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Journal of Clinical Medicine 7 (11): 415 (2018)
Piccoli, Giorgina
Zakharova, Elena
Attini, Rossella
Ibarra Hernandez, Margarita
Orozco Guillien, Alejandra
Alrukhaimi, Mona
Liu, Zhi-Hong
Ashuntantang, Gloria
Covella, Bianca
Cabiddu, Gianfranca
Li, Philip Kam Tao
Garcia-Garcia, Guillermo
Levin, A. (Adeera)
Pregnancy is possible in all phases of chronic kidney disease (CKD), but its management may be difficult and the outcomes are not the same as in the overall population. The prevalence of CKD in pregnancy is estimated at about 3%, as high as that of pre-eclampsia (PE), a better-acknowledged risk for adverse pregnancy outcomes. When CKD is known, pregnancy should be considered as high risk and followed accordingly; furthermore, since CKD is often asymptomatic, pregnant women should be screened for the presence of CKD, allowing better management of pregnancy, and timely treatment after pregnancy. The differential diagnosis between CKD and PE is sometimes difficult, but making it may be important for pregnancy management. Pregnancy is possible, even if at high risk for complications, including preterm delivery and intrauterine growth restriction, superimposed PE, and pregnancy-induced hypertension. Results in all phases are strictly dependent upon the socio-sanitary system and the availability of renal and obstetric care and, especially for preterm children, of intensive care units. Women on dialysis should be aware of the possibility of conceiving and having a successful pregnancy, and intensive dialysis (up to daily, long-hours dialysis) is the clinical choice allowing the best results. Such a choice may, however, need adaptation where access to dialysis is limited or distances are prohibitive. After kidney transplantation, pregnancies should be followed up with great attention, to minimize the risks for mother, child, and for the graft. A research agenda supporting international comparisons is highly needed to ameliorate or provide knowledge on specific kidney diseases and to develop context-adapted treatment strategies to improve pregnancy outcomes in CKD women.
Journal ofClinical MedicineReviewPregnancy in Chronic Kidney Disease: Need forHigher Awareness. A Pragmatic Review Focused onWhat Could Be Improved in the Different CKDStages and PhasesGiorgina B. Piccoli 1,2,* , Elena Zakharova 3,4,5, Rossella Attini 6, Margarita Ibarra Hernandez 7,Alejandra Orozco Guillien 8, Mona Alrukhaimi 9, Zhi-Hong Liu 10, Gloria Ashuntantang 11,Bianca Covella 2, Gianfranca Cabiddu 12 , Philip Kam Tao Li 13, Guillermo Garcia-Garcia 7and Adeera Levin 141 Department of Clinical and Biological Sciences, University of Torino, 10100 Torino, Italy2 Néphrologie, Centre Hospitalier Le Mans, 72000 Le Mans, France; biancacovella@gmail.com3 Nephrology, Moscow City Hospital n.a. S.P. Botkin, 101000 Moscow, Russia; helena.zakharova@gmail.com4 Nephrology, Moscow State University of Medicine and Dentistry, 101000 Moscow, Russia5 Nephrology, Russian Medical Academy of Continuous Professional Education, 101000 Moscow, Russia6 Obstetrics, Department of Surgery, University of Torino, 10100 Torino, Italy; rossella.attini@gmail.com7 Nephrology Service, Hospital Civil de Guadalajara “Fray Antonio Alcalde”, University of GuadalajaraHealth Sciences Center, Guadalajara, Jal 44100, Mexico; maribaher@yahoo.es (M.I.-H.);ggarcia1952@gmail.com (G.G.-G.)8 Instituto Nacional de Perinatologia, Mexico D.F. 01020, Mexico; ale_gaba@hotmail.com9 Department of Medicine, Dubai Medical College, P.O. Box 20170, Dubai, UAE; mona_539@yahoo.co.uk10 National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School ofMedicine, Nanjing 210000, China; zhihong–liu@hotmail.com11 Yaounde General Hospital & Faculty of Medicine and Biomedical Sciences, University of Yaounde I,P.O. Box 337, Yaounde, Cameroon; maglo09@hotmail.com12 Nefrologia Ospedale Brotzu, 09100 Cagliari, Italy; gianfranca.cabiddu@tin.it13 Prince of Wales Hospital, Department of Medicine and Therapeutics, Chinese University of Hong Kong,Hong Kong; philipli@cuhk.edu.hk14 Department of Medicine, Division of Nephrology, University of British Columbia, Vancouver, BC V6T 1Z4,Canada; alevin@providencehealth.bc.ca* Correspondence: gbpiccoli@yahoo.it; Tel.: +33-669-733-371Received: 7 October 2018; Accepted: 31 October 2018; Published: 5 November 2018Abstract: Pregnancy is possible in all phases of chronic kidney disease (CKD), but its managementmay be difficult and the outcomes are not the same as in the overall population. The prevalenceof CKD in pregnancy is estimated at about 3%, as high as that of pre-eclampsia (PE), abetter-acknowledged risk for adverse pregnancy outcomes. When CKD is known, pregnancy shouldbe considered as high risk and followed accordingly; furthermore, since CKD is often asymptomatic,pregnant women should be screened for the presence of CKD, allowing better management ofpregnancy, and timely treatment after pregnancy. The differential diagnosis between CKD and PEis sometimes difficult, but making it may be important for pregnancy management. Pregnancyis possible, even if at high risk for complications, including preterm delivery and intrauterinegrowth restriction, superimposed PE, and pregnancy-induced hypertension. Results in all phasesare strictly dependent upon the socio-sanitary system and the availability of renal and obstetriccare and, especially for preterm children, of intensive care units. Women on dialysis should beaware of the possibility of conceiving and having a successful pregnancy, and intensive dialysis(up to daily, long-hours dialysis) is the clinical choice allowing the best results. Such a choice may,however, need adaptation where access to dialysis is limited or distances are prohibitive. Afterkidney transplantation, pregnancies should be followed up with great attention, to minimize theJ. Clin. Med. 2018, 7, 415; doi:10.3390/jcm7110415 www.mdpi.com/journal/jcmJ. Clin. Med. 2018, 7, 415 2 of 21risks for mother, child, and for the graft. A research agenda supporting international comparisonsis highly needed to ameliorate or provide knowledge on specific kidney diseases and to developcontext-adapted treatment strategies to improve pregnancy outcomes in CKD women.Keywords: chronic kidney disease (CKD), dialysis; kidney transplantation; pregnancy; pregnancycomplications1. IntroductionChronic kidney disease (CKD) is a well-acknowledged risk factor for adverse pregnancyoutcomes [1–7]. The literature on this issue is rapidly accumulating and the term “obstetric nephrology”has been proposed to identify this important clinical and research field [8].However, awareness of the importance of identifying CKD in pregnancy is still insufficient andthe experience is mainly limited to some large, but still few, referral centers [3,9–12].This narrative review, in association with a review on pregnancy and acute kidney injury (p-AKI),has been based on the theme of the World Kidney Day 2018, which highlighted women’s health andkidney disease [13]. Importantly, the focus of this narrative is on what could be done to improve CKDcare