Pregnancy in Chronic Kidney DiseaseKavitha Vellanki

Despite vast improvements in fetal outcomes, pregnancy in womenwith CKD is fraught with hazards; worsening of renal func-

tion and complications like preeclampsia and premature delivery are common. To date, there is no accurate formula to calculate

glomerular filtration rate (GFR). Also, whether the current CKD classification is better than the older classification at predicting

outcomes in pregnant women with CKD is unknown. Women with an estimated GFR $1.4 mg/dL are at increased risk of pro-

gressive worsening of renal function regardless of the cause of the underlying kidney disease. Preeclampsia is difficult to diag-

nose in pregnant women with underlying CKD, and serum markers such as soluble fms-like tyrosine kinase 1 (sFlt1) and

placental growth factor (PIGF) may lead theway for definitive diagnosis. New-onset lupus or lupus flare is an indication for kid-

ney biopsy during pregnancy; cyclosporine is safe and is the most effective agent that can be used during pregnancy. Women

with adult polycystic kidneydisease are at increased risk of hypertension andpreeclampsia duringpregnancy, aswell as hepatic

cysts later in life, the latter occurring with multiple pregnancies. Strict blood pressure control is important in pregnant women

with diabetic nephropathy. A multidisciplinary team that includes nephrologists and obstetricians who deal with high-risk

pregnancies should be involved in the care of pregnant women with CKD for successful pregnancy outcomes.

Q 2013 by the National Kidney Foundation, Inc. All rights reserved.Key Words: Pregnancy in kidney disease, Preeclampsia, Lupus nephritis, ADPKD, Diabetic nephropathy, Reflux nephropathy

Despite vast improvements in fetal outcomes in thepast few decades, pregnancy in women with kidney

disease is fraught with hazard and continues to generateapprehension in physicians involved in their care. Themost compelling risk that differentiates pregnant womenwith CKD from other women with normal pregnancies isthe loss of renal function,which is seldom reversible. Thereappears to be a critical degree of renal insufficiency thatputs women who conceive at a greater risk for a rapid de-cline in renal function irrespectiveof the causeof theunder-lying kidney disease. Evidence of this long-standingobservation has been slow in coming because few womenof childbearing age have CKD, only a small number ofpregnant women with CKD are cared for at one center,and pregnancy does not lend itself to randomization.

From Department of Medicine, Division of Nephrology and Hypertension,Loyola University Medical Center, Maywood, IL.

The author has no conflicts of interest to disclose.

Address correspondence to Kavitha Vellanki, MD, Loyola University Med-

ical Center, Renal Section, Building 102, 2160 South First Avenue, Maywood,IL 60153. E-mail: kpotluri@lumc.edu

� 2013 by the National Kidney Foundation, Inc. All rights reserved.

1548-5595/$36.00http://dx.doi.org/10.1053/j.ackd.2013.02.001

CKD Classification in Pregnancy

CKD is now widely classified into 5 stages (Table 1). It isestimated that 1 in 750 pregnancies is complicated bystages 3-5 CKD.1 Most of the available literature onpregnancy outcomes is from an era before the currentCKD classification was developed. Pregnant womenwith CKD were arbitrarily classified into 3 categoriesbased on level of serum creatinine as mild (serumcreatinine ,1.5 mg/dL), moderate (1.5-2.5 mg/dL), andsevere (.2.5 mg/dL) renal dysfunction. Recent studieshave used the current classification in assessing preg-nancy outcomes, but it is important to note that to datewe do not have an accurate formula for calculating GFRin pregnant women. Neither the Cockroft-Gault nor theModification of Diet in Renal Disease formulas havebeen validated in the pregnant population. The ModifiedModification of Diet in Renal Disease underestimatesGFR in pregnant patients,2 whereas the Cockroft-Gaultformula overestimates GFR by 40mL/minute when com-pared with creatinine clearance.3 Whether the current

Advances in Chronic Kidney Disease, Vo

CKD classification is better than the older arbitrary clas-sification in predicting maternal and fetal outcomes inpregnant women with CKD is not known.

