention rates achieved for this challenging cohort.  179  Self-reported drug history is also subject to recall or reporting biases due to memory failure.  93  This may be due to the effects of the drugs used or a result of the time that may  have elapsed since the event. Time elapsed makes it more difficult to remember exact dates and may result in drug use that occurred during pregnancy being reported as prior to pregnancy.  63  5.3.4  SAMPLE  SIZE  The sample size of this analysis was restricted to the number of participants that were enrolled in the primary study. Furthermore, the analysis for this thesis identified two groups of women from the original study cohort. Since this identification was guided by responses of self-reported drug use from the original questionnaire, it was subject to missing and ambiguous responses that further reduced the sample size.  Small sample size has several implications. First, it will result in a loss of power to the study; that is, the probability that the null hypothesis will be rejected if it is in fact false. This affects the ability of the study to demonstrate an association if one exists.  93  Secondly, small sample size may yield a smaller number of outcome events. The number of events per variable needs to be considered in the multi-variable analysis and a smaller number may require restriction of the number of variables that can be entered into the model.  For this analysis, the number of outcome events at the onset of the study was 53; however, due to missing data the number of outcome events retained in the multi-variable analysis was only 45. Therefore, the number of explanatory variables that could be introduced was limited by the small sample size and subsequent reduced number of adverse events. However, with only 45 events the model was still able to include all the predictor variables that were significant in the univariate analysis as well as additional demographic and obstetric variables of interest.  64  5.3.5  COLLINEARITY  The main study variables in this analysis, stimulant use and opiate use, demonstrated a collinear relationship, primarily a result of high rates of concurrent substance use. This analysis was a secondary analysis and was, therefore, restricted to the data from the primary study. Little could be done to rectify the collinearity between these variables, unless important predictors had been omitted. Future studies should be aware of the potential relationships between explanatory variables. It is likely, however, that little can be done to resolve this issue since it is dependent on the study population and the extent to which they use substances concurrently. High rates of concurrent substance use are well recognized among illicit drug users as previously discussed in the literature review of this thesis.  5.4  IMPLICATIONS  This study provides evidence that the infants of pregnant drug users suffer increased adverse neonatal outcomes. The results of this study, therefore, reinforce the importance of services to reduce drug use among drug-addicted mothers. Among the facilities that offer services and care to pregnant women with substance use problems is Fir Square; a combined care unit at B C Women's Hospital that is staffed by specially trained doctors and nurses. Its initiatives aim to reduce drug use and improve perinatal outcomes, and include a harm reduction approach that facilitates access to methadone maintenance programs.  181  This study highlights the need for continued government support of such  programs as well as improved efforts to increase awareness in the community about the services offered.  65  In addition, this study serves as a reminder that concurrent substance use is high among substance-using pregnant women, including those in our province. Thus, social workers and health care providers, in BC, need to consider multiple substance use while continuing their efforts to reduce drug use and improve the health of these mothers and their babies. 