throughout and after pregnancy.The review follows the classic, even if not necessarily sequential, phases of renal diseases: chronickidney disease, dialysis, and transplantation, and focuses on the knowledge gaps, on the delay ofapplication of what is known into the clinical practice, and on the potential interventions that couldimprove the care of mother and child during and after pregnancy.2. Chronic Kidney Disease2.1. State of the Art: What We Know on the CKD-Pregnancy Relationship: CKD StagesKidney function is of crucial importance in healthy pregnancy [8].Several changes in kidney function occur in the pregnant woman, affecting the vascular,glomerular, and tubular components, ultimately resulting in increased renal clearances and“physiological” proteinuria, decrease in blood pressure, and expansion of the intravascularvolume [8,14–17].The kidney is the target and the central player in the hypertensive disorders of pregnancy, anumbrella term that gathers the most common pregnancy-induced disorders: isolated hypertension(usually identified by the acronym PIH: pregnancy induced hypertension), pre-eclampsia (PE),in which hypertension is usually associated with proteinuria and may be associated with acuteand transient reduction of the kidney function (now considered a hallmark of the PE syndrome,even in the absence of proteinuria), HELLP syndrome, an acronym for haemolysis, elevated liverenzymes, low platelets, a severe, occasionally life-threatening, endothelial disorder [8,14–20]. Isolatedproteinuria may also transiently appear in pregnancy and is usually indicated as “pregnancy-inducedproteinuria”. Proteinuria may precede PE, but even when isolated, it heralds a risk of adversepregnancy outcomes, including growth restriction and preterm delivery; the differential diagnosisbetween pregnancy-induced and pre-existent proteinuria may not be easy [20–23].Due to the central role of the kidney, target, and actor in the pathogenesis of the hypertensivedisorders of pregnancy, it is not surprising that a reduction of the kidney function may affectpregnancy outcomes [1–9,24]. What may be surprising is that kidney diseases are associated with asignificant increase in the risk of adverse pregnancy outcomes even in the absence of kidney functionreduction [4,5,25–30].J. Clin. Med. 2018, 7, 415 3 of 21In this regard, interesting insights come from the analysis of pregnancy after kidney donation,which shows that this condition of “healthy” reduction of the kidney parenchyma is associated with ahigher risk of pre-eclampsia and hypertensive disorders of pregnancy [25,26,31–33].Overall, the risks of adverse pregnancy outcomes increase from CKD stage 1 to CKD stage 5, andare further increased in diabetic nephropathy and in systemic autoimmune diseases, such as systemiclupus erythematosus (SLE) [1–9,34–40].In each CKD stage, hypertension and proteinuria are important modulators of the entity ofpregnancy-related risks; however, the specific role of each element (kidney disease, stage, hypertension,and proteinuria) is not fully known, thus limiting the information available for counseling [41–44](Table 1). Furthermore, perinatal outcomes depend also upon the setting of care, an issue that has to betaken into account both in interpreting results and in planning treatment strategies.Table 1. Clinical features affecting pregnancy-related risks in CKD patients.Clinical Feature Effect on Pregnancy Effect on Maternal HealthCKD stageIncrease across stages (from stage 1 tostage 5) of preterm delivery, caesareansection, SGAIncrease in risk of kidney function impairment,development of hypertension, and proteinuriaImmunologic diseasesPE risk may be increased at least in somediseases (IgAGN, SLE); differentialdiagnosis with flares may be difficultIn CKD, maternal deaths are mainly described in SLEnephropathy (immunologic flares)Diabetes and diabeticnephropathyIncreased risk in malformations, linked todiabetes, proportional to diabetes control Same as CKDBaseline hypertension May be associated with a higher risk ofpreterm or SGA babies Risk of kidney function impairment may be increasedBaseline proteinuria May be associated with a higher risk ofpreterm or SGA babiesRisk of kidney function impairment and of persistenthypertension may be increasedCKD: chronic kidney disease; IgAGN: IgA nephropathy; SLE: systemic lupus erythematous; SGA: small forgestational age baby.As it will be further discussed, our knowledge on the specific risks linked with the differentkidney diseases is limited; overall, we know more about glomerular diseases, and the most commonones, such as IgA nephropathy, are extensively studied; conversely, the specific risks associated withinterstitial nephropathies or polycystic kidney disease (ADPKD) are not fully appreciated [7,9,45–51].Table 2 resumes the main pregnancy-related risks in CKD patients: overall, malformations arenot increased with respect to the overall population (out of the context of inherited diseases and ofdiabetic nephropathy); maternal death is exceptional, at least in highly resourced countries.Conversely, the incidence of preterm delivery and of small babies (Figure 1) is increased alreadyin stage 1 CKD, with respect to the overall population, and rises along with the increase of CKDstages [1–7,24,27,28]. Likewise, the effect of pregnancy on CKD progression is debated, also on accountof the different study designs, obstetric policies, and duration of follow-up of CKD women afterpregnancy. Overall, short- and long-term decrease in the kidney function is exceptional in the firstCKD stages, but rapid decrease of the kidney function may be an issue in late CKD stages [1–7].Once more, studies are heterogeneous and evidence is limited; as a consequence, entity of the riskof CKD progression has been variously estimated (Table 2).The information on the outcomes of pregnancy in the last CKD phases is still scant. Fertility isusually reported as reduced in the last CKD stages, but it is possible that the attitude of discouragingpregnancy in advanced CKD has induced a selection bias [52,53].J. Clin. Med. 2018, 7, 415 4 of 21Table 2. Adverse pregnancy outcomes in CKD patients and in their offspring [13].Term Definition Main Issues in CKDMaternal death Death in pregnancy or within 1week–1 month postpartumToo rare to be quantified, at least in highly resourcedsettings, where cases are in the setting of severe flares ofimmunologic diseases (SLE in primis).CKD progression Decrease in GFR, rise in sCr, shiftto a higher CKD stageDifferently assessed and estimated; may be linked toobstetric policy (anticipating delivery in the case ofworsening of the kidney function); 20% and 80% inadvanced CKD. Probably not increased in early CKD(stages 1–3a).Immunologic flares andneonatal SLEFlares of immunologic diseases inpregnancyRisks are mainly but not exclusively limited to patientswho start pregnancy with active disease or recent flare-up.Definition of a “safe” zone is not agreed; in quiescent,well-controlled diseases are probably equivalent tononpregnant, carefully-matched controls.Transplant rejection (kidney) Acute rejection in