Pregnancy with Preexisting Kidney Disease


Chapter 45

Pregnancy with Preexisting Kidney Disease



Mark A. Brown


Historically, renal disease was considered a contraindication to pregnancy, but now many pregnant women with chronic kidney disease (CKD) have successful outcomes. Accordingly, nephrologists and obstetricians need to be skilled in the management and counseling of such women. This chapter details the outcomes and management of such pregnancies. More recently, information indicates that even women with the earliest stages of CKD and those with previously treated lupus nephritis carry increased pregnancy risks, and that fetal survival continues to improve in well-dialyzed pregnant women.



Chronic Kidney Disease: Adverse Effects on Pregnancy


Up to 3% to 10% of women of childbearing age have CKD stages 3 to 5.1 Available data on pregnancy outcomes are mainly from studies published 10 to 20 years ago and probably overestimate risk compared to outcomes achieved with modern care, particularly with improvements in neonatal intensive care. This is changing, with more recent emphasis on assessing pregnancy outcome according to pre-pregnancy estimated glomerular filtration rate (eGFR) when possible, but there are still fewer data for pregnancy outcomes assessed by this method than by pre-pregnancy serum creatinine alone. The key pre-pregnancy factors predicting outcome include the following:



In most circumstances, these features are more important in predicting outcome than the mother’s specific renal disease.


The traditional view was that most women with mild renal impairment (serum creatinine <1.5 mg/dl; 130 µmol/l) and controlled hypertension have a successful pregnancy outcome, with preexisting hypertension the main predictor of pregnancy outcome in women with mild renal impairment. However, more recent studies challenge this. Perinatal mortality, preterm delivery, small-for-gestational age rates, and development of superimposed preeclampsia appear high even in women with creatinine less than 125 µmol/l before conception, but more than 100 µmol/l in early pregnancy, and indeed, even in women with normal GFR but dipstick proteinuria and one or more other risk factors for preeclampsia.2 Those with moderate (serum creatinine 1.5 to 2.5 mg/dl; 130 to 220 µmol/l) to severe (>2.5 mg/dl; 220 µmol/l) renal impairment, particularly when accompanied by hypertension and heavy proteinuria, have a lower chance of live birth and a greater risk for maternal complications, including progression of their renal disease (Box 45-1).





Progression of Chronic Kidney Disease


The risk of progression of renal disease during the pregnancy likewise depends less on the specific renal disorder and more on baseline serum creatinine, control of hypertension, and increasing proteinuria or onset of superimposed preeclampsia. The natural history of most mild CKD is that accelerated deterioration during a pregnancy is unlikely; the main exception is lupus nephritis, which can flare, leading to worsening renal disease during the pregnancy. However, 50% of women with moderate baseline renal impairment (serum creatinine >1.5 mg/dl; 130 µmol/l) have a significant rise in serum creatinine in the third trimester or early postpartum. If this occurs, almost one in five progress to end-stage renal disease (ESRD) within 6 months after delivery.




Fertility


Fertility rate is reduced in women with moderate to severe CKD, but the only estimates are imprecise. Even women receiving dialysis may become pregnant, so all women should be advised to use contraception unless planning a pregnancy.



Management Common to All Pregnancy with Preexisting Kidney Disease


Box 45-3 summarizes the general principles of management of pregnancy in women with CKD.




Pre-pregnancy Counseling


It has long been known that any woman with CKD stage 3 to 5 should receive pre-pregnancy counseling. We now know that this should also apply to women with CKD stage 1 or 2, particularly if they have hypertension, significant proteinuria, a poor obstetric history, recurrent urinary tract infection (UTI), inheritable renal disease, or other disease (e.g., SLE) likely to worsen during pregnancy. Studies from Italy have found that preterm delivery, cesarean rates, and need for neonatal intensive care were higher than in the general population, even in women with stage 1 CKD; this was particularly true if baseline proteinuria was more than 1 g/day.5,6 Another meta-analysis included older studies but also a large number of women in stage 1 CKD; both maternal and fetal outcomes were worse in women with any form of CKD.7 A study from Arabian Gulf countries examined outcomes of women with stage 1 and 2 CKD and also showed unexpectedly high rates of preterm delivery, fetal growth restriction, and fetal death in women with eGFR as high as 60 to 89 ml/min.8 Although this may not be a worldwide experience, it now seems prudent to follow all women with any CKD more closely during pregnancy, not just those with impaired GFR or proteinuria above 1 g/day. This is more relevant because CKD stage 1 or 2 affects 3% of women of childbearing age, whereas CKD stage 3 to 5 affects about 1 in 150 of these women.9 Box 45-4 summarizes issues that should be covered in counseling.




