Normal pregnancy is characterized by profound kidney structural, vascular, hemodynamic, and tubular changes that are essential to maternal-fetal health ^, (summarized in Table 58.1 ). Systemic vascular resistance (SVR) decreases and arterial compliance increases by 6 weeks’ gestation, long before uteroplacental circulation is established. ^, Consequently, mean arterial blood pressure (BP) falls by an average of 10 mm Hg, with nadir at 18 to 24 weeks’ gestation. Sympathetic activity is increased, with a 15% to 20% increase in heart rate. The net effect is increased cardiac output in the early first trimester, which peaks at 50% above prepregnancy levels by the middle of the third trimester ( Fig. 58.1 ).

Hemodynamic changes in pregnancy.

Shown are the percentage changes from prepregnancy values in heart rate, stroke volume, and cardiac output measured throughout pregnancy.

Modified from Robson SC, Hunter S, Boys RJ, et al. Serial study of factors influencing changes in cardiac output during human pregnancy. Am J Physiol. 1989;256:H1060–H1065.

The renin-aldosterone-angiotensin system (RAAS) is activated in pregnancy, ^, which leads to salt and water retention. Renal interstitial compliance is increased, whereby the renal interstitial pressure remains low despite increased renal interstitial volume. This may contribute to volume retention via an attenuation of the renal pressure natriuretic response. ^, Total body water increases by 6 to 8 L, causing plasma volume and interstitial volume expansion with a fall in osmolality, counteracted by cumulative retention of average of 950 to 1000 mmol of sodium distributed between the maternal extracellular compartments and fetus. The resultant plasma volume increase leads to mild dilutional anemia. Plasma volume expansion resets the antidiuretic hormone (ADH; also known as “arginine vasopressin”) release threshold and increases atrial natriuretic peptide secretion by the late first trimester. ^,

Kidney size and volume increases by 1 to 1.5 cm and up to 30%, respectively. Asymptomatic, physiologic, mild dilatation of the collecting system occurs in 50% of women, more frequently on the right. These changes may be due to mechanical compression of the ureters by the gravid uterus, plus effects of estrogen, progesterone, and prostaglandins on ureteral structure and peristalsis.

Glomerular filtration increases by about 40% to 50% within weeks of conception and is maintained at this level until late pregnancy. In early pregnancy, this is mediated primarily by an increase in renal plasma flow ( Fig. 58.2 ). In the second half of pregnancy, renal plasma flow declines toward prepregnancy levels, yet glomerular filtration rate (GFR) remains high, reflecting relatively increased filtration fraction. The maintenance of high GFR despite a fall in renal plasma flow is possible due to decreased capillary oncotic pressure and increased K _f (the product of hydraulic permeability and total surface area available for filtration).

Changes in glomerular filtration (GFR), renal plasma flow (RPF), and filtration fraction (FF) during gestation by week (wk).

From Odutayo A, Hladunewich M. Obstetric nephrology: renal hemodynamic and metabolic physiology in normal pregnancy. Clin J Am Soc Nephrol . 2012;7:2073–2080

The increase in GFR results in a physiologic decrease in serum creatinine, urea, and uric acid. ^, Normal creatinine clearance in pregnancy rises to 150–200 mL/min (up to 50% increase), and average serum creatinine falls from 0.8 to 0.5 to 0.6 mg/dL by the second trimester. ^, Hence “normal” serum creatinine for a nonpregnant individual reflects kidney impairment in a pregnant woman. Standard estimated GFR equations based on serum creatinine are not validated in pregnancy. The Cockcroft-Gault formula underestimates GFR compared with inulin clearance and overestimates it compared with 24-hour urine creatinine clearance. The Modification of Diet in Renal (Disease and CKD-EPI) formulas underestimate GFR. It is important to note that a small rise in serum creatinine back to prepregnancy levels in the third trimester is normal and does not necessarily reflect kidney impairment. Cystatin C is not routinely used as a reliable marker of kidney function in pregnancy, nor is it widely available.