pregnancyKidney rejection episodes are not increased with respect tomatched controls; may be an issue in unplannedpregnancies.Abortion Foetal loss, before 21–24gestational weeksScant data on advanced CKD. An issue in immunologicdiseases (not exclusively linked to LLAC) and in diabeticnephropathy.Stillbirth Delivery of a nonviable infant,after 21–24 gestational weeksProbably not increased in early CKD, too few data in lateCKD stages; may be an issue in dialysis patients; when notlinked to extreme prematurity, may be specifically linkedto SLE, immunologic diseases, and diabetic nephropathy.Perinatal death Death within 1 week–1 monthfrom deliveryUsually a result of extreme prematurity, which bears a riskof respiratory distress, neonatal sepsis, cerebralhaemorrhage.Small, very small baby A baby weighing <1500–2500 g atbirthGestational age adjusted weight may be a better riskmarker; however, very low birth weight may bear risks forfuture health, even without SGA. Different cut-points areused, the most common are 1500 for very small and 2500for small baby.Preterm, early extremely preterm Delivery before 37, 32, or 34; 28completed gestational weeksRisk of preterm delivery increases across CKD stages.Definition of preterm and extremely preterm are agreed(<37 and <28 weeks, respectively); two cut-points are usedfor early preterm (<32 and <34 weeks)Small for gestational age (SGA) <5th or <10th centile forgestational ageSGA and IUGR may be associated, but IUGR is also adynamic event, characterised by flattening of the growthcurve. Both are better defined when several data inpregnancy are available.Intrauterine growth restriction(IUGR)<5th centile or flattening of thegrowth curveSmall, SGA, and IUGR babies are at higher risk ofdeveloping hypertension, metabolic syndrome, and CKDin adulthood.Malformations Any kind of malformationsMalformations are not increased in the absence ofteratogen drugs; exception is diabetic nephropathy(increase in malformations attributed to diabetes);hereditary diseases may not be evident at birth.Hereditary kidney diseases Any kind of CKDSeveral forms of CKD have a hereditary pattern orpredisposition, among them, ADPKD, Alport’s, vescicoureteral reflux and CAKUT, IgA, kidney tubular disorders,and mitochondrial diseases.CKD-hypertension Higher risk of hypertension andCKD in adulthoodLower nephron number in preterm babies; the risks areprobably higher in SGA–IUGR babies than in pretermbabies adequate for gestational age.Other long-term issues Developmental disorders Cerebral haemorrhage or neonatal sepsis, not specific ofCKD, are a threat in all preterm babies.CKD: chronic kidney disease; ADPKD: autosomal dominant polycystic kidney disease; CAKUT: complex anomaliesof the kidney and of the urinary tract; SLE: systemic lupus erythematous; LLAC: lupus-like anticoagulant; SGA: smallfor gestational age baby; IUGR: intrauterine growth restriction; GFR glomerular filtration rate; MMF: mycophenolicacid; ACEi: angiotensin-converting enzyme inhibitors; ARBS: angiotensin receptor blockers.J. Clin. Med. 2018, 7, 415 5 of 21J. Clin. Med. 2018, 7, x FOR PEER REVIEW 5 of 21 Figure 1. The different “small babies”: Growth curve of small, small for gestational age (SGA), intrauterine growth restricted (IUGR) babies (Y axis: weight and reference curves; X axis: gestational weeks). Legend: (A) is a very small, early preterm normal for gestational age child; (B) is a very small, early preterm, SGA but harmoniously grown, preterm child (mother and father also of small body size); child (C) is a small, SGA, preterm child with a flattening of the growth curve. Although (B,C) are identified also as IUGR, flattening of the growth curve may have a different (unfavorable) meaning as for life-long complications. (Courtesy of R. Attini and P. Gaiotti). 2.2. A Particular Case: Systemic Immunologic Diseases Kidney disease in SLE is a critical concern for pregnancy. Kidney involvement includes lupus nephritis (LN), characterized by glomerular damage and interstitial and vascular lesions. Beyond risk factors associated with CKD (proteinuria, hypertension, and impaired kidney function, Tables 1 and 2), SLE is associated with a specific increase in miscarriages and perinatal death. All risks are higher in active SLE, and adverse outcomes are associated in particular with LN class 3 and 4, history of renal flares, longer disease, hypocomplementemia, presence of antiphospholipid antibodies (aPL), and antiphospholipid syndrome (APS) [5–7,54,55]. Conversely, pregnancy carries a risk of SLE flares: high estrogen level may act as triggers, by mediating transcription activity of the intracellular estrogen receptors and interacting with regulatory T cells, key modulators of maternal–foetal tolerance [56]. Upregulation of IFN-α may also play a role in SLE and LN: this cytokine, highly expressed by the placenta, contributes to placentation and increases susceptibility to SLE [57–59]. Low C3 and high anti-DNA antibodies predict renal flares, whereas high anti-C1q antibodies and low C4 predict early flares. Pregnancy complications, along with vascular thrombosis, are the main clinical criteria for antiphospholipid syndrome, which may be isolated (primary forms) or associated to SLE or other autoimmune disorders. The disease directly affects placental vasculature, ultimately resulting in placental dysfunction: antiphospholipid antibodies affect the cytotrophoblast via thrombosis, inflammation, apoptosis, and immunomodulatory impairment; direct damage of endometrial cells has also been described [60,61]. APS-related complications in pregnancy include the whole list of pregnancy complications: recurrent miscarriage, preterm delivery, IUGR, stillbirth, fetal distress, fetal or neonatal thrombosis, PE, eclampsia, HELLP syndrome, arterial or venous thrombosis, and placental insufficiency. High titers and triple positivity for aPL (usually defined as positivity for LLAC and for anti-cardiolipin (aCL) and anti-β2GPI antibodies of the same isotype by the same method) are associated with mother and foetal complications, including miscarriage [60–69]. A particularly severe syndrome, named catastrophic APS (CAPS), combines all these damages into multiorgan failure [60–68]. The occurrence of HELLP syndrome in a patient with APS should raise the suspicion of CAPS, and defines a permanent risk for further pregnancies [69]. The link between pregnancy-induced thrombocytopenia or endothelial damage and other causes, including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), now often referred to as thrombotic microangiopathies (TMA), is not fully clear; the diseases may overlap and the differential diagnosis may become evident only after pregnancy (Table 3) [70]. Fig re 1. he iffere t “s all babies”: Growth curve of s all, s all for gestatio al age (S ),i tra teri e r t restricte (I ) a ies ( axis: ei t a refere ce c r es; axis: estati alee s). e e : ( ) is er s ll, e rl reter r l f r est ti l e c il ; ( ) is er s ll,l t , t i l , t il ( t f t l f lli ); il ( ) is a small, SGA, preterm child with a flatteni g of the growth curve. Although (B,C) areid