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Renal Disorders
Pregnancy induces many changes to both renal function and physiology. Physiologic adaptations to the renal system that occur in normal pregnancy are the subject of Chapter 9 . The focus of this chapter is to describe the effects of various preexisting renal conditions in pregnancy and discuss the implications of various obstetrical conditions on the renal system. Although women with preexisting chronic kidney disease typically have stable or transient worsening of their kidney function during pregnancy, pregnancy-related conditions may occasionally induce permanent worsening of kidney function. Pregnant women with chronic renal disease often have a higher risk for associated obstetric comorbidities. We begin this chapter with acute causes of renal dysfunction in pregnancy including preeclampsia, one of the more common complications of pregnancy that affect renal function. We next describe chronic renal disease in pregnancy, management of pregnant women receiving dialysis or with a renal allograft, and associated outcomes of neonates born to women with chronic kidney disease.
Acute Renal Failure in Pregnancy
As described in Chapter 9 in this edition, there are a number of physiologic changes to the renal system in pregnancy that result in an increased glomerular filtration rate and subsequent increased creatinine clearance, leading to a lower serum creatinine compared to nonpregnant individuals. Mean serum creatinine levels in pregnancy in the first, second, and third trimesters are 0.7 mg/dL, 0.6 mg/dL, and 0.5 mg/dL, respectively, compared to the mean serum creatinine in the nonpregnant population of 0.83 mg/dL. Fortunately, prolonged renal failure resulting from an acute obstetrical etiology remains rare.
Acute renal failure in pregnancy may occur secondary to azotemia from vascular depletion, sepsis, severe cardiopulmonary disease, ovarian hyperstimulation syndrome (OHSS), preeclampsia, HELLP syndrome ( h emolysis, e levated l iver enzymes, and l ow p latelets), hemolytic uremic syndrome or thrombotic thrombocytopenic purpura (HUS/TTP), acute fatty liver of pregnancy (AFLP), and intrapartum outlet obstruction.
Etiologies in Early Gestation
The estimated incidence of acute kidney injury (AKI) during early pregnancy is less than 1 in 20,000 pregnancies. The most frequent cause of AKI in early pregnancy is prerenal azotemia secondary to volume-depleting conditions, commonly hyperemesis gravidarum or nausea and vomiting associated with acute pyelonephritis. Clues to this diagnosis include a history of vomiting and physical signs of volume depletion (e.g., orthostasis, flat neck veins, dry mucous membranes). The patient’s laboratory studies may reveal an elevated blood urea nitrogen (BUN) level out of proportion to the elevation in creatinine. Treatment with intravenous isotonic fluids results in normalization of renal function.
Although rare in developed countries, septic abortion remains an important clinical problem in low- to middle-income countries and in countries where induced abortion is illegal or inadequately accessible. Women with septic abortion typically present with vaginal bleeding, fever, and lower abdominal pain, usually within hours to days after the attempted abortion. AKI complicates up to 73% of cases of septic abortion, and it is often characterized by anuria caused by renal cortical necrosis from systemic sepsis.
Ovarian hyperstimulation syndrome (OHSS) can also be a cause of AKI early in pregnancy. Seen primarily in women undergoing ovulation induction with gonadotropins for infertility, OHSS results in increased vascular permeability leading to a shift of intravascular volume (third space loss) to serous spaces and increased risk for venous thromboembolic events. Arterial vasodilation accompanies this intravascular hypovolemia, and in severe cases of OHSS the resultant renal hypoperfusion can lead to AKI.
The key issues in the treatment of AKI in pregnancy due to any cause are restoration of fluid volume deficits, maternal and fetal stabilization, and assessment of delivery timing based on the etiology of the AKI. No specific therapy has been shown to be effective in acute cortical necrosis except for dialysis when needed. Both peritoneal dialysis and hemodialysis have been used during pregnancy and are further described later.
Preeclampsia
Preeclampsia, a systemic syndrome of pregnancy characterized by new-onset hypertension and proteinuria after 20 weeks’ gestation, affects 3% to 5% of all pregnancies and is a major cause of maternal, fetal, and neonatal morbidity and mortality worldwide. Preeclampsia presents heterogeneously and includes a spectrum of conditions including preeclampsia without severe features, preeclampsia with severe features, and HELLP syndrome. In severe cases of preeclampsia with severe features or HELLP syndrome, preeclampsia can lead to acute renal failure. Fortunately, only a small minority of patients with severe forms of preeclampsia require hemodialysis for the management of acute renal failure. In patients with preeclampsia with severe features and renal failure, major obstetric complications such as placental abruption are common; typically perinatal outcomes are poor. A more extensive discussion of preeclampsia is the subject of Chapter 45 .