5.5  FURTHER RESEARCH  While the results of this study are interesting continued research in the area is necessary. From the study limitations described above, it follows that any subsequent studies should address these limits. A prospective cohort study with an increased sample size would be an ideal follow-up to this thesis study. A larger study sample would provide increased power for the study as well as allow for additional sub-analyses, particularly on the individual neonatal outcomes. A study that provides additional data regarding drug use details would enhance the analysis and offer a means of establishing a dose-response relationship. As well, inclusion of a method to assess the validity of selfreported answers would be useful; for example, using urine samples to detect drug use.  5.6 CONCLUSIONS  This study has provided a comprehensive descriptive profile of pregnant women living with hepatitis C in British Columbia. This profile includes patterns of illicit and licit substance use, sociodemographic characteristics, obstetrical and medical data, and sexual behaviour. 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Maintaining challenging cohorts: A report on the recruitment methods and successes of following pregnant, hepatitis C-positive women for up to two years in British Columbia, Canada. Proceedings of the International Society for Sexually Transmitted Disease Research Congress; 2003 July 27-30; Ottawa, Canada. Abstract No. 0532. Gordis L. Epidemiology. 2 Ed. W.B. Saunders Company: Toronto; 2000. nd  Fir Square Combined Care Unit. BC Women's Hospital and Health Centre. http://www2.vpl. vancouver.bc.ca/DBs/RedBook/orgPgs/1 / l 1185.html  87  APPENDIX 1: H E P A T I T I S C V E R T I C A L TRANSMISSION S T U D Y B A S E L I N E Q U E S T I O N N A I R E  HCV QUESTIONNAIRE Subject code:  Date of interview:  (DD/MM/VY)  / would like to ask you a number of questions about yourself and your pregnancy, including general information and medical history. In order to determine any possible factors that may be involved in transmission of hepatitis C from mother to infant and also to identify potential factors that may have been involved in your infection, I would like to ask detailed questions regarding any possible drug use exposure, about other possible sources such as tattooing and details about types of sexual exposure. Some of these questions may seem completely unrelated to you, but all study participants will be asked the same questions. Some of these questions may make you uncomfortable, so I want you to know that you are free to refuse to answer any of them at any stage. This interview should take approximately 30-60 minutes, depending on any questions you may have, (interviewer make note of questions either not asked or not answered)  SECTION A Demographics In the following section I will be asking you some general questions about your background. If you are uncomfortable with any of the questions, please let me know and we can skip a question or stop at any time. 1. Birthdate:  (DD/MM/YY)  3. S e x : 1.  Male  2.  Female  2. Age: 3.  Transgender  4. "How would you d e s c r i b e your current marital s t a t u s ? " 1.  Single  2.  Married  5.  4,  Widowed  Separated  3.  Divorced  6.  Living with partner > 1 year  5. Ethnic group: "How would you d e s c r i b e your ethnic background?" 1.  Caucasian  2.  Black  3.  South Asian  4.  Asian  5.  Hispanic  6.  F i r s t Nations/aboriginal (please indicate one of t h e following) •  Status  •  Non-status  •  Metis  •  Inuit  •  O t h e r - specify 88  7.  O t h e r - specify  6. Place of b i r t h : 1.  Canada  7.  Africa  2.  USA  8.  Asia  3  Caribbean  9.  A u s t r a l i a / P a c i f i c Islands  4.  C e n t r a l / S o u t h America  10.  5.  W e s t e r n Europe  6.  E a s t e r n Europe  other - specify  7. I f born outside of Canada, year of arrival in Canada: 8. Postal code ( f i r s t 3 l e t t e r s ) 9. Occupation: current 10.  Ever  _  11. Age when stopped fulltime attendance in school: 12. Last education completed: 1.  grade/elementary school  2.  high school  3.  college/university: years completed  13. Yearly gross household income 1.  < $10,000  3.  $30,000 - 50,000  2.  $10,000-30,000  4.  > $50,000  14. Social assistance/welfare  No  Yes - category (i.e. disability)  SECTION B Obstetrical - Gynaecological  History  In this section I would like to ask you some questions about your current pregnancy, past pregnancies, and your gynaecological history. If you are uncomfortable with any of the questions, please let me know and we can skip a question or stop at any time. 1. L M P  (DD/MM/YY)  Sure  2. Cycle length 3. Date of positive pregnancy t e s t  (DD/MM/YY)  4. Did you have pre-pregnancy counselling?  Yes  No  5. Did you take folic acid prior to conception ? Y e s  No  6. Current gestational age: 7. Number of f e t u s e s ? 11. I V F ? 1.  yes  wks  8. Singleton 12.  9. Twins  10. Multiples  no  13. When is your expected delivery date?  (DD/MM/YY)  89  14. I f this is not your f i r s t pregnancy, describe each pregnancy outcome, starting with most recent: Preg. No. 0 = currently preg 1 = live b i r t h  2  2 = induced abortion  3  3 = neonatal death (<28 days pp)  4  4 = s t i l l b i r t h (>= 20 wks gest)  5  5 = spontaneous abortion (< 20 wks)  6  6 = tubal or ectopic pregnancy  7  7 = hydatidaform mole  8  ( &  P  Outcome Gest. (wks)  Date ( M M / Y Y )  Mode  1  L  SA  TA  )  15. I f you have any other children, please answer oldest:  the following f o r each child, starting f r o m the  (it may be useful to ask the woman the d a t e / y e a r t h a t she was diagnosed with H C V at this point) C H I L D #1 Date of b i r t h :  (DD/MM/YY)  B e f o r e or a f t e r H C V diagnosis? Mode of delivery:  Sender:  before  Male  Female  after  SVD  IVD  forceps  scalp monitor  elective C S - reason: emergency C S - reason: Breast f e d ?  Yes  T e s t e d f o r HCV?  No No  Yes - d a t e / r e s u l t :  •  Other problems?. CHILD #2 Date of b i r t h :  (DD/MM/YY)  B e f o r e or a f t e r H C V diagnosis? Mode of delivery:  Sender:  before  Male  Female  Male  Female  after  SVD  IVD  forceps  scalp monitor  elective C S - reason: emergency C S - reason: Breast f e d ?  Yes  T e s t e d f o r HCV?  No No  Yes - d a t e / r e s u l t :  \  Other problems?. CHILD #3 Date of b i r t h :  Gender.  (DD/MM/YY)  Before or a f t e r H C V diagnosis? Mode of delivery.  SVD forceps  before  after  IVD scalp monitor  elective C S - reason: emergency C S - reason: Breast f e d ?  Yes  No  90  T e s t e d f o r HCV?  No  Yes - d a t e / r e s u l t :  O t h e r problems?  .  CHILD #4 Date of b i r t h :  (DD/AAM/YY)  B e f o r e or a f t e r H C V diagnosis? Mode of delivery:  Gender:  before  Male  Female  after  SVD  IVD  forceps  scalp monitor  elective C S - reason: emergency C S - reason: Breast f e d ?  Yes  T e s t e d f o r HCV?  No No  Yes - d a t e / r e s u l t :  O t h e r problems?  :  16. Do you plan to b r e a s t f e e d this child?  Yes  No  I f no, reason f o r not breastfeeding? H C V status  Personal  17. Early pregnancy complications: 1.  Nausea/vomitting  2.  Bleeding  3.  Infection  18. Late pregnancy complications? 1.  Gestation hypertension  7.  Too little fluid around the baby  2.  Gestational diabetes  8.  Too much fluid around the baby  3.  P r e t e r m labor  9.  Placental abruption  4.  Premature cervical dilation  10.  Placenta previa  5.  Rupture of the membranes  11.  Other  6.  Growth problems of the baby  19. Did you have any of the following? 1.  Maternal serum screening - date  2.  Amniocentesis - date  3.  Chorionic villus sampling - date  (DD/MM/YY) (DD/MM/YY) (DD/MM/YY)  20. Did you have prenatal ultrasound y e t ? Date  Yes  No  Place  Findings  1. 2. 3. 4. 21. Have you had any of the following infections in pregnancy? 1.  Urinary t r a c t infection  6.  2.  Yeast infection  7.  Syphillis  3.  Bacterial Vaginosis  8.  Genital W a r t s  4.  Trichomonas  9.  Herpes  5.  Chlamydia  10.  Other  91  Gonococcal  22. Beginning with the most recent, list the d i f f e r e n t kinds of B I R T H C O N T R O L methods you have used. Give the total number of months used f o r each method. Specify: ( B C P / I U D / c a p / e t c )  Method  Months used  1. 2.  '  3.  •  4.  5. 6. 7. 8.  