ntified also s IUGR, flattening of the growth curve may have a different (unfavorable) meaning asfor life-long complications. (Cour esy of R. Attini and P. Gaiotti).2.2. A Particular Case: Systemic Immunologic DiseasesKidney disease in SLE is a critical concern for pregnancy. Kidney involvement includes lupusnephritis (LN), characterized by glomerular damage and interstitial and vascular lesions. Beyondrisk factors associated with CKD (proteinuria, hypertension, and impaired kidney function, Tables 1and 2), SLE is associated with a specific increase in miscarriages and perinatal death. All risks arehigher in active SLE, and adverse outcomes are associated in particular with LN class 3 and 4, historyof renal flares, longer disease, hypocomplementemia, presence of antiphospholipid antibodies (aPL),and antiphospholipid syndrome (APS) [5–7,54,55].Conversely, pregnancy carries a risk of SLE flares: high estrogen level may act as triggers, bymediating transcription activity of the intracellular estrogen receptors and interacting with regulatoryT cells, key modulators of maternal–foetal tolerance [56]. Upregulation of IFN-αmay also play a role inSLE and LN: this cytokine, highly expressed by the placenta, contributes to placentation and increasessusceptibility to SLE [57–59]. Low C3 and high anti-DNA antibodies predict renal flares, whereas highanti-C1q antibodies and low C4 predict early flares.Pregnancy complications, along with vascular thrombosis, are the main clinical criteria forantiphospholipid syndrome, which may be isolated (primary forms) or associated to SLE or otherautoimmune disorders. The disease directly affects placental vasculature, ultimately resultingin placental dysfunction: antiphospholipid antibodies affect the cytotrophoblast via thrombosis,inflammation, apoptosis, and immunomodulatory impairment; direct damage of endometrial cellshas also been described [60,61]. APS-related complications in pregnancy include the whole list ofpregnancy complications: recurrent miscarriage, preterm delivery, IUGR, stillbirth, fetal distress,fetal or neonatal thrombosis, PE, eclampsia, HELLP syndrome, arterial or venous thrombosis, andplacental insufficiency. High titers and triple positivity for aPL (usually defined as positivity for LLACand for anti-cardiolipin (aCL) and anti-β2GPI antibodies of the same isotype by the same method)are associated with mother and foetal complications, including miscarriage [60–69]. A particularlysevere syndrome, named catastrophic APS (CAPS), combines all these damages into multiorganfailure [60–68]. The occurrence of HELLP syndrome in a patient with APS should raise the suspicionof CAPS, and defines a permanent risk for further pregnancies [69].The link between pregnancy-induced thrombocytopenia or endothelial damage and other causes,including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), nowJ. Clin. Med. 2018, 7, 415 6 of 21often referred to as thrombotic microangiopathies (TMA), is not fully clear; the diseases may overlapand the differential diagnosis may become evident only after pregnancy (Table 3) [70].Table 3. The differential diagnosis of disorders associated with AKI and thrombocytopenia in pregnancy(modified from 70).Pre-Eclampsia/HELLP Hemolytic Uremic Syndrome(HUS)Thrombotic ThrombocytopenicPurpura (TTP)Usual time of onset After 20 gestationalweeks postpartum 2nd and 3rd trimesterArterial hypertension +++ + +Renal failure + (mainly in HELLP) +++ +Renal prognosis Recovery 75% ESRD Usually goodNeurological impairment + + +++Hemolytic anemia ++ (HELLP) +++ +++Low platelet count +++ (HELLP) +++ +++Intravascular coagulation + Usually absent ++Proteinuria +++ + RareAbnormal liver function tests +++ (HELLP) Usually absent Usually absentComplement alternativepathway activation + (HELLP) +++ Usually absentReduced ADAMTS13 + Usually absent +++Treatment Supportive treatmentPlasmapheresis; plasmainfusionAnti-MAC antibodiesPlasmapheresis; plasma infusionAnti-CD20 antibodiesHELLP: hemolysis, elevated liver enzymes, low platelets. + present; ++ frequent and severe; +++ very frequentand severe.Among other common autoimmune diseases, rheumatoid arthritis (RA) mostly affects womenof perimenopausal age; however, its incidence is non-negligible in younger patients (8.7 per 100,000per year at age 18–34 and 36.2 per 100,000 at age 35–44). CKD in RA may result from RA-associatedglomerulonephritis, chronic inflammation, comorbidities, nephrotoxic antirheumatic drugs, andamyloidosis [71–78]. Specific pregnancy risks linked to RA are not clearly defined, even if an increasein preterm delivery and low birth weight has been reported (Tables 1 and 2). Interestingly, RApatients may experience remission during pregnancy, presumably due to changes in sex hormonesprofiles [75–80]. Similar considerations may apply to systemic sclerosis (SS), a severe immunologicdisease mostly affecting women of postmenopausal age, but present also in a younger population,where it carries a risk for prematurity and IUGR and SGA babies. Conversely, SS flares are rare butmay be life-threatening in pregnancy [81–84].2.3. What is Missing, and What We Still Need to KnowIndirect estimates of the prevalence of CKD in pregnancy come from the assumption that fertilityis not affected in early CKD and that the prevalence of early kidney disease is the same as in theoverall population [1,85]. Based upon this assumption, it has been suggested that early-stage CKD ispresent in 3:100 pregnancies and later-stage CKD in 1:750 pregnancies [1,85]. Interestingly, the reportedprevalence of CKD is strikingly similar to that of PE, much better acknowledged as an important riskin pregnancy [1,85,86]. Furthermore, the estimation of the prevalence of CKD in pregnancy, in theclassic paper by Williams and Davison, is based upon an evaluation performed in western, highlyresourced countries, and may be underestimated in medium- and low-income countries, in which theprevalence of CKD is usually higher [1,85–91]Assessing the actual prevalence of CKD in pregnancy should therefore be a health care priority,also since pregnancy may represent an underutilised, but highly valuable, occasion for the diagnosis ofCKD, in particular in disadvantaged populations in which the opportunities for early CKD diagnosisare few [90–94]. In fact, pregnancy is often the first occasion in which an apparently healthy womanJ. Clin. Med. 2018, 7, 415 7 of 21undergoes a clinical and laboratory evaluation, which has the potential to timely reveal the presence ofunderlying CKD. However, the only assessment systematically done and regarding the kidney is theurinalysis, which is usually interpreted only with regard to the presence of proteinuria, or of urinarytract infection [95–97].Simple and inexpensive measures, such as including the assessment of serum creatinine inthe routine pregnancy tests, could improve early diagnosis of kidney diseases, in particular if thephysiological decrease of serum creatinine levels, due to physiological changes in pregnancy, isacknowledged. In this regard, there is also a need to determine reference values for creatinine