Both glomerular filtration rate (GFR) and effective renal plasma flow decrease in preeclampsia. Because the decrement in filtration is less than 25%, and lower in mild cases, the GFR in women with preeclampsia often remains above values in nonpregnant women, despite pathologic evidence of ischemia and an obliterated urinary space. However, although functional decrements are usually mild or moderate and reverse rapidly after delivery, an occasional preeclamptic patient may progress to acute renal failure, especially when treatment or intervention is delayed or when there is associated severe obstetric hemorrhage resulting in hypovolemia. The mechanism (or mechanisms) responsible for the compromised renal function in preeclampsia may be related to renal vasoconstriction and to the glomerular endotheliosis classically noted on renal biopsies.
Evidence suggests that preeclampsia is primarily a multisystem endothelial disease that leads to development of hypertension, proteinuria, and progressive edema. Several studies have reported a strong association between altered circulating angiogenic factors and preeclampsia. These factors include circulating antiangiogenic proteins such as soluble fms-like tyrosine kinase 1 (sFLT1) and soluble endoglin, and the proangiogenic protein placental growth factor (PlGF). Abnormalities in these circulating angiogenic factors not only are present during clinical disease but also antedate clinical signs and symptoms by several weeks ( Fig. 57.1 ). , , Levels of circulating angiogenic factors in patients with preeclampsia correlate with severe disease, including acute renal failure. These markers may be particularly useful in diagnosing preeclampsia in clinical situations that make it difficult to distinguish preeclampsia from progression of their underlying medical conditions such as preexisting hypertension and renal disease. , In addition, these angiogenic markers may be useful to differentiate HELLP syndrome from other causes of thrombocytopenia such as gestational thrombocytopenia.
Although the only known method to start recovery from preeclampsia has been delivery of the placenta, one novel treatment that may delay the need for delivery is peripheral extracorporeal apheresis to neutralize or remove harmful angiogenic factors such as sFLT1. This technique has been shown in two pilot studies to decrease proteinuria and prolong pregnancy in patients with very-preterm preeclampsia. ,
For women with preeclampsia with severe features causing acute renal failure, delivery is recommended. Typically, delivery is advised for pregnant patients with preeclampsia and new renal insufficiency with a creatinine of 1.1 mg/dL or with a doubling of their baseline creatinine in the absence of baseline renal disease. Oliguria in preeclampsia with severe features is thought to be secondary to vasospasm of the intrarenal vasculature leading to renal sodium retention and subsequent water retention. The amount of proteinuria by itself no longer dictates delivery timing nor categorizes a patient as having severe disease, though patients with preexisting renal disease with proteinuria are at increased likelihood of developing preeclampsia. Delivery of the placenta usually produces prompt improvement in renal function, although in a few cases, when the disease is severe and advancing rapidly, renal function may take days or sometimes weeks to improve, occasionally requiring hemodialysis.
Studies have evaluated the effect of nonsteroidal antiinflammatory drugs (NSAIDs) on resolution of postpartum hypertension; randomized trials have not shown a difference in the duration of severe-range blood pressures following delivery for preeclampsia. NSAIDs therefore are reasonable to use in the postpartum period in the setting of preeclampsia There is a plausible effect of NSAIDs causing delay in resolution of renal failure in the postpartum period in patients with preeclampsia; studies evaluating this outcome were not powered adequately or excluded patients with a creatinine >1.0 mg/dL. Brief postpartum furosemide therapy for patients with severe preeclampsia has been shown to enhance recovery by normalizing blood pressure more rapidly and reducing the need for antihypertensive therapy.