Renal Hemodynamics in Pregnant Women withCompromised Renal Function

Pregnancy causes significant changes in the kidney, bothanatomic and physiologic, and these changes have beenwell described in women with normal renal function.Although it is widely perceived that such changes donot always occur in women with CKD, to what extentthe "normal" physiologic changes seen in pregnancyare "abnormal" in women with kidney disease is notknown. Pregnancy-induced hyperfiltration also occursin women with pre-existing kidney disease, but this isrestricted to women with only mild reductions in GFR.A study conducted in 17 women with known chronicglomerulonephritis (GN) before pregnancy showed in-creases in GFR and renal blood flow (RBF) during preg-nancy similar to those seen in normal pregnancies.4 Anincrease in GFR is generally compromised when serumcreatinine before pregnancy is .1.4 mg/dL.5 The gesta-tional rise in GFR becomes attenuated as the severity ofunderlying disease worsens; in 1 study, only 50% ofwomen with moderate kidney disease and no women

l 20, No 3 (May), 2013: pp 223-228 223

Vellanki224

with severe kidney disease showed any rise in GFR dur-ing pregnancy.6

Fertility in Women with CKD

The fertility rate inwomenwithCKD isunknown. The stageof CKD at which infertility develops is also unknown, butfertility rates are thought to decline proportionatelywith de-clining renal function.Pregnancy isuncommonwhenserumcreatinine is.1.5mg/dL. The reasons for infertility in CKDare not clear. Abnormalities in the hypothalamic-pituitary-gonadal axis and hyperprolactinemia generally developlater in the course of the disease. (Please review ‘‘Changesin Fertility and Hormone Replacement Therapy in KidneyDisease’’ in this issue.) Nonetheless, pregnancy occurs fre-

CLINICAL SUMMARY

� In women with 1.4 mg/dL, pregnancy may cause rapid

worsening of renal function. Most infants survive but are

often premature.

� Preeclampsia is common and is difficult to diagnose in

women with CKD regardless of glomerular filtration rate.

The risk of preeclampsia can be decreased by administra-

tion of low-dose aspirin (50-150 mg) started in the 12th

week of gestation and continued until term.

quently enough that birthcontrol should be discussed.If a woman with CKDshould conceive, the com-plications of pregnancy arehigher than those of usingoral contraceptives, solow-dose estrogen can beused safely when there isno previous history ofthrombosis or poorly con-trolled hypertension.

� Womenwith lupus nephritis are at risk for a lupus flare and

even for renal failure regardless of renal function at

conception. New-onset lupus during pregnancy is an indi-

cation for biopsy. Pregnancy outcomes are best in women

who have been in remission for at least 6 months.

� Pregnant women with ADPKD are at increased risk for

hypertension and preeclampsia during pregnancy and for

hepatic cysts later in life.Womenwith ADPKD and brain an-

eurysms are advised to consider elective cesarean section.

� The outcome of pregnancies in women with diabetic

nephropathy is improved by 6 months of strict glucose

control and ACE inhibitor treatment before conception.

ACEI and ARB should be discontinued before pregnancy.

Effects of Pregnancy onWomen with KidneyDisease

Decline in RenalFunction

Despite a major increase inGFR during pregnancy, nolong-term effects on glomer-ular function or structurehave been noticed inwomen with normal renalfunction even with multiple

pregnancies. In pregnant women with underlying CKD,there are enough data to suggest that renal failure mayprogress rapidly with serum creatinine $1.4 mg/dL atconception. In a report of 82 pregnancies in 67 womenwith primary renal disease and a mean serum creatinineof 1.9 mg/dL before conception or in the first trimester,worsening renal function was more common in womenwith serum creatinine .2.0 mg/dL at the start of preg-nancy. The incidence of hypertension and high-gradeproteinuria (defined as .3000 mg/L) nearly doubledduring the third trimester.7 A prospective study pub-lished in 2007 compared the rate of loss of renal functionbefore and after conception in women with stages 3-5CKD. Of note, all the enrolled women were white with

relatively low body weight, and glomerular disease wasthe predominant cause of CKD. Forty-nine pregnancieswere studied over a period of 27 years, and the mean se-rum creatinine at conception was 2.1 mg/dL. The rate ofdecline in GFR was not significantly different from con-ception to after delivery, but in subgroup analyseswomen who had a GFR ,40 mL/minute/1.73 m2 and24-hour proteinuria .1 g had an accelerated rate ofGFR loss.8