duringpregnancy, by race and pregnancy trimester. Addition of serum creatinine will not solve all problems,but may allow identifying at least cases with kidney function impairment. Indeed, many kidneydiseases are fully asymptomatic; not all kidney diseases manifest with hypertension and proteinuria,the symptoms on which attention is more focused; haematuria or electrolyte derangements may beoverlooked in pregnancy and there is a consistent overlap of signs and symptoms between PE andCKD in pregnancy [98–101]. These diagnostic challenges are summarised in Table 4.Furthermore, signs and symptoms of CKD and PE may overlap, and there is a need for establishingcommon lines for systematically considering the differential diagnosis between CKD and PE inpregnancy; while a combination of Doppler flows and the biomarkers employed in the assessment ofPE may support diagnosis, large prospective studies are needed to refine the procedures and validatetheir use [101–103].3. Dialysis3.1. The State of the ArtFertility is reduced in end-stage kidney disease; Australian and European data suggest thatpregnancy occurs ten times less frequently in patients with kidney transplantation than in the generalpopulation and that pregnancy occurs ten times less frequently in dialysis patients compared withkidney transplant patients. In other words, a woman on dialysis has a probability of having a babythat is 1% of the overall population [104–106].While the first sporadic cases of successful pregnancy on dialysis were described in the seventies,it was only in the new millennium that pregnancy on dialysis became an acknowledged clinicalpossibility [104–110]. So far, more than 1000 pregnancies have been reported in dialysis patients, withan increasing trend worldwide [109].The most important advance in this field has been the demonstration of a strict relationshipbetween the intensity (frequency and duration) of the dialysis sessions and pregnancy results, thusleading to intensify dialysis up to daily, favoring also long-hours treatment as compared to standardschedules [107–110].The improvement in results recorded with daily, extended-hours dialysis not only allowed amore permissive attitude towards pregnancy in dialysis, but is also leading to a more positive attitudetowards pregnancy in advanced CKD, often previously discouraged for the fear of needing to startdialysis during gestation [107–114].While the “best” (if any) dialysis prescription is still not agreed upon, some common lines areemerging, specifically from the Canadian experience: in patients without residual renal function, atleast 36 h of dialysis per week should be prescribed, and daily frequency should be chosen; weightloss during the session should be very slow, hypotension should be avoided, and hypertensionnot hypercorrected; heparin anticoagulation is safe (more experience with unfractioned heparin);biocompatible membranes should be used; multivitamin supplementation and high-protein dietsshould be prescribed to compensate for intradialytic nutrient loss; phosphate supplements may alsobe needed. Low blood and dialysate flows should allow a “soft” dialysis; Kt/V is not the ideal markerof dialysis efficiency and the target is set at “near normal” predialysis urea (after the day break)(Table 4) [10,109,111].J. Clin. Med. 2018, 7, 415 8 of 21Table 4. Challenges for the diagnosis of kidney diseases in pregnancy.Sign or Symptom Interference in Pregnancy Potential CorrectionHypertensionBlood pressure is physiologically reduced,particularly in the 1st trimester; mild–moderatehypertension may be masked by the physiologicchanges in early pregnancy.Attention to “high normal” BP; strict monitoringin presence of risk factors (obesity, diabetes,family history, age, CKD); if associated withproteinuria, interference in PE diagnosis.Kidney function reductionKidney function physiologically increased, inparticular in 1st–2nd trimester; CKD stages 2–3 maybe missed, in particular if reference eGFR ofnonpregnant women is employed.Lack of hyperfiltration is a potential sign of initialreduction of kidney function; “normal” valuesoutside pregnancy should be interpreted withcaution in pregnancy.HematuriaPresence of contaminant RBCs in the urine iscommon and microhematuria may be misinterpretedas of gynaecologic origin. Possible underestimationin polyuria.Microscopic examination, search for urinary casts,and attention to correct sampling avoid missingthis sign pointing to a glomerular origin (mostfrequent, IgA nephropathy).ProteinuriaThe physiologic limit is increased to 300 mg/day.Proteinuria may show day-to-day and circadianvariations. If assessed on spot urine collection, mildproteinuria may be missed in patients with polyuria.Repeated tests and 24 h urine assessment in caseswith trace proteinuria may avoid missinglow-grade (albeit clinically relevant) proteinuria.Tubular derangementsThe usual workout of physiologic pregnancyincludes the major ions (Na, K, Calcium). Mildhypokalaemia and hyponatremia are common, dueto physiologic hemodilution.Tubular derangements may be elusive.Phosphate, Mg, bicarbonate should be controlledin severe hypokalaemia, severe hyponatremia, orunexplained polyuria.Urinary infectionUrinary infections are common and usuallyasymptomatic. Several societies suggest at least oneurinary culture per trimester.Repeatedly positive urinary cultures suggestperforming ultrasounds of the kidney andurinary tract.CKD: chronic kidney disease; PE: pre-eclampsia; BP: Blood pressure; RBCs: red blood cells. Na: sodium, K:potassium, eGFR: estimated glomerular filtration rate.In settings where dialysis is available without restrictions, pregnancy in dialysis is becoming morecommon, though still a rare occurrence, underlining the importance of a network of care for sharingopinions, gathering data, and optimizing results [110,114].Conversely, in poorly resourced countries, pregnancy is a common precipitating event of severeCKD, often not previously diagnosed; furthermore, in these settings, p-AKI is more common and maynot be reversible in 5–30% of the cases, further underlining the complex link between PE, p-AKI, andCKD in pregnancy [115–118].3.2. What Is Missing and Could Be Done in the Clinical PracticeThe evidence on pregnancy and dialysis is heterogeneous and several questions are stillunanswered. Two of them are of pivotal importance: when to start dialysis in pregnancy and how wecan mediate between the excellent results obtained by Hladunewich in Canada with long-hours dailydialysis and the limited access to dialysis in many developing countries.The issue of dialysis start in pregnancy is complex; the Canadian data, which indicate that atarget of predialysis “near normal” urea level is associated with better outcomes, are often taken as anindication to start dialysis early. While this attitude may be reasonable, it has not been proven, andis not in keeping with the recent indications to start dialysis within an “intent to delay” policy in allother categories of patients [111,119–122].As a consequence of this uncertainty, the residual kidney function at dialysis start in pregnancyranges from 