Preeclampsia and Future Risk for End-Stage Renal Disease and Vascular Disease
There is extensive evidence that although preeclampsia may initially manifest during a pregnancy, preeclampsia is a systemic vascular disorder, and patients are at increased risk of future comorbidities including increased cardiovascular morbidity and end-stage renal disease (ESRD). Although follow-up studies in women with acute renal failure related to preeclampsia are limited, a large contemporary cohort demonstrated that women with a history of preeclampsia have an increased relative risk of at least 4.7 for developing ESRD. Although the absolute likelihood remains low, preeclampsia was consistently associated with future permanent kidney injury, even when controlling for preexisting kidney disease, essential hypertension, or diabetes mellitus. Another longitudinal study conducted in Norway described a 1.2-fold increased risk for death in women with preeclampsia compared with women without preeclampsia after a median follow-up of 13 years. The risk was augmented to 2.7-fold in women with preterm preeclampsia, presumably because of the higher burden of disease that accompanies preterm as compared with term preeclampsia. Moreover, the cardiovascular risk increased 8.1-fold in preterm preeclampsia compared with women without preeclampsia. A positive relationship of cardiovascular risk with disease severity was reported in another study, in which the relative risk for future cardiovascular risk ranged from 2 to 5.3 in the next 14 years depending on the severity of the preeclampsia. Similarly, studies have linked preeclampsia not only to a higher risk for ESRD but to a higher risk for other vascular diseases such as hypertension, cerebrovascular disease, and venous thromboembolism. ,
Despite the strong association between preeclampsia and vascular diseases, the exact pathophysiology remains controversial. Preeclampsia may itself cause permanent vascular injury or, alternatively, women with preeclampsia may have underlying risk factors for preeclampsia, cardiovascular disease, and ESRD. In a case-control study, women with higher blood pressures (even within normal range) and higher insulin and cholesterol levels early in pregnancy were more likely to develop preeclampsia later in that pregnancy, suggesting that derangements predisposing to hypertension, vascular disease, and renal disease preceded the preeclampsia. Similarly, another study reported that more than 10% of patients with early-onset preeclampsia had previously unrecognized renal disease.
Preexisting renal dysfunction predisposes patients to develop preeclampsia. Because of this predisposition and increased risk for preeclampsia, various modalities have been evaluated as a means of modifying this risk. Low-dose (81 mg) aspirin has been shown in meta-analyses to reduce the risk for preeclampsia in women at high risk for the condition. In one meta-analysis of 2 large, multicenter randomized controlled trials (RCTs) and 13 smaller RCTs of high-risk women, there was a 24% relative reduction in the risk for preeclampsia and a 20% relative risk reduction in the rate of fetal growth restriction (FGR) with use of low-dose aspirin. There were no developmental harms in the offspring. Based on these data, the US Preventive Services Task Force (USPSTF) recommended initiation of daily low-dose aspirin beginning at 12 weeks gestation for pregnant patients with preexisting renal disease, hypertension or autoimmune disease, multiple gestation, or a history of preeclampsia. A well-designed retrospective analysis of two consecutive cohorts of pregnancies screened for early preeclampsia demonstrated a statistically significant reduction with use of low-dose aspirin (150 mg). In the intervention cohort, women were given low-dose aspirin if their risk for early-onset preeclampsia exceeded 2% based on an algorithm using maternal demographic, biophysical, uterine artery Doppler pulsatility index, and pregnancy-associated plasma protein A (PAPP-A) parameters. The rate of early preeclampsia (requiring delivery before 34 weeks) was reduced 10-fold to 0.04% ( P < .01), and there was a twofold reduction in the risk of delivery for preeclampsia before 37 weeks. The above data strongly support the use of low-dose aspirin for women at risk for preterm preeclampsia.
Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura
Two other entities that may result in acute renal failure in pregnancy include hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). HUS and TTP are important causes of AKI characterized by thrombocytopenia and microangiopathic hemolytic anemia. Traditionally, TTP is considered when neurologic abnormalities are dominant, and HUS when there is profound renal failure, especially in the postpartum period.
TTP is 10-fold more common in pregnant patients than in the general population (occurring in up to 1 in 25,000 pregnancies); up to 10% of all patients with TTP are pregnant patients. , The risk for TTP increases as the pregnancy advances, with the majority of cases occurring either in the second or third trimester or postpartum. , In one of the largest cohorts of pregnant women with TTP ( n = 166), the median gestational age with an initial presentation of TTP was 23.7 ± 9 weeks. Unfortunately, even in contemporary times, the likelihood of fetal demise when TTP occurred in the second trimester was 45%; the risk for maternal mortality was 9%, even with a 96.5% utilization of plasmapheresis.