The mechanism by which pregnancy accelerates pro-gression of moderate to severe kidney disease is un-known. In nonpregnant patients, prolonged periods ofrenal vasodilation in some types of chronic progressivekidney disease can lead to an increase in intraglomeru-lar pressure (PGC), contributing to further progression

of kidney disease.9 How-ever, in such settings therenal vasodilation is pre-dominantly of the afferentarteriole causing a rise inPGC. In normal pregnan-cies, there is a parallel re-duction in tone of bothafferent and efferent arteri-oles with no increase inPGC. Whether these parallelchanges in both the afferentand efferent systems is dis-rupted in pregnant womenwith CKD, leading to in-creased PGC and a progres-sive decline in kidneyfunction, needs to be ex-plored. Nitric oxide (NO)is thought to play a keyrole in renal hemodynamicadaptations to pregnancy.Chronic nonselective inhi-bition of NO synthase inrats prevents a gestationalrise in the GFR and renal

vasodilation causing systemic hypertension,10 but thereare there are no clinical studies that address the role ofNO in normal human pregnancies. Pregnancy inwomen with CKD is frequently accompanied by hyper-tension, but an accelerated decline in renal function hasbeen described in some women with an unequivocallynormal BP throughout pregnancy.11 Whatever themechanisms, pregnancy exerts adverse effects only af-ter a critical amount of renal function has been lost re-gardless of the cause of CKD. Once a decline in renalfunction has occurred, it cannot be predictably reversedeven by terminating the pregnancy. Women who startdialysis for progressive renal insufficiency during preg-nancy usually require continued dialysis postpartum.12

Women with a pregnancy-related decline in renal

Table 1. Stages of CKD

Stage Description

GFR in

mL/m/m2

1 Kidney damage with normal or

raised GFR

.90

2 Kidney damage with mildly

lower GFR

60-89

3 Moderately lower GFR 30-59

4 Severely low GFR 15-29

5 Kidney failure ,15 or dialysis

Abbreviation: GFR, glomerular filtration rate.

Pregnancy in Chronic Kidney Disease 225

function account for approximately 20% of women whoreceive dialysis during pregnancy.12

Proteinuria

Protein excretion of more than 300 mg in a 24-hour periodis considered abnormal in pregnancy, and if noted for thefirst time after the 20th week of gestation it is a sign ofpreeclampsia until proved otherwise. It is speculatedthat an increase in GFR and RPF, along with pregnancy-induced anatomic changes, leads to an increase in proteinexcretion during pregnancy, which generally reversespostpartum. In a study that included 202 pregnant womenwith no baseline proteinuria (only 1 patient had CKD), sig-nificant proteinuria defined as $11 protein on the urinedipstick test was detected in 3.8%, 10.6%, and 10.7% infirst, second, and third trimesters, respectively.13 Protein-uria disappeared in all patients postpartum and nonehad deterioration in renal function. Studies in womenwith known CKD have shown that severe proteinuriaearly in pregnancy is a major risk factor for adverse neona-tal outcomes irrespective of BP control.14,15 Proteinuria canbe noted for the first time during pregnancy either becausepre-existing renal disease is detected or because of new-onset renal disease. Definitive diagnosis can be delayeduntil after pregnancy unless there is serologic evidenceof lupus or the patient has profound hypoalbuminemiawith severe complications of nephrotic syndrome.

Hypertension and Preeclampsia

Women with CKD have chronic hypertension at baselineand many receive antihypertensive medications beforeconception. Angiotensin-converting enzyme inhibitors(ACEIs) and aldosterone receptor blockers (ARBs) arewidely used for the management of hypertension, makingprepregnancy counseling extremely important. ACEIs andARBs should be discontinued before conception. BecauseBP fluctuates early in the course of pregnancy, antihyper-tensive medications need frequent adjustment, requiringclose monitoring with home BP readings. In pregnantwomen who have undergone kidney transplantation andhaveunderlyingCKDand inwhomhypertension is relatedto volume expansion unrelated to pregnancy, diuretics are

frequently needed forBPcontrol. In suchpatients, diureticscanbeusedwith cautionwhile avoidingvolumedepletion.Most physicians agree that hypertension, when pre-existing or developing early in pregnancy, should betreatedmore aggressively in patients with underlying kid-ney disease than in patients with isolated essential hyper-tension. The optimal BP goal for pregnant women withCKD is still debated, but best fetal outcomeswere reportedwhen diastolic BP was between 80 and 90 mmHg.15