SECTION C Medical History In this section I would like to ask you some questions about your medical and health history. If you are uncomfortable with any of the questions, please let me know and we can skip a question or stop at any time. 1. Do you have any medical problems t h a t we should be aware o f ? 1.  Hypertension  2.  Diabetes  3.  Others  2. Have you had any operations?  Yes  3. Did you have any complications f r o m surgery?  No Yes  No  I f yes, details: 4. Do you currently take any medications? 1.  Prescription  2.  OTC  3.  Herbal?  4.  Other:  5. A r e t h e r e any diseases that run in your family? (provide details o f what and who)  6. Does anyone in your immediate family have H C V infection? (who)  7. " W h a t year did you receive your f i r s t HCV+ t e s t ? " :  92  8. "What was t h e reason t h a t you had t h e t e s t ? " : 1.  jaundice  4.  unexplained hepatitis  2.  pregnancy  5.  high risk behaviour - specify  3.  transfusion history  6. O t h e r 9. Estimated year of infection: 10. Year of jaundice illness: 11. Current treatment?  —  12. "Have you ever been diagnosed with any o f t h e following?": 1. 2.  HBV HAV  3.  HTLV  4.  O t h e r - specify  13. Have you ever been t e s t e d f o r H I V ?  Yes N o  14. Have you ever had a positive H I V t e s t ? Y e s  No  15. Date: 16. I f yes, have you ever had treatment f o r your H I V ?  Yes  17. A r e you currently on medication f o r your H I V ? Y e s  No No  18. Details:  19. "Have you ever been diagnosed with any other type of liver disease, such as:" 1. Drug/medication etiology 4. . alcohol-related 2. 3.  gallstones autoimmune  5.  o t h e r - specify  20. I f "yes" to # 4 above, can you describe f o r me your alcohol-related medical history? (narrative):  SECTION D Behavioural / risk factors In this section, I would like to ask you about some of the lifestyle practices and known risk behaviours that have been linked to hepatitis C transmission. If you are uncomfortable with any of the questions, please let me know and we can skip a question or stop at any time. 1. Have you ever smoked cigarettes?  Yes  No  2. I f yes, how old were you when you s t a r t e d ? 3. Do you still smoke? Y e s  No  4. I f no, how old were you when you quit? 5. W h a t is t h e average number of cigarettes you smoke(d) per day?  93  6. W h a t has been your usual use of each of t h e following during the past year: 1.  Beer (12 oz bottles per week)  2. 3.  Wine (4 oz glasses per week) Liquor (1.5 oz drinks per week)  7. "Have you ever had a blood transfusion?"  Yes  No  8. I f yes, f o r each transfusion: Date ( D D / M M / Y Y )  # units  9. Have you ever been a blood donor? Y e s *  No  10. Dates:  * N O T E : I t is standard practice to request permission f r o m HCV+ blood donors to notify the Canadian Blood S e r v i c e 11. Have you ever been hospitalised, had a major accident, or had surgery (including c-sections)? Yes No Date  Location  12. Have you ever had hemodialysis?  Reason  Yes  No  13. Years 14. A r e you or have you ever been a health care worker? 15. Have you ever had a needlestick injury? Yes  Yes  No  No  16. I f yes, date(s): 17. Have you ever had any other type of potential exposure to another person's body fluids (i.e. sputum or vomit, exposures to eyes, contact with broken skin)?  No  Yes  18. I f yes, please describe and date(s):  19. Have you ever had any other type of potential exposure to another person's body fluids through any other type of work (i.e. sputum or vomit, exposures to eyes, contact with broken skin)? No  Yes  20. I f yes, please describe and date(s):  21. A r e you aware whether or not your mother is infected with hepatitis C?  94  Yes  No  22. "Have you ever experimented with or used injection drugs?" Y e s N o 23. I f yes, have you ever shared needles? # of years using: 1.  < 1 year  3.  6 - 1 0 years  5.  2.  1 - 5 years  4.  11 - 20 years  > 20 years  24. W h a t , i f any, o f t h e following drugs have you used? 1.  Crack cocaine (dates:  2.  nasal cocaine (dates:  3.  Subcutaneous (skin popping) drugs  4.  Heroin (dates:  5.  Other  ) ) (dates:  )  ) (dates:  )  25. Do you have any tattoos or body branding? Y e s N o 26. I f yes, were they done at a licensed tattooing f a c i l i t y ?  