TTP results from a deficiency of von Willebrand factor cleaving protease (ADAMTS13) activity caused by either an acquired inhibitor or a congenital deficiency, which results in intravascular accumulation of very large von Willebrand multimers ensnaring platelets and causing thrombi. Most cases of pregnancy-associated TTP occur during the second or third trimester. Pregnancy appears to be a trigger for new onset or relapse of TTP, perhaps because pregnancy is associated with decreases in ADAMTS13 levels. Presentation of a patient with severe thrombocytopenia, microangiopathic hemolytic anemia, renal impairment, and fluctuating neurological signs and fever is more likely to represent TTP rather than HELLP syndrome. Pregnancy is a risk factor for TTP; a flare in pregnancy is associated with significant risks for fetal demise and maternal morbidity, particularly without prompt treatment with plasmapheresis and delivery.
Pregnancy-related atypical HUS (aHUS), as in the nonpregnant state, is the result of complement dysregulation most often secondary to mutations in genes encoding complement regulatory proteins. Pregnancy can be a trigger for aHUS; however, unlike TTP that can occur throughout gestation, it most commonly presents in the peripartum or postpartum period. Inhibition of C5 by eculizumab appears safe and effective in pregnant women; thus a high level of suspicion for aHUS to allow for early diagnosis and treatment is critical. Eculizumab, a monoclonal antibody against complement protein C5, has emerged as the mainstay treatment for aHUS. , Although data are limited to case reports, use of eculizumab is the treatment of choice for aHUS in pregnancy; the treatment is approved by the US Food and Drug Administration (FDA) outside of pregnancy. There are data supporting its safety in pregnancy for treatment of a separate hematologic disorder. Misdiagnosis unfortunately is common, and outcomes are better with shorter duration from diagnosis to initiation of treatment.
Preeclampsia shares many similarities with HUS/TTP ( Table 57.1 ), and distinguishing HUS/TTP from preeclampsia with severe features or HELLP syndrome can be difficult. Thrombocytopenia, microangiopathic hemolytic anemia, AKI, proteinuria, and hypertension occur in both HUS/TTP and HELLP, although elevated liver enzymes are more common in HELLP syndrome. Although many of the laboratory findings in preeclampsia and HUS/TTP overlap, the degree of renal impairment is worse in HUS/TTP and will not typically improve after delivery. Both HUS/TTP and HELLP syndromes can occur in the third trimester or in the immediate postpartum period and may include hypertension and proteinuria as part of the presenting syndrome. Similarly, these conditions can be difficult to discern from HUS/TTP as both can present with central nervous system changes and elevated levels of lactate dehydrogenase. Whereas HELLP and even normal pregnancy can be associated with lower levels of ADAMTS13, severe deficiency (<5%) strongly suggests TTP. , , The time course after delivery may be helpful in differentiating between these syndromes, as preeclampsia typically improves with delivery, whereas TTP requires directed therapy with plasmapheresis. , , Acute renal failure associated with preeclampsia may become transiently worse before improving. Failure of the condition to improve with plasmapheresis suggests aHUS, and eculizumab should be considered. Further complicating the diagnostic quandary is the possibility that HELLP and HUS/TTP may coexist in the same patient and may even share similar underlying pathophysiologic mechanisms.
TABLE 57.1
Comparison of Clinical and Laboratory Features of HUS/TTP, HELLP, and AFLP
Reproduced with permission from Maynard SE, Karumanchi SA, Thadhani R. Hypertension and kidney disease in pregnancy. In: Taal MW, Chertow GM, Marsden PA, et al., eds. Brenner and Rector’s the Kidney . 9th ed. Philadelphia, PA: Saunders; 2011.
| Clinical Feature | HUS/TTP | HELLP | AFLP |
|---|---|---|---|
| Hemolytic anemia | +++ | ++ | +/− |
| Thrombocytopenia | +++ | ++ | +/− |
| Coagulopathy | − | +/− | + |
| Central nervous system symptoms | ++ | +/− | +/− |
| Renal failure | +++ | + | ++ |
| Hypertension | +/− | +++ | +/− |
| Proteinuria | +/− | ++ | +/− |
| Elevated AST | +/− | ++ | +++ |
| Elevated bilirubin | ++ | + | +++ |
| Ammonia | Normal | Normal | High |
| Effect of delivery on disease | None | Recovery | Recovery |
| Management | Plasma exchange | Supportive care, delivery | Supportive care, delivery |
AFLP, Acute fatty liver of pregnancy; AST, aspartate transaminase; HELLP, hemolysis, elevated liver enzymes, low platelets; HUS/TTP, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura.