Preeclampsia is a multisystem disease that is unique tohuman pregnancy. It is the most common renal complica-tion seen in pregnancy, occurring in 3% to 5% of all preg-nancies. It is characterized by new-onset hypertensionand proteinuria after the 20th week of gestation and iscommonly associatedwith edema andhyperuricemia. Al-though it mostly occurs in women without previouslyknownrisk factors, preeclampsia ismore common inpreg-nant womenwith underlying hypertension, diabetesmel-litus, or kidneydisease of any cause or severity.16 It is oftendifficult to diagnose preeclampsia in patients with under-lying CKD especially because most of these patients havehypertension, edema, and proteinuria at baseline. Overthe years, there has been an intense search to identifypreeclamptic circulating factors that can help in the earlydiagnosis of preeclampsia.Wenowhave enough evidencesuggesting a role for placental antiangiogenic factors suchas soluble fms-like tyrosine kinase-1 (sFlt1), a circulatingantagonist to both vascular endothelial growth factorandplacental growth factor (PIGF), in producing endothe-lial dysfunction in preeclampsia.17 Although the idealscreening test for definite diagnosis is yet to be identified,assays of sFlt1 and PIGF appear to provide important di-agnostic information in pregnancies in which the diagno-sis of preeclampsia based on clinical findings ischallenging, such as in women with CKD. A recent studyreported sFlt1 and PIGF levels in women with CKD, andsignificant differences were noted in both sFlt1 and PIGFlevels in patients with preeclampsia superimposed on un-derlying CKD compared with those in women who haduneventful pregnancies.18More studies are needed to val-idate these findings. (For more discussion, please review‘‘Emerging Biomarkers of Preeclampsia’’ in this issue).Treatment of preeclampsia involves prevention of mater-nal seizures with magnesium, which needs careful titra-tion in women with CKD, but the definitive treatmentfor preeclampsia is delivery of the fetus and placenta.Since women with CKD are at moderate to high risk forthe development of preeclampsia, low-dose aspirin (50-150 mg/day) should be started from the 12th week ofgestation and continued until the birth of the fetus forprophylaxis against preeclampsia.19

Anemia

Hematocrit values drop in normal pregnancy because thered cell mass increases by only 18% to 30% when the

Vellanki226

plasma volume expands by 40% to 50%. This drop is fur-ther exacerbated in pregnant women with CKD by de-creased erythropoietin generation. A sharp drop in thehematocrit value is generally noted as early as the firstfew weeks after conception. Current available forms oferythropoietin-stimulating agents (ESAs) are labeled ascategory C drugs because human data are lacking. ESAsare being used in pregnant patients with CKD, and no un-toward effects have been reported thus far. Target hemo-globin levels for pregnant patients with CKD receivingESAs have not been established, but it would be reason-able to consider ESAs when the hemoglobin value is ,9g/dL despite adequate repletion of iron stores.

Bone Disease

In normal pregnancies, hypercalciuria occurs as early asthe 12th week of gestation as a consequence of increasedintestinal absorption. Total calcitriol levels double or tri-ple early in pregnancy and stay elevated until delivery.Intact parathyroid hormone levels fall to low-normallevels in the first trimester and increase to midnormalranges by term.20 Data onmetabolic bone disease in preg-nant patients with CKD are lacking. Phosphate bindersand vitamin D analogues are currently used with no un-toward effects reported thus far. There is limited experi-ence with cinacalcet or lanthanum carbonate.