Excretory Renal Function


During normal pregnancy, GFR rises by about 50%, typically apparent by the end of the first trimester (see Chapter 43). Serum creatinine greater than 1 mg/dL (88 µmol/l) in a pregnant woman generally indicates reduced GFR. The Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations or other formulas that estimate GFR are not valid for pregnancy; whereas it is reasonable to assess pregnancy risks based on pre-pregnancy eGFR, these formulas should not be applied in pregnancy. Measurement of creatinine clearance is the only clinical way of truly assessing GFR in pregnancy but requires 24-hour urine collection, which is cumbersome, and even when conducted diligently, may be inaccurate because of ureteral dilation, which results in pooling of urine and an incomplete collection. Serum cystatin C is being evaluated but also appears inaccurate. Serum creatinine remains the clinical standard for assessing GFR during pregnancy.



Blood Urea Nitrogen


Increments in blood urea nitrogen (BUN) and creatinine may indicate deteriorating GFR and the need for initiation of dialysis if the pregnancy is to succeed (see Dialysis in Pregnancy). However, a rising BUN, particularly when accompanied by rising hemoglobin or hematocrit, may represent intravascular contraction, typically seen in preeclampsia. The main role for BUN in pregnancy is for monitoring the effectiveness of dialysis.



Serum Electrolytes, Albumin, and Volume Homeostasis


Serum sodium and bicarbonate are slightly reduced, potassium is at the lower end of the normal range, and albumin and uric acid are lower than in the nonpregnant state. Increases in serum sodium to those of nonpregnant women should suggest (reversible) pregnancy-specific diabetes insipidus (from excess placental vasopressinase). In general, this is a mild disorder, but DDAVP should be given if serum sodium rises above 150 mmol/l with low urine osmolality.


Adequate intravascular volume is essential to preservation of GFR and good pregnancy outcome for mother and baby. Clinically, it is difficult to assess maternal volume homeostasis. Edema is an unhelpful sign in pregnancy, so hematocrit should be measured in women with underlying CKD at the initial first trimester visit, along with serum albumin. Both measures should fall slightly as pregnancy progresses. A rise in either value strongly suggests intravascular volume contraction, although there is no absolute discriminant value. Conversely, a significant fall in either value does not by itself diagnose excessive volume expansion, because the hematocrit depends on other factors, and serum albumin may fall in patients with nephrotic syndrome, who in turn may have reduced intravascular volume.


In practice, provided there is no respiratory compromise and BP can be controlled, volume excess is more favorable for maternal renal function and fetal growth than volume depletion. When there is concern about fetal growth or deteriorating GFR in women with CKD, and reduced intravascular volume is suggested by the change in hematocrit and albumin from baseline, a trial of intravenous normal saline (no more than 1 liter) under observation in hospital is a reasonable clinical approach.



Urinalysis


A dipstick test showing negative or trace protein in most (but not all) cases excludes true proteinuria. Any woman with 1+ (0.3 g/L) proteinuria or above should have formal quantification of protein excretion either with a spot urine protein-creatinine (PC) ratio or 24-hour urine collection. Glycosuria may be normal and is not itself diagnostic of diabetes mellitus, but when glycosuria is detected in early pregnancy in a woman with CKD, a 75-g oral glucose tolerance test should be performed. Dipstick hematuria during pregnancy is common and often resolves after delivery. Provided there is no UTI, urine sediment is inactive, and serum creatinine normal, this is not associated with adverse maternal or fetal outcomes during pregnancy and can be investigated if persistent postpartum.10 Pregnancy may be the woman’s first urinalysis, so previously undetected renal disorders are diagnosed at this point.