Management of Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura
The mainstay of treatment for TTP is plasmapheresis, , which has been associated with dramatic improvement in maternal survival, whereas the mainstay of treatment for aHUS is eculizumab. Despite this progress, HUS and TTP continue to carry a significant risk for maternal and fetal mortality. Therefore prompt initiation of plasmapheresis should be initiated even before the diagnosis of TTP is confirmed; confirmation of a diagnosis with severely depressed ADAMTS13 levels may be delayed while being processed in the laboratory. , Plasmapheresis may be helpful in removing autoantibodies to ADAMTS13, restoring depleted ADAMTS13, and clearing high-molecular-weight von Willebrand factor multimers. Because of the possibility of an autoimmune etiology in many cases, corticosteroids are often used in conjunction with plasmapheresis, but the benefits have not been established in randomized trials. Nonetheless, in any patient with suspected HUS or TTP, plasmapheresis should be empirically used early in the clinical course, particularly in view of the limitations of diagnostic tests such as ADAMTS13 and functional complement cascade testing. Because atypical HUS and TTP are often associated with alterations in complement regulatory proteins, it is possible that agents that inhibit the complement cascade may be used to manage pregnant women with this condition.
Acute Fatty Liver of Pregnancy
Acute fatty liver of pregnancy (AFLP) is an extremely rare complication that is estimated to occur in about 1 in 10,000 pregnancies. These patients present typically in the third trimester with nausea and vomiting, jaundice, and abdominal pain with elevated creatinine, bilirubin, transaminitis, thrombocytopenia, hypofibrinogenemia, and an elevated international normalized ratio. Some patients will have hypoglycemia that signifies synthetic hepatic dysfunction. The condition is more common in twins but rare enough that a high degree of suspicion is warranted in all patients who present with the aforementioned symptoms and laboratory abnormalities. The histologic abnormalities consist of swollen hepatocytes filled with microvesicular fat and modest hepatocellular necrosis. However, diagnosis of AFLP is usually made on clinical and laboratory findings as described above, rather than on histologic results from biopsy or radiologic evidence of a fatty liver.
Clinically, the disorder results in significant maternal and fetal morbidity and occasionally mortality. A recent cohort of 51 women with acute fatty liver of pregnancy revealed a 55% likelihood of blood and component transfusion, a 16% likelihood of pancreatitis, a 14% likelihood of ICU admission, a 4% likelihood of maternal death, and a 12% risk for stillbirth. Three-fourths of these patients had acute renal failure with a creatinine of 1.5 mg/dL; although the majority of women returned to their baseline creatinine documented at the initiation of their prenatal care, this laboratory improvement took an average of 8 to 9 days. A minority (2%) of women needed dialysis; the etiology of this kidney injury is thought to be secondary to prerenal state and hypoperfusion of the kidneys. A defect in fetal mitochondrial fatty acid oxidation caused by mutations in the HADHA gene, which cause long-chain 3-hydroxyacyl CoA dehydrogenase deficiency, has been hypothesized as a risk factor for development of AFLP. The clinical features of AFLP may overlap with HELLP syndrome (see Table 57.1 ), and management is similar for both: supportive treatment and prompt delivery. Management of AFLP includes early recognition, aggressive management of the coagulopathy, correction of any hypoglycemia, and prompt delivery. The syndrome typically remits after the birth with no residual hepatic or renal impairment, although it can cause significant morbidity and may recur in subsequent pregnancies.
Chronic Kidney Disease and Pregnancy
Assessment of Glomerular Filtration Rate
The GFR increases during pregnancy as a normal physiologic change in gravidas. Use of the GFR in pregnancy is limited because of the reduced feasibility in accurately estimating its value.