Physiologic urinary protein excretion rises in normal pregnancy up to 300 mg/day in later pregnancy due to increased GFR, increased permeability of the glomerular basement membrane, and reduced tubular reabsorption of filtered protein. The higher end of physiologic proteinuria may result in a positive urine dipstick test, particularly on a concentrated urine sample. Women with preexisting proteinuria may have worsening proteinuria in pregnancy, beyond physiologically expected levels.

Due to the large increase in GFR, glomerular tubular balance requires a concomitant increase in tubular solute reabsorption to avoid excessive renal losses. Renal adaptation ensures pregnant women have normal excretion of exogenous solute load and still appropriately conserve sodium when intake is restricted. For example, serum uric acid reaches a nadir of 2.0 to 3.0 mg/dL by 22 to 24 weeks, returning to nonpregnant levels by term due to increased renal tubular absorption of urate.

The osmotic threshold for stimulation of both ADH release and thirst is decreased, mediated by human chorionic gonadotropin (hCG) and relaxin. This results in mild hyponatremia: The serum sodium typically falls by 4 to 5 mM/L below nonpregnancy levels.

Circulating levels of vasopressinase, which hydrolyzes ADH (arginine vasopressin), are increased during normal pregnancy. Rarely this may lead to a reduction in circulating ADH such that polyuria and polydipsia appear (i.e., transient diabetes insipidus of pregnancy).

Pregnancy also causes a progesterone-mediated stimulation of respiratory drive with mild respiratory alkalosis and compensatory renal bicarbonate excretion.

Pregnancy induces a widespread decrease in vascular tone, with BP and SVR falling early in pregnancy. Multiple hormones and signaling pathways, including estrogen, progesterone, relaxin, and prostaglandins, contribute to the systemic vasodilatory response. Reduced vascular responsiveness to vasopressors such as angiotensin-2 (AT ₂ ), norepinephrine, and vasopressin in pregnancy all contribute to vascular relaxation in pregnancy. ^{, , ,} Relaxin is a corpus luteal hormone that rises early in gestation in response to hCG and may also drive the global and renal vasodilatory response. Relaxin upregulates intrarenal endothelin and nitric oxide production, leading to generalized renal vasodilation, decreased renal afferent and efferent arteriolar resistance, and increase in renal blood flow and GFR (see Table 58.1 ).

The low-resistance, high-flow circulation of the fetoplacental unit also contributes to the low SVR that is characteristic of the second and third trimesters of pregnancy. During placental development, the high-resistance uterine arteries are transformed into larger-caliber capacitance vessels ( Fig. 58.3 ). This transformation is driven by invasion of the maternal spiral arteries by fetal-derived cytotrophoblasts, which convert from epithelial to endothelial phenotype as they replace the endothelium of the maternal spiral arteries. The mechanisms governing this vascular mimicry or “pseudovasculogenesis” have become clearer in recent years. The dysregulation of angiogenic factors such as vascular endothelial growth factor (VEGF) and angiopoietins has emerged as a key player in understanding placental pathology and its clinical manifestations such as preeclampsia (see “ Pathogenesis of Preeclampsia ” later).

Placentation in normal and preeclamptic pregnancies.

In normal placental development (upper panel), invasive cytotrophoblasts of fetal origin invade the maternal spiral arteries, transforming them from small-caliber resistance vessels to high-caliber capacitance vessels capable of providing placental perfusion adequate to sustain the growing fetus. During the process of vascular invasion, the cytotrophoblasts differentiate from an epithelial phenotype to an endothelial phenotype, a process referred to as “pseudovasculogenesis” or “vascular mimicry.” In preeclampsia (lower panel), cytotrophoblasts fail to adopt an invasive endothelial phenotype. Instead, invasion of the spiral arteries is shallow, and they remain small-caliber resistance vessels.

From Lam C, Kim KH, Karumanchi SA. Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia. Hypertension 2005;46:1077–1085.

The incidence of preeclampsia varies among populations. Most cases of preeclampsia occur in healthy nulliparous women in whom the incidence of preeclampsia has been reported as high as 7.5%. While classically a disorder of first pregnancies, multiparous women who are pregnant with a new partner appear to have an elevated preeclampsia risk similar to that of nulliparous women. This effect may be due to increased interpregnancy interval rather than the change in partner. ^, Similarly, women who are pregnant at an advanced maternal age (>40 years) have a higher risk of preeclampsia.