Proteinuria and Nephrotic Syndrome


The upper limit of normal protein excretion during pregnancy is defined as 300 mg/day. In a midstream specimen of urine, a PC ratio greater than 30 mg/mmol (0.27 mg/mg) correlates with more than 300 mg/day proteinuria.11



New-Onset Proteinuria


Isolated non-nephrotic proteinuria may develop de novo during pregnancy.12 In these women, with normal GFR, one of the following three scenarios usually unfolds:



In my experience, the third scenario is an uncommon event.



Preexisting Proteinuria


Although the spot urine PC ratio in pregnancy is a reasonably reliable method of determining whether protein excretion is abnormal, serial measurements of urine PC ratio are not recommended for reliably predicting changes in proteinuria. When a true increase in protein excretion occurs during pregnancy in women with underlying renal disease, few therapeutic options exist besides ensuring BP control (see later discussion).



Nephrotic Syndrome


The one situation in which 24-hour urinary protein excretion should be measured in these women is to diagnose nephrotic syndrome. Serum albumin falls in most pregnancies as a result of volume expansion and is often below 30 g/l, so this is not a reliable indicator of nephrotic syndrome. A spot urine PC ratio greater than 230 mg/mmol indicates protein excretion above 3 g/day,13 which should be confirmed by 24-hour urinary protein measurement. These women will generally have edema, but this is unhelpful because it occurs in two thirds of normal pregnancies. Although increased serum cholesterol is typical of nephrotic syndrome, this frequently occurs during normal pregnancy.


Confirmation of true nephrotic syndrome has important implications in pregnancy. There will be urinary loss of vitamin D–binding protein, transferrin, immunoglobulins, and antithrombin III (accompanied by increased hepatic synthesis of clotting factors) and a propensity for intravascular volume contraction. These changes can result in calcium deficiency, iron deficiency, increased likelihood of infection, thrombosis, and reduced uteroplacental blood flow with fetal growth restriction or death; some patients have reduced renal blood flow with worsening renal function. Adequate fetal growth and amniotic fluid should be evaluated by serial ultrasound. Treatment requires oral calcium, vitamin D and iron supplementation and subcutaneous heparin for thrombosis prophylaxis, and reassessment of maternal serum creatinine on a regular basis. If nephrotic syndrome occurs early in pregnancy, I add vitamin D for prophylaxis against osteoporosis, although there are no controlled trials to test this practice.



Hypertension


Hypertension in pregnancy is defined as blood pressure above 140/90 mm Hg, and this is generally the threshold for treatment, with an acceptable range on treatment of 110 to 140 systolic and 80 to 90 mm Hg diastolic. This range is not based on solid pregnancy outcome data but is thought to be the range that reduces maternal risk from severe hypertension while providing sufficient systemic BP to maintain placental perfusion. Although the target BP for nonpregnant women with CKD is also less than140/90 mm Hg, it is probably lower (≤125/75 mm Hg) if proteinuria is more than 1 g/day; therefore a pregnant woman with proteinuric CKD may have about 40 weeks when BP is above usual target, which may contribute to progressive renal impairment postpartum. Nevertheless, if a pregnant woman develops BP below 110/80 mm Hg, my practice is to reduce antihypertensive drugs and avoid the risk of fetal hypoperfusion.


Most pregnant women with CKD will not exhibit the usual first-trimester fall in BP, and in many, BP increases as the pregnancy progresses. The reason is not clear. Normal pregnancy is accompanied by significant volume expansion, which does not usually induce hypertension. In CKD, however, there is often inability to excrete a sodium load with accompanying hypertension, and this mechanism likely contributes in pregnancy. Other factors almost certainly playing a role in this hypertension include stimulation of the renin-angiotensin and sympathetic nervous systems, alterations in endothelial factors such as prostacyclin, nitric oxide, and endothelin, and particularly in transplant patients, the drugs used, such as calcineurin inhibitors and corticosteroids. Regardless of its cause, persistence of hypertension is an adverse factor in pregnancy outcome.14 Concern about using antihypertensives in pregnancy has been associated with poorer pregnancy outcomes, at least in women with renal transplant.15


Blood pressure will often rise significantly soon after delivery. Therefore, BP measurement and treatment should be undertaken diligently in the early postpartum period.