Accurate estimation of the absolute value of GFR in pregnancy can be difficult, as standard clearance methodologies that rely on timed urine collection are complicated by the dilated lower urinary tract in pregnancy, which can lead to a significant delay in the formation of urine compared with the collection of urine. Additionally, standard equations for the estimation of GFR in pregnancy commonly used in nonpregnant women are inaccurate. The modification of diet in renal disease (MDRD) equation is the most commonly used formula for the estimation of GFR; however, studies comparing GFR estimated by inulin clearance in early and late normal pregnancy and in pregnancies complicated by preeclampsia show that the MDRD equation significantly underestimates GFR in pregnancy and therefore cannot be recommended for use in routine clinical practice. ,
Chronic kidney disease (CKD) has classically been divided into five stages based on the GFR, as estimated by the MDRD equation. These stages were formalized in the Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical practice guidelines for chronic kidney disease set forth by the National Kidney Foundation. , Stage 1 CKD represents kidney damage with normal or increased GFR (i.e., ≥90 mL/min/1.73 m 2 ), and stages 2 to 5 represent progressively worsening GFR ( Table 57.2 ).
TABLE 57.2
Stages of Chronic Kidney Disease
From National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002 ;39(2 Suppl 1):S1–S266.
| Stage | Description | Estimated GFR (mL/min/1.73 m ) |
|---|---|---|
| 1 | Kidney damage with normal or increased GFR | ≥90 |
| 2 | Kidney damage with mildly reduced GFR | 60–89 |
| 3 | Moderately reduced GFR | 30–59 |
| 4 | Severely reduced GFR | 15–29 |
| 5 | End-stage renal failure | <15 or dialysis |
GFR, Glomerular filtration rate.
Therefore, to determine whether renal function is deteriorating during pregnancy, the appropriate and typically used measurement is the change in the level of serum creatinine over the course of pregnancy. The average serum creatinine and BUN levels in pregnancy are 0.6 mg/dL (50 μmol/L) and 9 mg/dL (3 mmol/L), respectively. Thus a serum creatinine of 0.8 or 0.9 mg/dL, considered within normal limits in most nonpregnant adult females, should be further investigated for causes of kidney injury. In gravidas with established CKD, failure of the serum creatinine level to decrease from its baseline value as would be expected (and certainly any increase above baseline) suggests worsening renal function that requires further evaluation.
Fetal Outcomes in the Presence of Chronic Kidney Disease
Perinatal complications such as preterm labor, preeclampsia, small-for-gestational-age (SGA) infants, and stillbirths are increased for all five stages of CKD, with risks increasing in parallel with the worsening degree of CKD.
With mild renal insufficiency, several authors report that pregnancies result in live births approximately 95% of the time , ; however, this was with an associated preterm delivery rate of 20% and an SGA birth weight rate of 24%. Preeclampsia is usually the indication for preterm delivery and has been diagnosed in 10% of reported pregnancies complicated by mild renal insufficiency.
Among women with a baseline serum creatinine level of 1.4 mg/dL or greater, the risk for prematurity is greatly increased to 59% compared with a rate of 10% among the general population. , Again, this increased rate of prematurity is largely secondary to indicated delivery for preeclampsia and FGR. In women with a serum creatinine level of 2.5 mg/dL or greater, the rate of preterm delivery is as high as 86%.
Effect of Pregnancy on Chronic Kidney Disease Progression
Stages 1 and 2 Chronic Kidney Disease
Women with stages 1 and 2 CKD, in general, have successful pregnancies and do not have an altered long-term renal prognosis, assuming that blood pressure is well controlled and proteinuria is minimal (<1 g per 24 hours). For example, one study analyzed outcomes of 360 women with chronic glomerulonephritis and normal renal function over a 30-year period: 171 became pregnant, and 189 did not. After an average of 15 years (and up to 30 years) of follow-up, no difference in the development of end-stage renal failure was noted between the two groups. Although the long-term renal prognosis for women with stage 1 and 2 CKD is reassuring, these pregnancies are at increased risk for developing preeclampsia and intrauterine fetal growth restriction, with one study of 46 women with stage 1 CKD in pregnancy reporting a 39% incidence of preeclampsia and a 17% incidence of SGA infants. A study compared pregnancy outcomes among 8900 women with no history of AKI and a serum creatinine available within 6 months of starting pregnancy to 105 women who had recovered from AKI (r-AKI). Both groups began their pregnancies with similar, normal serum creatinine values (∼0.7 mg/dL); however, the r-AKI group had a 23% risk for preeclampsia compared with a 4% risk (adjusted odds ratio [aOR] = 6.5, P < .001) in the no-AKI group. Similarly, the risk for SGA neonates was 15% in the r-AKI group compared with 9% in the controls (aOR = 2, P = .02). This study demonstrated that even a history of acute kidney injury led to a higher risk of preeclampsia and associated complications; however, the mechanisms involved remain poorly understood.