Low-Protein Diet

Pregnant patients are generally counseled to have high-protein intake even when the ideal protein intake innormal pregnancy has not yet been assessed. Low-proteindiets are considered an important tool in the managementofpatientswithCKD.Little isknownabout the riskandben-efits of a low-protein diet in pregnant patients with CKD.Onestudyof12pregnancies reported thesafetyof avegetar-ian supplemented low-protein diet in pregnant patientswith CKD with good maternal and fetal outcomes.21

Effects of Maternal Kidney Disease on FetalOutcomes

Despite the risk of progression of renal failure in womenwith moderate to severe kidney disease, the likelihood ofpregnancy resulting in a surviving infant is good, and in-fant survival is.75% even in women requiring dialysis.12

The most common fetal adverse outcomes are intrauterinegrowth retardation (IUGR) and prematurity. Long-termfollow-up data on surviving infants are not available.

Pertinent Aspects Related to Pregnancy andUnderlying Kidney Disease

Lupus Nephritis

Lupus nephritis (LN) is among the most variable andmost dangerous renal diseases affecting pregnant women.

The rule of renal failure not progressing when serum cre-atinine is ,1.4 mg/dL does not apply to women with lu-pus. Fertility in women with LN is similar to that of thegeneral population if renal function is normal, except inwomen who have been treated with large doses of cyclo-phosphamide. Pregnancy-induced immunologic and hor-monal changes are associated with flares of systemiclupus erythematosus and LN in particular. Increasedrisk of LN flare during pregnancy was reported in multi-ple studies that used a patient’s own nonpregnant coursefor comparison.22,23 Women with class III and class IV LNare at increased risk of hypertension during pregnancyand renal flares when compared with women with classII and class V LN.24 In a recentmeta-analysis that included37 studies on pregnancy outcomes in systemic lupus er-ythematosus and LN,womenwith active LNduring preg-nancy had an increased risk of maternal hypertension andpremature delivery, whereas women with a history of LNwere more prone to the development of hypertension andpreeclampsia.23 Fetal outcomes are generally good whenspontaneous abortions (16%) are excluded, with IUGRand premature delivery being the most common compli-cations.23 One of the most characteristic problems in theneonate is congenital heart block associated with maternalanti-SSA antibody. The prognosis for infants with heartblock is variable. Antiphospholipid antibodies are associ-ated with both fetal and maternal complications. Someimprovements in outcomes have been reported withchronic anticoagulation (low-dose aspirin and heparin)in such patients.25 New-onset lupus or lupus flare is an in-dication for biopsy during pregnancy in the first and sec-ond trimesters because it facilitates disease-specifictreatment. Typically, renal biopsy is avoided after 32weeks of gestation, at which time the risks and benefitsof biopsy vs delivery should be considered. Treatment op-tions are limited because of the teratogenic effects of my-cophenolate and cyclophosphamide, the latter beingteratogenic in the first trimester. Cyclosporine is safeand is the most effective agent that can be used duringpregnancy. Azathioprine and prednisone can be usedsafely as well. Mycophenolate is contraindicated andshould be discontinued 6 weeks before planned concep-tion. For womenwith pre-existing LN, pregnancy is safestif the disease has been in remission with the patient re-ceiving ,10 mg daily of prednisone for 6 months, serumcreatinine is ,1.5 mg/dL, and BP is well controlled.

Primary Glomerulonephritis in Pregnancy

Pregnancy does not adversely affect the course of mater-nal renal disease in women with underlying primary GNas long as renal function is near normal. In the largestpublished cohort of 360 women with various histologicforms of GN, overall end-stage renal disease–free sur-vival did not differ significantly in women who becamepregnant (n ¼ 171) after clinical onset of kidney disease

Pregnancy in Chronic Kidney Disease 227

and those who did not conceive (n ¼ 189).26 Hyperten-sion, BP .140/90 mm Hg, and the histologic form ofGN were predictive factors for subsequent developmentof end-stage renal disease, with the odds ratio beingsignificantly higher for focal and segmental glomerulo-sclerosis and membranoproliferative GN than for mem-branous nephropathy (increased risk seen in IgA didnot reach statistical significance).26

Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD)does not affect fertility in women with normal renal func-tion.Reportsof ectopicpregnancieshavenotbeenvalidatedin large studies.27 In 1994 in the largest published report onpregnancy outcomes in ADPKD, Chapman and col-leagues28 comparedoutcomes in605pregnancies inwomenwith ADPKD and 244 pregnancies in women withoutADPKD. Women with ADPKD had a significantly higherfrequency of maternal complications such as hypertensionand preeclampsia comparedwithwomenwithout ADPKD(35% vs 19%; P , .01). Normotensive women with normalrenal function generally have uncomplicated pregnancies,and renal function is not affected despitemultiple pregnan-cies. However, in the study by Chapman and colleagues,16% of normotensive women experienced new-onset hy-pertension in pregnancy, with 11% having preeclampsia.Also, fetal prematurity frompreeclampsiawas significantlyhigher in women with ADPKD (28% vs 10%; P , .01).28

Women with ADPKD and multiple pregnancies are morelikely to have hepatic cysts later in life. Women withADPKD are advised to undergo brain imaging for aneu-rysms before delivery, and if aneurysms are present to con-sider elective cesarean section rather than natural birth;evidence for such recommendations is yet to come.

Reflux Nephropathy

Reflux nephropathy is a common cause of CKD inwomen of childbearing age. Persistent vesicoureteral re-flux is not associated with increased fetal loss or maternalrisk as long as renal function is normal before conception.The risk of preeclampsia has been reported to be greaterin women with bilateral renal scars than in those withunilateral involvement.29 Recurrent urinary tract infec-tion is the most frequent maternal complication seen dur-ing pregnancy. Acute pyelonephritis is more common inwomenwith persistent vesicoureteral reflux at the time ofconception than in women who had surgical correctionbefore pregnancy. Prophylactic correction may be advis-able in womenwho have had repeated episodes of pyelo-nephritis in adult life.30

Diabetic Nephropathy

In women with underlying diabetic nephropathy, preg-nancy is not associated with a greater decline in renal

function when the serum creatinine is normal. In gen-eral, pregnancy outcomes in women with diabetic ne-phropathy are favorable as long as the serumcreatinine is ,1.4 mg/dL, proteinuria is ,1 g/24 hours,and BP is well controlled.31 Increased risk ofpreeclampsia, IUGR, preterm delivery, and develop-mental disabilities in the child have been reported inpregnant women with diabetic nephropathy. Higherrates of successful pregnancy outcomes have been re-ported with treatment with ACEIs combined with strictmetabolic control for at least 6 months before concep-tion.32 ACEIs and ARBs should be discontinued beforeconception. However, the risk of congenital malforma-tion is so low that pregnancy should not be terminatedif the fetus is exposed to these drugs during organogen-esis.33 The goals of antihypertensive treatment includeBP ,135/85 mm Hg, which is stricter compared withthat in other pregnant women, and urine albumin excre-tion of ,300 mg/24 hours.33 Low-dose aspirin (50-150mg) daily should be started in all women with diabeticnephropathy at 12 weeks of gestation for primary pre-vention of preeclampsia.

CKD Diagnosed During Pregnancy

CKD can be diagnosed for the first time during preg-nancy. It is important to note that serum creatininevalues of 1.0 mg/dL, which are considered normal fornonpregnant women, are of concern in normal preg-nancy and can be an indication of CKD that was undiag-nosed before pregnancy. Kidney biopsy is usuallyavoided in pregnancy because of fear of bleeding fromthe biopsy site, but whether there is an actual increasedrisk of bleeding is not clear. Percutaneous ultrasono-graphically guided biopsy can be performed whenneeded with the patient in the usual prone position orlying on the right side. Biopsy is indicated when a treat-able renal disorder is suspected, especially early in thecourse of pregnancy, as in LN, sudden worsening in re-nal function, or proteinuria in the severe nephrotic rangewith profound hypoalbuminemia. In the last situation, itis useful to know if the disease responds to corticoste-roids.

Conclusions

Women with severe renal impairment have the greatestdifficulty conceiving, the highest rate of miscarriage,and the poorest pregnancy outcomes. For a womanwith renal insufficiency who conceives, that pregnancymight be the last opportunity for childbearing, so when-ever possible, pregnancy in women with CKD should beplanned and a team of obstetricians who deal with high-risk pregnancies, nephrologists, neonatologists, anddisease-specific specialists should be involved in the pa-tient’s care.

Vellanki228

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