Control of BP is imperative to successful pregnancy outcome in women with underlying renal disease. Diuretics are not recommended during pregnancy because any reduction in maternal plasma volume may have adverse effects on uteroplacental or renal per­fusion. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) must be discontinued, preferably before pregnancy but certainly as soon as pregnancy is diagnosed, because of increased risks of fetal growth restriction, oligohydramnios, neonatal renal failure, and probably cardiac and neurologic developmental abnormalities. Aldosterone antagonists should also be avoided, and atenolol has been associated with fetal growth restriction. Suitable antihypertensives include methyldopa, labetalol, oxprenolol, hydralazine, prazosin, and nifedipine, and all may be used in conventional doses. Diltiazem may also have a small benefit on reducing proteinuria, but this has not been addressed specifically for pregnancy.



Superimposed Preeclampsia


Preeclampsia is a placental disorder of unknown etiology that has several predisposing risk factors, one of which is CKD (see Chapter 44). The maternal renal effects of preeclampsia include a reduction in renal blood flow, increased sodium and uric acid reabsorption, reduced circulating renin and aldosterone concentrations, proteinuria, and impaired GFR. Superimposed preeclampsia in a woman with underlying renal impairment will lead to worsening renal function, exaggerated hypertension and proteinuria with risks of nephrotic syndrome, short-term and long-term risks to maternal renal function, as well as increased risks for fetal growth restriction, prematurity, and perinatal mortality.


However, it is difficult to diagnose superimposed preeclampsia in a woman who begins her pregnancy with renal impairment or proteinuria. An increase in BP, decline in GFR, increased plasma uric acid, or increasing protein excretion can all be caused by progression of the underlying renal disorder rather than superimposed preeclampsia, and no definitive diagnostic test yet exists. However, when these features are accompanied by neurologic symptoms, such as hyperreflexia with clonus, or by abnormal liver transaminases or new-onset thrombocytopenia (except in SLE), it is highly likely that superimposed preeclampsia has developed. Typically, these changes occur after 20 weeks’ gestation. It has been proposed that an increased ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is diagnostic of preeclampsia and distinguishes this condition from pregnant women with CKD.16 Although prom­ising, incorporated this into routine clinical practice is not yet recommended.


Diagnosing superimposed preeclampsia in women with CKD is somewhat unnecessary. Clinicians managing the woman with underlying renal disease should be vigilant for changes in maternal and fetal condition in all cases, and the indications for delivery in women with preeclampsia are broadly the same as those in women with progressive underlying renal disease (Box 45-5). On the other hand, it is now well recognized that preeclampsia is associated with long-term cardiovascular, metabolic, and renal risks for the mother so it is practical to error on the side of caution and “overdiagnose” this disorder because this may prompt better long-term follow-up.17



Limited studies suggest that aspirin is of benefit in reducing superimposed preeclampsia and perinatal death in women with underlying renal disease. A review found that the number needed to treat was 9 to 57 women for prevention of preeclampsia and 42 to 357 to prevent perinatal death.18 The PARIS study also found that aspirin reduced superimposed preeclampsia in women with underlying renal disease, but only 450 women were included in this analysis.19 My practice is to use low-dose aspirin (100 to 150 mg/day) for all women with CKD and creatinine greater than 1.5 mg/dl (130 µmol/l) or for those with lower creatinine who have had early-onset or severe preeclampsia or fetal loss in a previous pregnancy. The effects of this dose of aspirin on renal function are minimal, and generally this is a safe approach. I also use calcium (1200 mg/day) as prophylaxis against preeclampsia when there is no concern about hypercalcemia. Data for calcium as prophylaxis are less convincing than for aspirin, but when used carefully, calcium has minimal effects and may have benefit.


Jun 4, 2016 | Posted by in NEPHROLOGY | Comments Off on Pregnancy with Preexisting Kidney Disease

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