Yes  No  35. Have you ever had a medical injection in a developing country? 36. I f yes, country  Yes  27. O t h e r location; 28. Dates: 29. Have you ever had any body piercing? 30.  ears only  31.  other - specify  Yes  No  32. Dates: 33. Have you ever had acupuncture? Y e s  No  34. Dates: No  37. Dates: 38. A r e you aware of any members in your household that are infected with HCV?  Yes  No  39. I f yes, what is your relationship to this person? 40. Have you shared with household members: 1.  Toothbrush?  2.  Razor?  SECTION E Sexual history In the next sectional would like to ask you some questions about your sexual practices.  I know  that these questions may make you feel uncomfortable or embarrassed, but all study participants will be asked these questions because they can be related to information about hepatitis C transmission.  I want to remind you that all the information you share is confidential and that  you are free to refuse to answer any questions that make you 1. A r e you currently in a sexual relationship(s)?  Yes No  2. I f yes, length of current relationship 95  uncomfortable.  3. Do you have any children? 4. Ages:  Yes  5. Any children with HCV? Yes  No No  6. How would you describe your sexual orientation? 1.  Heterosexual  3.  Bisexual  5.  2.  Gay/lesbian  4.  Transexual/transgender  Other  7. How many sexual partners have you had in the past year? 1.  none  4.  6 to 10  2.  one  5.  more than 10  3.  2 to 5  6.  not sure  8. How many sexual partners have you had in t h e past five years? 1.  none  4.  6 to 10  2.  one  5.  more than 10  3.  2 to 5  6.  not sure  9. How many sexual partners have you had in t h e past 10 years? 1.  none  4.  6 to 10  2.  one  5.  more than 10  3.  2 to 5  6.  not sure  10. How many sexual partners have you lived with in the past year? 1.  one  2.  two  3.  more than two  11. How many sexual partners have you lived with in t h e past five years? 1.  one  2.  two  3.  more than two  12. How many sexual partners have you lived with in the past 10 years? 1.  one  2.  two  3.  more than two  13. How many sexual partners have you had in your lifetime?: 14. How old were you when you f i r s t experienced sexual intercourse?: 15. How long have you been in your current sexual relationship? 16. Have you ever had sex with someone you know has used injection drugs? Yes  No  Dates: 17. Have you ever had sexual contact with gay/bisexual men? Yes  No  Dates: 18. Have you ever had sex with someone with genital herpes or who had genital sores? Y e s Dates:  No  19. In the past 12 months have you had sex with someone whose sexual background whose sexual background you don't know? Yes No 20. In t h e past 12 months have you had sex with anyone who may be at an increased risk f o r getting A I D S , H I V or Hepatitis infections f r o m t h e i r sexual practices or other high risk activities? Yes No 21. Have you ever had any sores or ulcers on your penis/vagina or genital area? Yes  No  22. Have you ever had any of the following: 1.  syphillis  4.  chlamydia  2.  gonnorhea  5.  genital warts  3.  genital herpes  6.  any other sexually transmitted disease - specify  96  23. Have you ever had sex with someone who you knew had hepatitis C? Yes  No  Dates: 24. Have you ever had sex with a male or female prostitute? Yes  No  Dates: 25. Have you ever paid or received money f o r having sex? Yes  No  26. Have you ever given or received sex f o r drugs?  No  Yes  I would now like to ask a few questions about the specifics of sexual practices. Again, if any of these questions make you uncomfortable f e e l f r e e to skip questions or stop at any time. 27. Do you or your live-in sexual partner use a condom?  Yes No  28. I f yes, what proportion of the time? 1.  all of the time  3.  some of the time  2.  most of the time  4.  never  29. Do you use a condom when you have sex with a partner you are N O T living with? Yes 30. I f yes, what proportion of the time? 1.  all of the time  3.  some of the time  2.  most of the time  4.  never  31. Have you ever participated in oral sex? 1.  