Although most cases of preeclampsia occur in the absence of a family history, the presence of preeclampsia in a first-degree relative increases a woman’s risk of severe preeclampsia twofold to fourfold, suggesting a genetic contribution to the disease. However, to-date results from genome-wide scans seeking a specific linkage to preeclampsia have not identified specific genetic mutations.

Several medical conditions are associated with increased preeclampsia risk including chronic hypertension, diabetes mellitus (types 1 and 2), obesity, and antiphospholipid antibody syndrome ( Table 58.3 ). Women with preeclampsia in a prior pregnancy have a high risk of preeclampsia in subsequent pregnancies. Women with early preterm preeclampsia have the highest rate of recurrence. Pregnancies that occur in adolescent girls also have a high risk of preeclampsia. Adults who were born with low birth weights are at increased risk of pregnancy complications including preeclampsia and GH (for further discussion see Chapter 20).

Conditions associated with increased placental mass, such as multifetal gestations and hydatidiform mole, are also associated with increased preeclampsia risk. Trisomy 13 is associated with a high risk of preeclampsia. Reduced paternal sperm exposure and shorter sexual cohabitation have a higher risk of preeclampsia. Sperm exposure orally similarly reduces the risk of preeclampsia. Pregnancies requiring assisted reproductive techniques (ARTs), such as in vitro fertilization/intracytoplasmic sperm injection, compared with spontaneous pregnancies have a higher rate of preeclampsia (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.46–1.73]). Interestingly, pregnancies with oocyte donation had the highest rate of preeclampsia (OR 4.96 [95% CI 3.52–7.0]). More recently frozen embryo transfers have higher odds of preeclampsia compared with fresh embryo transfers.

Several putative risk factors remain controversial. Congenital or acquired thrombophilia is associated with preeclampsia in some but not all studies. Racial differences in the incidence and severity of preeclampsia have been difficult to assess due to confounding by socioeconomic and cultural factors. Although population-based studies have reported a higher rate of preeclampsia among black women and Pacific Islanders, these findings have not been confirmed in studies confined to healthy, nulliparous women. This suggests that the increased preeclampsia incidence noted in some studies may be attributable to the higher rate of chronic hypertension in these populations, as chronic hypertension is itself a strong risk factor for preeclampsia.

The longer duration of hypertension before pregnancy and the lack of treatment for prepregnancy chronic hypertension are further risk factors for preeclampsia in women with chronic hypertension. However, the effect of prepregnancy BP on pregnancy is a continuum, with evidence that prehypertension (systolic and/or diastolic hypertension) increases the risk of preeclampsia.

In recent years there has been a greater concordance between the definitions of preeclampsia across international groups. Generally, a diagnosis of preeclampsia may be made with the new inset of hypertension and evidence of end organ dysfunction (see Table 58.2 ). The requirement of the presence of proteinuria is no longer necessary. Historically, edema was considered part of the clinical presentation or preeclampsia. However, edema is present in 60% to 80% of normal pregnancies and, as such, it is no longer required due to its lack of specificity and sensitivity for the diagnosis of preeclampsia. Similarly, an elevated serum uric acid was considered important for the diagnosis of preeclampsia. The serum uric acid is positively correlated with the severity of preeclampsia. However, it is of limited clinical utility in distinguishing preeclampsia from other HDPs or as a predictor of adverse outcomes. Similarly, it has no role in the decision to deliver a woman with preeclampsia.

Generally, preeclampsia begins to remit soon after delivery of the fetus and placenta and complete recovery is the rule. However, normalization of BP and proteinuria often takes days to weeks and generally any clinical findings that persist beyond 3 months postpartum should prompt investigation. Management of hypertension postpartum is similar to the management during pregnancy ( Table 58.5 ). However, as the fetus is delivered, there are some additional treatment options available.