20 mL/min, a level that would not have supported the indication to start RRT outside ofpregnancy, to the usual levels of less than 10 mL/min [123,124].There are very few position statements from scientific societies on these issues; the most recentItalian one leaves the question open, advocating an individualised approach [6,111]. Furthermore, therole of nutritional support to delay dialysis start in pregnancy has been insufficiently studied, and thepromising results obtained with plant-based diets need large-scale validation [125–127]. There is anurgent need for gathering and exchanging data on this crucial issue to ensure the best timing of startof dialysis in pregnancy, in the interest of the mothers and the babies.J. Clin. Med. 2018, 7, 415 9 of 21The second issue, regarding the difficulty in implementing the long, daily dialysis schedules,is also open; this is of utmost importance in developing countries, such as Mexico, where intensivedialysis may lead to a competition for a lifesaving treatment [92]. Shorter dialysis schedules andperitoneal dialysis are reported as alternatives, but publication bias is an important limit to assess thereal equivalence of these more easily manageable treatments [128–132]Low income should not become synonymous with low quality, and data coming frommedium–low-income countries show that very good results can be obtained in all settings; thepopulations may, however, be different, as well as the kidney diseases. There is a need for establishing acommon language, allowing exchanging on dialysis approaches and detailed results to allow tailoringdialysis to patients, considering also the available resources. Some open questions regarding themanagement of the dialysis schedules are summarized in Table 5.Table 5. Some challenges and open questions in the practical management of hemodialysis patientsin pregnancy.Item Indications Open IssuesNumber of sessions Daily hemodialysis (DHD) is superior tothrice weekly dialysisDHD is differently defined (5–7 sessions/week); no data onadjustment per body size or residual renal function (RRF):urea level should probably guide the choice. Unclearadvantage of shorter/more frequent or of longer/lessfrequent sessions in presence of RRF.Duration of session The longest, the best, according to theCanadian experienceScattered positive experience with short DHD; difficult todistinguish between effect of frequency and duration.Long-hours dialysis is more effective in removal of middlemolecules and phosphate.Weight loss The lowest, the best; attention to avoiddehydration and oligoamniosThe evaluation of weight gain remains empiric. Unclear rolefor bioimpedance, BNP, BP. Unclear role of biomarkers(s-Flt1, PlGF) in diagnosis of PE.Blood flow Low blood flow (150–250 mL/min) may bereasonable in intensive HDLower blood flow has to be balanced with higher need foranticoagulation. Long-hours dialysis is associated withbetter removal of middle molecules and compartmentalisedtoxins: depuration markers alternative to urea are notidentified. Hypophosphatemia is often found: subtle deficitsof trace metals or vitamins may be relevant; the role ofmultivitamin supplementation is not clear.Dialysate flow Low dialysate flow advised in long-hoursdialysis (300 mL/min)Dialysis efficiencyThe most common target is “near normal”urea (10–15 umol/L) following theday breakDialysis membrane Biocompatible membranesNo study addressed to different membranes; low-fluxmembranes limit nutrient loss; high-flux membranesincrease middle molecules clearance, but increase alsonutrient loss and may induce back-filtration.CKD: chronic kidney disease; PE: pre-eclampsia; BP: blood pressure; BNP: brain natriuretic peptide; HD:haemodialysis; DHD: daily haemodialysis; s-Flt1: soluble fms like tyrosine kinase 1; PlGF: placental growthfactor; RRF: residual renal function.4. Kidney TransplantationFertility is at least partly restored after kidney transplantation, and the possibility to undertakea successful pregnancy is usually considered an added value of a functioning kidney graft. Reportson pregnancies after kidney transplantation rapidly followed the development of kidney transplantprograms and thousands of pregnancies have now been reported all over the world [133–140].However, even in an ideal situation, the risk of complications is higher than in the generalpopulation and was recently described as corresponding to stage-1 CKD in native kidneys, in patientswith potentially progressive CKD [140,141]. If teratogen drugs are avoided (Appendix A Tables A1–A4),pregnancy after kidney transplantation shares the same risk factors with CKD pregnancies, suggestingthat kidney function, hypertension, and proteinuria matter more than treatments [141]. Indeed, thereduced nephron mass of a solitary transplanted kidney may not be resilient enough to the stressors ofhyperfiltration of pregnancy, even in the presence of normal kidney function.The profile of the “ideal” candidate for pregnancy after transplantation is well defined: a young,nonobese, normotensive woman, with normal kidney function, in the absence of proteinuria, withoutany rejection episode, or at least any recent rejection episode, with good compliance, and at leastJ. Clin. Med. 2018, 7, 415 10 of 21two years from transplantation [133,134,140–144]. However, a univocal definition of age, kidneyfunction, and interval after the last rejection episode is missing, and the grading of the risks is notclear, in particular in women with signs of kidney function impairment. This “ideal” situation isindeed not always the rule, in particular in deceased donor transplantation. In fact, expanded donorpolicies may lead to suboptimal kidney function; higher age at transplantation and reduced fertilityare not infrequent; conversely, the good results of pregnancy after kidney transplantation are somehowsmoothing the contraindications, with a widespread agreement on a shorter stabilization time, and apermissive attitude towards pregnancy with less-than-optimal kidney function [133–144].The literature is rich with reports on extreme situations, including kidney transplantation duringpregnancy; while single cases cannot lead to potentially risky changes in daily practices, such cases dowarn against fully negative attitudes and suggest an individually based decision [145–151].In particular in western countries, where age of the transplant recipients is often older, assistedfertilization is increasingly popular. Besides the ethical challenges, whose discussion is beyond thescope of this review, assisted fertilization techniques, in particular those in vitro, are associated withan increase of pregnancy complications and of hypertensive disorders of pregnancy, with a potentialnegative effect on the kidney function [152–156]. The scattered data on assisted fertilization in kidneytransplant recipients are, however, encouraging; once more, the series are very small, most of themregarding single cases, and, in such a context, it is highly probable that reports are influenced by apublication bias [152–156].What Is Missing and Could Be Done in the Clinical PracticeMost