active  2.  Yes  No  No  passive  W i t h i n the past year? Yes  No  32. Have you ever participated in anal sex?  Yes  No (if " N O , " skip the following question  regarding fisting) 1.  insertive ("top")  33. Within the past year?  2. Yes  receptive ("bottom") No  34. Have you ever participated in fisting? 1.  active  2.  35. Within the past year?  Yes  passive Yes  No  36. Have you ever participated in oral-anal sex ("rimming")? 1.  active  2.  37. Within the past year?  No  Yes  No  passive Yes  No  38. I s t h e r e any other information about your history t h a t we have not asked about that you think may be important f o r our study? 39. W h a t have you been told about the transmission of hepatitis C f r o m mother to infant?  97  A P P E N D I X 2: HEPATITIS C V E R T I C A L TRANSMISSION STUDY M A T E R N A L QUESTIONNAIRE  FOLLOW-UP  Study I D Number:  H C V Vertical Transmission Study Maternal Data Form  Date of completion: ( M M / D D / Y Y ) : 1111  1  I  Maternal data f o r m completed by: Section A : BASELINE CHARACTERISTICS 1. Gravity: 2. Parity: 3. Date of last menstrual period (MM/DD/YY):  r m  4. Estimated date of conception (MM/DD/YY): 5. Gestational age (in weeks) at study enrolment: 6. Date of HCV diagnosis (MM/DD/YY) Section B: T E S T S PERFORMED DURING PREGNANCY 1. Rh:  positive  2. Amniocentesis •  negative •  yes •  no  I f yes, when was this test performed? at Reason(s): 98  weeks.  •  Were any abnormalities indicated? I I f yes, specify:  I yes I  I no  3. Additional information about tests performed during pregnancy  4. Hepatitis B (antibody +) LZH •  yes LZ]  If yes, was it treated?  no  Hepatitis B (sAg+)  no Year of diagnosis: I  Comments:  5. HIV (antibody +) •  •  yes •  no  I I I I  no  I f yes, is it being treated?  no Year of diagnosis: I  L  Comments: 6. RPR (Syphilis) •  •  yes •  no  If yes, is it being treated?  no Year of diagnosis:  Comments: 7. Varcella (Chicken Pox) •  •  yes •  no  If yes, is it being treated?  no Year of dlagnosis:  Comments:  Section C: A N T E N A T A L INFECTIOUS DISEASES 1. Candida (vaginal) •  If yes, was it treated?  •  yes •  no no Year of diagnosis  Comments:  99  O  n  2. Bacterial Vaginosis •  •  yes •  no  If yes, was it treated?  n  no Year of diagnosis:  Comments: 3. CMV •  yes I  no  I  If yes, was it treated?  no Year of diagnosis:  Comments: 4. Genital herpes •  I  I yes I  I no  If yes, was it treated?  no Year of diagnosis:  Comments: 5. Other Antenatal infectious diseases? • •  yes •  no  If yes, specify (i)  Was it treated?  •  yes •  no Year of diagnosis: 1  1  Comments: •  If yes, specify (ii)  Was it treated? Comments:  •  no Year of diagnosis: ,  If yes, specify (iii)  Was it treated?  no Year of diagnosis:  Comments: •  Additional information about antenatal infectious diseases  100  I  Section C: PRESCRIPTION  MEDICATIONS  1. Is this patient currently being treated for HIV infection? • •  yes •  no  I f yes, complete the following section ANTIRETROVIRAL  Drug name  THERAPY (for those with HIV infection only)  Gest. Age  Gest. age  at start  at stop  Dose/freq  Toxicities  Adherence code  Comments  2. Is this patient taking any other significant prescriptions or over the counter medications? •  v e . n no  I f yes, complete the following section OTHER PRESRICPTION/OTC MEDICA TTONS Drug name  Gest. age  Gest. age  at start  at stop  Dose/freq  101  Toxicities  Comments  S e c t i o n D; O T H E R S U B S T A N C E S 1.  Does t h i s patient use tobacco o r alcohol? • •  yes •  no  I f yes, complete t h e following section.  Substance  Check all  Gest. age  Gest. age  Amount per  that apply  at start  at stop  day/week  Comments  Alcohol: •  Beer  •  Wine  •  liquor  Tobacco  2.  A n y additional information about prescription o r non-prescription drugs used during this pregnancy?:  102  S e c t i o n E: L A B O R A T O R Y R E S U L T S  Date(AAM/DD/yy) Gestational Age (weeks) CD4 count HIV RNA (copies/ML) HGB . WBC Platelets AST ALT AST Alk Phosp &&T  Bilirubin PT, PIT Alb PT, PTT Alb HCV RNA HCV PCR  103  S e c t i o n F: A N T E N A T A L C O M P L I C A T I O N S 1. Has this patient experienced any antenatal complications? » I f yes, complete the following section.  