Several studies have shown that loop diuretics (furosemide [20–40 mg] or other pregnancy-safe diuretics) in the short term (up to 5 days postpartum) can be used safely in the management of hypertension. These studies have shown a reduction in the development of persistent hypertension as measured on discharge and an increase in the rate of fall in the BP during hospitalization. There was no increase in the rate of acute kidney injury or breastfeeding-related issues. It may be beneficial to start these agents for treating hypertension in the postpartum compared with other agents. ^,

Similar to antenatally, postnatally there is a lack of data on the superiority of any class of antihypertensive agents compared with another. However, it is important to note that angiotensin-converting enzyme inhibitors (ACEIs) can be used in the postpartum period with some consideration of the excretion of these agents in the breast milk. Enalapril, captopril, and quinapril or their metabolites have been shown to have minimal or no excretion in breastmilk and, as such, can be used for the treatment of hypertension in the postpartum. ^,

Lastly, nonsteroidal antiinflammatory drugs (NSAIDs) are used routinely after birth as they have demonstrated excellent analgesic efficacy. However, in the context of women with already elevated BP (regardless of the type of HDP), it is generally suggested that the routine use of NSAIDs be avoided.

It is now well described that although the clinical signs of preeclampsia and GH may remit soon after delivery, women who developed these disorders have an increased risk of longer-term cardiovascular, cerebrovascular, and kidney disease. This is above and beyond the increased risk of pregnancy complications in any future pregnancy (e.g., preeclampsia). Women who have experienced severe preeclampsia, recurrent preeclampsia, preeclampsia with preterm birth, and preeclampsia with intrauterine growth restriction (IUGR) are most strongly associated with the remote consequences linked to adverse pregnancy outcomes. ^,

As early as 1 year after the affected pregnancy, women with preeclampsia have an increased risk of hypertension, obesity, hypercholesterolemia, microalbuminuria, and new-onset diabetes mellitus, when compared with control women who have not had preeclampsia. Relative risk (RR) of ischemic heart disease, stroke, cardiomyopathy, and cardiovascular mortality are more than doubled in women who have had preeclampsia. ^, Severe preeclampsia, recurrent preeclampsia, preeclampsia with preterm birth, and preeclampsia with IUGR are most strongly associated with adverse cardiovascular outcomes.

Preeclampsia, especially in association with low neonatal birth weight, also carries an increased risk of later maternal kidney disease requiring a kidney biopsy. Several large studies using birth and kidney registry data showed that preeclampsia increases the risk of subsequent kidney failure by almost fivefold. ^, This finding has subsequently been confirmed in other populations. Familial aggregation of risk factors does not seem to explain increased ESRD risk after preeclampsia. Although it appears that preeclampsia is associated with increased risk of subsequent kidney failure, the absolute risk is low (e.g., 4.72 per 10,000 person-years in the Taiwanese study). Similar to cardiovascular disease, women with recurrent or preterm preeclampsia demonstrated a greater risk of future kidney disease.

Preeclampsia and cardiovascular, cerebrovascular, and kidney disease share many common risk factors, such as chronic hypertension, diabetes, obesity, kidney disease, and metabolic syndrome. Still, the increase in long-term cardiovascular mortality holds even for women who develop preeclampsia in the absence of any overt vascular risk factors. Whether these observations result from vascular damage or persistent endothelial dysfunction caused by preeclampsia or simply reflect the common risk factors shared by preeclampsia and cardiovascular disease remains speculative. Regardless of etiology, it is recommended that women who experience preeclampsia, especially with preterm birth or IUGR, receive screening for potentially modifiable cardiovascular and kidney disease risk factors (hypertension, diabetes mellitus, hyperlipidemia, obesity) at their postpartum obstetrician visit and yearly thereafter. This also includes an appreciation that a 24-hour ambulatory BP assessment may be helpful in identifying women with chronic hypertension. ^,

The offspring of pregnancies complicated by preeclampsia similarly have in epidemiologic studies been shown to have an increased risk of future adverse outcomes remote from pregnancy and the effects of prematurity. It remains unclear whether these adverse effects are related to environmental, developmental, genetic, or epigenetic causes. ^,

Because it is increasingly recognized that there are preventive strategies for women developing preeclampsia subsequently in a pregnancy, a means of identifying women at risk earlier in their pregnancy becomes increasingly important. Differences in a woman’s medical and family history, clinical findings, circulating biomarkers, and uterine arterial studies individually may not have adequate predictive utility, but when combined, they do hold more promise.