of the available data on kidney transplantation regard pregnancies in ideal or “almost ideal”clinical conditions; there is very little evidence available on pregnancy in patients with reduced kidneyfunction. In these cases, in which counseling is particularly important, the data we now have are scantand we can rely only on personal experience or indirect evidence.There is a need for gathering data on these situations, to improve counseling and to increaseawareness of the challenges of pregnancy in patients with a failing graft.Pregnancy represents an immunologic challenge and is a potential cause of hyperimmunization,a well-known problem for transplantation. Living unrelated grafts increasingly offer a clinical solutionwithin couples: the eventual role of pregnancy as an immunologic trigger leading to rejection of thegrafted kidney should be clarified to optimize the outcomes of transplantation between husband andwife [142].Not least, long-term data on children born from a transplanted mother are still lacking, andattention should be focused on this important issue [157].5. ConclusionsPregnancy is now possible in all phases of chronic kidney disease, but its management may bedifficult and the outcomes are not the same as in the overall population.There is a lot to do to improve pregnancy outcomes in CKD, whose prevalence in pregnancyis probably as high as that of PE, a better-acknowledged risk for adverse outcomes. When CKD isknown, pregnancy should be considered as at high risk and followed accordingly, since the earlieststages. Furthermore, since CKD is often asymptomatic, pregnant women should be screened for thepresence of CKD, allowing better management of pregnancy and timely treatment after pregnancy.The differential diagnosis between CKD and pre-eclampsia may be difficult but is important forpregnancy management.Women on dialysis should be aware of the possibility of conceiving and having a successfulpregnancy, and intensive, long-hours, quotidian dialysis is the choice allowing the best results; theseindications have, however, to be adapted to poorly resourced countries, where daily dialysis may notbe feasible for clinical, economical, or logistic issues.J. Clin. Med. 2018, 7, 415 11 of 21After kidney transplantation, pregnancies should be followed up with great attention to minimizethe risks for mother, child, and for graft.Specialized and committed teams are crucial for optimizing the care of pregnant CKD patients,and efforts should be done to organise such teams.The advances in our knowledge are strictly linked to the progress in research, and internationalcomparisons are highly needed to ameliorate our understanding and to define treatment strategies.The research agenda is long, from epidemiology of CKD to differential diagnosis between CKD andPE, evaluation of target blood pressure in CKD pregnancies, or the role of the nutritional follow-up.Furthermore, dialysis start, dialysis policy, and modulation of posttransplant therapies should bediscussed on a global basis, to identify the best context-sensible policies to allow more CKD women toattain successful pregnancy.Author Contributions: Conceptualization, G.B.P., A.L., E.Z., R.A., M.I.-H., B.C., M.A., L.Z.-H., G.A., A.O.G.;Writing-Original Draft Preparation, G.B., R.A., G.C.; Writing-Review & Editing, G.B.P., A.L., E.Z., R.A., M.I.-H.,B.C., M.A., L.Z.-H., G.A., A.O.G.; Supervision, G.C., P.K.T.L., G.G.-G.Funding: This research received no external funding.Acknowledgments: To Susan Finnel for her careful language editing.Conflicts of Interest: The authors declare no conflicts of interest.Appendix ATable A1. Main immunosuppressive drugs for CKD patients in pregnancy.Drug Main Features FDAUsually considered as relatively safe, when absolutely neededAzathioprine (AZA)It is teratogenic in animal models, at high doses, but not in humans, possiblybecause the foetal liver is not able to activate the drug. KDIGO and EuropeanBest Practice Guidelines suggest switch from Mycophenolate to AZA beforepregnancy.DCyclosporine A (CyA)Hypertension, hyperglycaemia and nephrotoxicity may be relevant in pregnancy.CyA has not been associated with teratogenicity; SGA babies and pretermdelivery have been reported, with an unclear link with maternal disease; levelsvary in pregnancy and need strict monitoring.CTacrolimus The drug has similar effects and side effects as CyA; the experience is morelimited than with CyA. CSteroidsThe most frequently used short-acting corticosteroids are prednisone,methylprednisolone and prednisolone; among long-acting betamethasone anddesamethasone. No major malformation reported, increase of labio-palatoschisisis debated. A risk of premature rupture of membranes has been reported, alongwith increased risk of infection and gestational diabetes.C prednisoneHydroxychloroquine This synthetic antimalaric agent crosses the placenta but was not associated withfoetal toxicity. BIV Immunoglobulin (IV Ig) IV Ig is indicated in SLE pregnant patients with recurrent spontaneous abortion.Safety has not been fully established. CRituximab Animal studies have shown adverse effects on the fetus; no adequate studies inhumans. Benefit may warrant use in highly selected cases. CBelimumab In exceptional cases. No adequate studies in humans. Benefit may warrant usedespite potential risks, in highly selected cases. CJ. Clin. Med. 2018, 7, 415 12 of 21Table A1. Cont.Drug Main Features FDATo be avoidedCyclophosphamide Reports suggest that pregnancy termination is common in case of inadvertentuse. A few positive reports, mainly in SLE are available. DMethotrexate Also employed for extrauterine pregnancy termination. Discontinuation forone–three menstrual cycles pre-conception is usually indicated. XMycophenolateSevere foetal malformations are reported, mainly cardiovascular and cranial.Discontinuation for at lest 6 months, also for stabilizing the kidney function, isusually indicted after kidney transplantation.Dm-Tor inhibitorsVery few studies regard their use in pregnancy. They are teratogenic in animals;discontinuation in humans is matter of debate; KDIGO guidelines suggestdiscontinuation in prevision of pregnancy.CThymoglobulin Animal studies are not available.There are no controlled data in human pregnancy. NABasiliximabAnimal studies failed to reveal embryotoxicity, or teratogenicity. IgG are cross theplacental barrier and the IL-2 receptor plays an important role in development ofthe immune system. There are no controlled data in human pregnancy.BAlemtuzumabIn animal studies no teratogenic effects are observed. However, there was anincrease in embryolethality in pregnant animals. There are no controlled data inhuman pregnancy, but potential benefits may warrant use of the drug in selectedpregnant women despite potential risks.CFDA site of the Food and Drug Administration; FDA rating: B. No evidence of risk in studies; C. Risk cannot beruled out; D. Positive evidence of risk; X. Contraindicated in pregnancy. NA. not available.Table A2. Main anti-hypertensive drugs for CKD patients in pregnancy.Drug Main Features FDAUsually considered as first choiceAlpha-methyldopa