Complication  Check all that apply  Gest. age at onset (weeks)  no  Comments  Gest. diabetes Hypertension Poor weight gain Oligohydram. IUGR Abruption Preterm labour PTD Premature ROM Antepart. Hem. Hyperemesis Cholestasis 2. Has this patient experienced any other significant antenatal complications?  1 I yes L_Z •  no I f yes, complete the following section.  Complication  Gest. age at onset (weeks)  Comments  104  A P P E N D I X 3: HEPATITIS C V E R T I C A L TRANSMISSION STUDY D E L I V E R Y F O L L O W - U P QUESTIONNAIRE  S t u d y I D Number  H C V Vertical Transmission Study ; .; Delivery Data Form  Date of completion: ( M M / D D / Y Y ) : Delivery data f o r m completed by:.  Section A: PREGNANCY OUTCOME 1. Date of delivery (or termination of pregnancy): (MM/DD/YY):  2. Outcome:  Live b i r t h  •  Spontaneous abortion Therapeutic abortion Reason: Intrauterine death S t i l l born  3. Duration of gestation period (in weeks) 4. I f abortus or stillborn - Pathology report results:  105  FTTT  S e c t i o n B: D E L I V E R Y I N F O R M A T I O N (LIVE BIRTH) 1. Gestational age at delivery (weeks): 2. Location (hospital) of delivery: Maternal health r e c o r d number: (Unit number of hospital)  4. P H N : I  5. Labour  1 yes I  1 no  I f yes, total length of labour (in hours) Rupture of membranes:  hours prior to delivery  Mechanism of labour:  spontaneous  induced  Monitoring during labour: f e t a l scalp electrode f e t a l scalp sampling Non reassuring f e t a l monitoring: •  yes •  •  yes •  no  •  yes •  no  no  I f yes, explain:  •  Vaginal delivery: • I f yes, was it?  yes •  vaginal, v e r t e x  Assistance:  •  Caesarean Section •  vaginal, breech  f o r c e p s - type  yes •  Booked/elective CIS,  •  no  vacuum  no I—I  Emergency C/5  Reason f o r CIS:  O B indications  Estimated Blood Loss:  <500 ml  W e r e prophylactic antibiotics used? •  H I V indications 5 0 0 - 7 0 0 ml I  yes •  106  no  I >700ml  Choice  9. Analgesia/anaesthesia:  anaesthetic •  10.  epidural  regional  W e r e t h e r e any complications?  General  spinal •  yes •  no  I f yes, complete the following section.  Complication  Check all that apply  Comments  Maternal f e v e r Meconium Haemorrhage  11. Placental pathology:  •  Did this patient receive any Intrapartum A R T ? ( H I V co-infected only) • I f yes, complete the following questions. I V A Z T : hours prior to delivery: O t h e r intrapartum A R T ? •  yes •  no  I f yes, specify: Time of last ART(routine) dose prior to delivery:  Section C: POSTPARTUM FOLLOW UP 1. Date of discharge: ( M M / D D / Y Y ) : 1  I  I  I  1  2. Number of days in hospital:  3. W e r e t h e r e any complications? •  yes •  no  I f yes, complete t h e following section.  107  I  yes •  no  Check all that apply  Complication  Comments  PPH - delayed O t h e r med. Compl. Episiotomy compl. Febrile (>38) Endometritis Mastitis Wound hematoma Wound infection  3. W e r e t h e r e any other complications?  no  I f yes, specify:  S e c t i o n C: N E O N A T A L I N F O R M A T I O N ( D E L I V E R Y T O O N E M O N T H ) 1. B i r t h weight:  grams (1 oz = 28.4 grams)  3.  Length (cm):  4.  Head circumference (cm):  4.  Cord blood gases: pH  5.  Resuscitation?  I  I yes I  I f yes, explain  6.  Apgars: 1 minute. 5 minutes  7.  Transfusion? I f yes, explain  I  1 yes I  1 no  1 no  8.  Birth Defects? •  yes •  no  I f yes, explain  9.  O t h e r neonatal complications? •  yes •  no  I f yes, explain  10.  Neonatal A R T s t a r t e d within 24 hrs ( H I V coinf ected only) •  yes •  no  I f yes, complete the following section.  Medication  •  Start date  Stop date  . W e r e t h e r e any A R T - r e l a t e d complications? •  Dose/mode  yes •  Indication  no  I f yes, explain  11. Was this infant admitted to: •  N u r s e r y : (#days)  •  Observation n u r s e r y (non-acute) (#days)  •  Long-term care* #days):  •  (  Neonatal intensive care unit* (#days) Roomed with mother (#days)  O t h e r Indication:  12.  