Stages 3 Through 5 Chronic Kidney Disease
Unfortunately, the renal outlook for patients with stages 3 to 5 CKD is less favorable. One of the largest studies examining renal outcomes in pregnant women with CKD was published in 1996 and included 82 pregnancies in 67 women with primary renal disease and a serum creatinine level of 1.4 mg/dL or greater, either before conception or in the first trimester. In this study, GFR was stable throughout pregnancy and to 6 months postpartum in 51% of patients, declined but returned to prepregnancy levels in 8%, declined and remained lower at 6 months in 31%, and declined between 6 weeks postpartum and 6 months postpartum in 10%. The likelihood of accelerated decline in renal function was greater in women whose first measured serum creatinine exceeded 2 mg/dL. Only 1 of 49 women with a serum creatinine level of 1.4 to 1.9 mg/dL experienced an accelerated decline, as opposed to 7 of 21 pregnancies in women with a baseline serum creatinine level of 2 mg/dL or greater. Eight women from this study group progressed to ESRD within 1 year of pregnancy.
A more recent study of 49 women with a mean serum creatinine level of 2.1 mg/dL and mean GFR of 35 mL/min/1.73 m 2 at the time of conception demonstrated that the combined presence of a baseline GFR of less than 40 mL/min/1.73 m 2 and proteinuria of greater than 1 g/d predicted accelerated loss of GFR after delivery compared with before conception. The presence of both risk factors also predicted a shorter time to reducing GFR by one-half, or the need to initiate dialysis.
With respect to obstetric outcomes, women with moderate to severe kidney disease have increased risks for preeclampsia (>70%), moderate to severe anemia (>60%), and SGA neonates (>50%). The rates of prematurity were increased given these aforementioned risks, with 6% of pregnancies delivered before 28 weeks, 24% of pregnancies delivered before 34 weeks, and 76% of pregnancies delivered before full term at 37 weeks’ gestation. , ,
Preconception Counseling in the Setting of Chronic Kidney Disease
Preconception counseling is advised in the setting of CKD given the known associated risks in a potential future pregnancy. The counseling should provide the patient with a comprehensive assessment of the potential maternal and fetal risks of a future pregnancy, outline guidance for management of a future pregnancy, and establish a multidisciplinary team to care for the patient in a future pregnancy. Though there is not a specific set threshold of creatinine where conception is absolutely contraindicated, the patient should receive counseling regarding the spectrum of pregnancy-related risk including preeclampsia, fetal growth restriction, and possible deterioration of her renal function based on the severity of her preexisting renal disease that can occasionally be permanent. Some clinicians advocate that pregnancy be avoided in women with a serum creatinine level of 1.4 mg/dL or greater, particularly if it is associated with difficult-to-control hypertension or significant proteinuria. Others use a serum creatinine level of 2 mg/dL as the level at which pregnancy is not recommended. Rather than focusing on specific cutoffs as the basis for a recommendation for or against pregnancy, each patient’s individual decision to attempt (or to continue) a pregnancy must be individualized, and the ultimate choice resides with the patient.
Patients should ideally enter pregnancy with optimal control of their preexisting kidney disease, with blood pressure controlled by agents that have a reasonable safety profile in pregnancy, including labetalol, nifedipine, and methyldopa. Medications that have known teratogenic potential, including angiotensin-converting enzyme (ACE) inhibitors, mycophenolate mofetil, and methotrexate, should be discontinued prior to pregnancy. Baseline proteinuria and creatinine evaluation is additionally advisable for comparison purposes later in pregnancy particularly if superimposed preeclampsia occurs. Particular considerations applicable to specific kidney diseases are discussed in more detail in this text but, in general, the following components should be part of the antenatal and postpartum care plan.
Antenatal and Postpartum Management
Blood Pressure Management
Blood pressure in pregnant patients should be closely monitored at every prenatal visit. Sudden appearance of hypertension after 20 weeks’ gestation or increasing blood pressure from the patient’s baseline may indicate the development of preeclampsia, particularly if associated with either new-onset proteinuria or worsening of the patient’s baseline proteinuria.