Widely used in pregnancy, with no reported negative effects. May not besufficient to correct severe hypertension in CKD. BNiphedipine The long acting form is commonly used. In CKD the side effect of increasingperipheral oedema may be relevant. CLabetalol Usually well tolerated, should be avoided in asthma. In a RCT it was comparableto alpha-methyldopa. CUsually considered as second choicesBeta-blockersThe main negative effect in older studies was foetal growth restriction, possiblyas an effect of overzealous correction of BP. Beta1 selective beta-blockers(atenolol) are more often in cause. May be more effective than alpha-methyldopa,alone or in combined therapy. At delivery they may induce hypoglycaemia,hypotension and bradycardia (usually mild and transient).D atenololB pindololC metoprolClonidineThe effect is similar to alpha-methyldopa; side effects may be more common andhypertensive rebounds at discontinuation are common; slowing fetal growth isoccasionally reported.CDiureticsThey are usually avoided in pregnancy except for cardiological indications.Thiazides may be continued in patients previously on treatment. In Gitelmansyndrome, amiloride may be needed.Bhydrocloro-thiazideTo be avoidedNiphedipine short acting Contraindicated by FDA, RCOG and AIPE for the risk of severe suddenhypotension with detrimental effect on placental flows. XACE-i/ARBs and related drugsBoth are contraindicated in all phases of pregnancy; different malformations,involging cardiovascular, central nervous system, renal and bone are reported.Recent studies suggest that the risk is limited to the second and third trimester.XFDA site of the Food and Drug Administration; FDA rating: B. No evidence of risk in studies; C. Risk cannot beruled out; D. Positive evidence of risk; X. Contraindicated in pregnancy. RCT: randomized controlled trial. RCOG:Royal College of Obstetricians and Gynecologists. AIPE—Italian Association on Preeclampsia.J. Clin. Med. 2018, 7, 415 13 of 21Table A3. Main antibiotics for CKD patients in pregnancy.Drug Main Features FDAUsually considered as first or second choicesAmpi-amoxycillin Ampicillin and Amoxicillin are the first-choice antibiotics. BClavulanic acid Indicated when therapy with the previous ones is not effective, or according to antibiogramme. BCephalosporins Available data do not indicate an increase of malformations; risk for kernicterus is increased(mainly ceftriaxone). BCarbapenems Meropenem is the first choice in severe infection; no demonstrated risks in humans; increased riskof malformations with imipenem-cilastatin in animals. BAztreonam Alternative in case of allergy to beta-lactams (parenteral only). BMacrolides Eritromicine is a good alternative in case of contraindication to beta-lactamics. Claritromicine andazitromicine are a second choice. BPhosphomycin Indicated in uncomplicated urinary tract-infections. BNitrofurantoin Contraindicated in G6PDH-deficiency. Contraindicated at the end of the pregnancy for risk ofhaemolytic anaemia in the new-born. BTo be avoided (except when lifesaving)Aminoglycosides Associated with ototoxicity in the foetus and newborn. DFluoroquinolones Associated with abnormalities in the development of cartilages in animal studies CTetracycline Cause of various bone abnormalities. DSulphonamides Sulfamethoxazole/trimethoprim is a folic acid antagonist that increases the risk of kernicterus. DFDA site of the Food and Drug Administration; FDA rating: B. No evidence of risk in studies; C. Risk cannot beruled out; D. Positive evidence of risk.Table A4. Other commonly prescribed drugs for CKD patients in pregnancy.Drug Main Features FDAUsually considered as relatively safe, when absolutely neededAcetylsalicylate At low doses may protect against pre-eclampsia; discontinuation before delivery isrecommended. ALow molecular weightheparinDo not cross the placenta. Safe for prophylaxis and treatment of thromboemboliccomplications in pregnancy and post-partum. BESAs Do not cross the placenta and are considered safe; there may a need to increase doses inpregnancy. Not assignedAllopurinolCrosses the placenta. Animal reproduction studies have shown potential adverse effects onthe fetus. No adequate studies in humans. Potential benefits may warrant use of in pregnantwomen despite potential risks.CVitamin DNo advantage when given regardless of blood levels Vitamin D3 is recommended to correctdeficiency. Cholecalciferol crosses the placenta but the transfer to the fetus is low; no evidenceof adverse effects. Calcitriol, paricalcitol are teratogenic in animal studies. Animal studieshave shown adverse effects of Ergocalciferol on the fetus. No adequate study in humans.Not assignedCholecalciferolC ErgocalciferolIron supplementsMultivitamin with iron is only recommended for use in pregnancy when benefit outweighsrisk. Ferrous sulfate use is the most frequently used. Maternal anemia increases the risk of lowbirth-weight, premature delivery, and impaired cognitive development. Recent studies havelinked high serum iron with an increased risk of gestational diabetesAMultivitaminwith ironNot assignedFerrous sulfateSodium bicarbonate No animal or human data availale. Sodium bicarbonate should only be given duringpregnancy when benefit outweighs risk CCalcium carbonateMalformation risk is unlikely in humans. In some patients, permanent hypercalcemia resultedin adverse effects on the fetus. No available data in humans. Low intake is associated withadverse pregnancy events.Not assignedTo be avoidedWarfarinEvidence of teratogenicity in animal studies. In humans, exposure during the first trimestercaused congenital malformations in about 5% of the exposed. Mental retardation, blindness,schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes havebeen reported following exposure in the second and third trimesters. Fatal fetal hemorrhageand an increased risk of spontaneous abortion and fetal mortality are also reported. Case bycase evaluation in the case of cardiac indications.Not assignedNovel anticoagulants Animal studies show adverse effects for Rivaroxaban, Dabigatran and Edoxaban. Noadequate study in humans, but potential benefits may warrant use in highly selected cases. CCalcimimetics Animal studies show adverse effects, and there is no adequate study in humans; potentialbenefits may warrant use in highly selected cases. CSevelamer Animal studies show adverse effects, and there is no adequate study in humans; potentialbenefits may warrant use in highly selected cases CFDA site of the Food and Drug Administration; FDA rating: A. Controlled human studies show no risk; B. Noevidence of risk in studies; C. 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eng
Reviewed
Vancouver : University of British Columbia Library
Multidisciplinary Digital Publishing Institute
CC BY 4.0
Faculty
Chronic kidney disease (CKD), dialysis
Kidney transplantation
Pregnancy
Pregnancy complications
Pregnancy in Chronic Kidney Disease: Need for Higher Awareness. A Pragmatic Review Focused on What Could Be Improved in the Different CKD Stages and Phases
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