Total Hospital stay:  Days admitted:  days  109  )  13.  Substance withdrawal syndrome •  yes •  no  I f yes, explain  •  S e v e r i t y of withdrawal -  _ [__ mildtZl  moderate •  severe  # wks Drug withdrawal therapy •  yes •  no  I f yes, specify  S e c t i o n D: M E D I C A L P R O B L E M S 1.  Did the infant experience any medical problems?  no  I f yes, complete the following section.  Complication  Check all; that apply  Comments  Prematurity Jaundice Feeding problems. Hypoglycaemia Pneumonia Meningitis Sepsis Viral infection RDS ICH  2.  Did the infant experience any other medical problems? • I f yes, specify.  110  y e s D no  3.  Was this infant discharged to:  Parental home I  F o s t e r home  1 Sunny Hill (mother)I  1 Sunny Hill (Ministry)  S e c t i o n E: B R E A S T F E E D I N G 1.  I s this mother breast feeding her child? •  yes •  I f yes, complete t h e following section. (a)  Maternal medications with BF? • I f yes, specify:  (b)  yes •  no  ;  I n f a n t side e f f e c t s to medications? I  1 yes I  I f yes, specify:  (c)  • »_•  Formula feeding?  yes l  l  no  I f yes, name: S t a r t date ( M M / D D / Y Y ) : Stop d a t e ( M M / D D / Y Y ) : (d)  Solids?  S t a r t date ( M M / D D / Y Y ) : 1 Stop d a t e ( M M / D D / Y Y ) : (e)  a  Feeding problems?  no 1  I  I  I  I  I I I II : I I yes 1 I no  I f yes, specify:  111  1 no  no  APPENDIX 4: H E P A T I T I S C V E R T I C A L TRANSMISSION S T U D Y P A E D I A T R I C F O L L O W - U P QUESTIONNAIRE  Infant Study ID Number:  HCV Vertical Transmission Study , Paediatric Data Form,  Date of data form completion: (MM/DD/YY): I—I—I—L Paediatric data form completed by: 1. Date of birth of infant (MM/DD/YY): I  I  I  I  J—I  Section A: INFANT: HEALTH (Birth to 6 months) 1. Skin problems? EH yes EZl no If yes, give details:  2. ENT problems? LZ] yes EH no If yes, give details:  3. G l problems? HZI yes CD no If yes, give details:  4. Enlarged liver? EZI yes EZI no If yes, give details:  112  Section B: VIROLOGY Date(MM/DD/YY) HIV Culture HIV PCR HCV PCR ,  ;  HCV AB  Section C: LABORATORY RESULTS Date(MM/DD/YY) AST ALT PT PTT Bili Alb AST = aspartate aminotransferase (normal values: 5-30 U/L) ALT = Alanine aminotransferase (normal values: 5-35 U/L) PT = Prothrombin Time (11.1-12.6 sec) PTT = Prothrombin Time (27.1-33.2 sec) Bili = Bilirubin (normal values: 0-1.3 mg) Alb = Albumin (normal values: 3.2-5.0 g)  A P P E N D I X 5: T H E HEPATITIS C V E R T I C A L TRANSMISSION STUDY GROUP  Team Leader:  Dr. Deborah Money, MD, FRCSC, Assistant Professor, Head, Division of Maternal Fetal Medicine Department of Obstetrics & Gynecology, U.B.C. At Children's & Women's Health Centre of B.C Team Members:  Dr. Mark Bigham, MD, FRCPC, Medical Consultant, Canadian Blood Services Dr. Kim Butt, MD, FRCSC, Perinatologist, Fredericton, New Brunswick Ms. Lesley Cole, RN, BSN, Project Coordinator, Division of Maternal Fetal Medicine Mr. Kevin Craib, BC Centre for Excellence in HIV/AIDS Dr. Simon Dobson, Clinical Associate Professor, UBC, Department of Pediatrics Dr. Patrick Doyle, Consult Pathologist, Division of Medical Microbiology and Infection Control Dr. Mel Krajden, Associate Professor, UBC, Director, BC Centre for Disease Control Ms. Fiona Liston, Project Coordinator, Division of Maternal Fetal Medicine Dr. Paula Lott, Obstetrics & Gynecology Resident, UBC Dr. Fergal Magee, Clinical Assistant Professor, UBC, Department of Pathology Dr. Chester Morris, MD, M.Sc, Director, HIV/AIDS Programs, Millwood, Virginia Dr. David Patrick, Associate Professor, UBC, Director, UBC Centre for Disease Control Dr. Vesna Popovska, Research Program Coordinator, Division of Maternal Fetal Medicine Ms. Valencia Remple, BSN, MScN, PHD Candidate, Research Program Coordinator, BCCDC Dr. Rick Schreiber, Clinical Associate Professor, UBC, Department of Pediatrics Dr. Chris Sherlock, MD, FRCPC, Full Professor, UBC, Head, Virology and Infection Control Dr. Eric Yoshida, MD, MHSc, FRCP(C), Associate Professor, UBC, Medical Director, BC Transplant Society, Division of Gastroenterology  114  

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