The choice of antihypertensive medications (discussed in detail elsewhere in this text) in pregnancy is very different from that in nonpregnant patients. Most notable is the contraindication of ACE inhibitors and angiotensin receptor blockers (ARBs) in pregnancy. Both classes of medications have been associated with impairment in fetal renal development and oligohydramnios, which can result in pulmonary hypoplasia and neonatal death as a result of respiratory failure. A 2006 epidemiologic study of 209 infants exposed to ACE inhibitors in the first trimester found an increase in the risk for major congenital malformations compared with 29,000 infants exposed to no antihypertensive medications. More recently, a much larger study of 2600 ACE inhibitor–exposed fetuses compared with 15,800 ACE inhibitor–unexposed fetuses of hypertensive women found no association with congenital malformations.
The goals of blood pressure management in pregnant patients have evolved based on updated recent data. There is broad consensus that blood pressure management in pregnancy should minimize the chance of sustained severe-range blood pressures (>160/110 mm Hg) and associated risks of placental abruption and acute neurologic or cardiovascular events. Prior meta-analyses have demonstrated that treatment of mild to moderate hypertension in pregnancy was associated with an increased risk for SGA infants but a reduced likelihood of severe-range blood pressures; there was no difference in the development of preeclampsia. Subsequent analysis of data from a large RCT evaluating tight versus less tight blood pressure control in pregnant women with proteinuric chronic or gestational hypertension revealed no differences in maternal or fetal outcomes. Most recently, the CHAP (Chronic Hypertension and Pregnancy) randomized controlled trial evaluated 2408 pregnant patients at 61 centers with singleton gestations and mild chronic hypertension. Participants were randomized to less tight blood pressure control (diastolic over 85 mm Hg) versus more tight blood pressure control (diastolic under 85 mm Hg) Outcomes demonstrated a reduction in the primary composite outcome including preeclampsia with severe features, medically indicated preterm birth less than 35 weeks’ gestation, placental abruption, or fetal or neonatal death (30.2% for tighter blood pressure control versus 37.0%; adjusted risk ratio 0.82; P < .001). There was no difference in rates of SGA neonates. Based on these data, treatment of mild chronic hypertension to maintain tighter control of blood pressures is appropriate to reduce the risk of certain obstetrical complications without increasing the risk of neonatal birthweight under 10th percentile.
Based on this recent evidence, current guidelines from the American College of Obstetricians and Gynecologists (ACOG) recommend utilizing a blood pressure threshold of 140/90 mm Hg for instituting or titrating medical management. The safety profiles of oral hydralazine, labetalol, methyldopa, or nifedipine are reasonable and equally efficacious at treating chronic hypertension in pregnancy.
In patients with CKD in pregnancy, tighter blood pressure control in pregnancy for renal protection is reasonable given data indicating no difference in maternal or fetal outcomes with such tight blood pressure control.
Additional Management Principles
Similar to all pregnant women, parturients with CKD should be monitored routinely for asymptomatic bacteriuria and promptly treated as necessary.
In addition to monitoring serum creatinine concentration periodically, proteinuria should be regularly assessed. A 24-hour urine collection has traditionally been used to determine the degree of proteinuria, but a protein-to-creatinine ratio spot urine analysis has been shown to strongly correlate with 24-hour urine protein excretion in pregnancy , and may be utilized for surveillance of CKD during pregnancy and for comparison purposes if a diagnosis of superimposed preeclampsia is being evaluated later in pregnancy. A 24-hour urine protein collection can be considered if the protein:creatinine ratio is greater than 0.15, as this cutoff has been noted to have strong sensitivity at ruling out a 24-hour urine protein under 300 mg.
In patients with CKD and chronic hypertension, close surveillance for the development of preeclampsia is appropriate, with laboratory surveillance as clinically indicated.
Both ACOG and the USPSTF recommend the use of daily low-dosage aspirin for prevention of preeclampsia in patients with preexisting renal disease, starting in the late first trimester. , Antiplatelet agents (e.g., aspirin) for preeclampsia prevention are discussed further in Chapter 45 .
As renal disease increases the likelihood of fetal growth restriction, periodic assessment of fetal growth during pregnancy is advised. The American College of Obstetricians and Gynecologists suggests use of fundal height measurements in addition to consideration of ultrasound to assess fetal biometry for the presence of FGR. Periodic fetal antenatal assessment with biophysical profile or nonstress tests is reasonable to consider in the setting of chronic renal disease, although the exact timing of and frequency are not well elucidated.
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