Different factors that can be identified in a woman’s medical history, family history, and early clinical factors are significantly different in women who will go on to develop preeclampsia later in that pregnancy compared with women who will not. These have been compiled to improve the predictive accuracy in identifying women at high risk to develop preeclampsia. The strength of these risk factors has varied significantly in the literature. Individually, these risk factors have lacked the utility to be used as a screening test for the development of preeclampsia. Several professional groups (e.g., National Institute for Health and Care Excellence and the American College of Obstetrics and Gynecology) have developed simple algorithms for these clinical risk factors that have improved screening utility. In this instance, risk factors are identified as minor or major (generally based on the RR of development of preeclampsia) to improve the screening utility.

Circulating markers have also been shown to differ early in pregnancy (the first trimester) in those women who will develop preeclampsia, although these markers individually have failed to have adequate predictive utility. Markers such as placental protein 13 (PP-13), PAPP-A, and angiogenic biomarkers (PlGF and sEng) have been shown to hold promise for screening of preeclampsia. PP-13 is thought to be involved in normal placentation and maternal vascular remodeling. Lower levels of PP-13 could identify women at high risk for preeclampsia as early as the first trimester. ^,

Presumably as a result of failed placental vascular remodeling, preeclampsia is associated with increased placental vascular resistance and uterine artery waveform abnormalities in the second trimester, as measured by uterine artery Doppler ultrasound. Dozens of studies have investigated the use of uterine artery Doppler for prediction of preeclampsia. Recent metanalysis has demonstrated a pool specificity of 88% (95% CI 0.83–0.92) and sensitivity of 59% (95% CI 0.49–0.68).

Data suggest that the greatest promise may be in combining uterine artery Doppler, with serum biomarkers for preeclampsia with a woman’s history (personal and family), as well as clinical findings such as BMI and BP. These have become increasingly used across the world. There are, however, limitations in access due to the requirement for expertise in undertaking these measurements and the increased cost burden of this predictive test. Given the increased cost in the care of premature newborns, as well as the cost of treating women with hypertension, there are increasing cost analyses demonstrating that these combined predictive tests may have a greater role in the future.

Many pharmacologic and nonpharmacologic interventions have been studied to prevent the development of preeclampsia in both low- and high-risk pregnancies. Preventative strategies that have been shown to be useful include antiplatelet agents, calcium supplementation, and moderate physical activity. Strategies that are currently not recommended due to a lack of consistent evidence or lack of evidence of any benefit include supplementation with long-chain fatty acid supplements, garlic, antioxidants (vitamins C and E), ^, oral magnesium, nitric oxide, statins, or dietary salt restriction. Several other agents have shown promise in animal or ex vivo studies and are still undergoing further human trials such as proton pump inhibitors or metformin. Suggested strategies during pregnancy to reduce small and vulnerable neonatal births are further discussed in Chapter 20.

The diagnosis of chronic hypertension in pregnancy is usually based on a documented history of hypertension before pregnancy or a BP > 140/90 before 20 weeks’ gestation.

The physiologic drop in BP in the second trimester, which nadirs at about 20 weeks’ gestation, occurs in women with chronic hypertension and can mask the presence of underlying chronic hypertension early in pregnancy if the chronic hypertension was not recognized before pregnancy. In such cases, a woman with chronic hypertension may be inappropriately diagnosed as having GH when the BP rises in the third trimester. The diagnosis of chronic hypertension is established when hypertension fails to resolve by 3 months postpartum.

The incidence of chronic hypertension in pregnancy is increasing over time, regardless of the age of the pregnant woman and BMI by 6% per year. Chronic hypertension is more common with advanced maternal age, obesity, and black race. Pregnant women with chronic hypertension have an increased risk of preeclampsia (21%–25%), premature delivery (33%–35%), IUGR (10%–15%), placental abruption (1%–3%), and perinatal mortality (4.5%). ^, However, most adverse outcomes occur in women with severe hypertension (SBP > 160 and/or DBP > 110 mm Hg) and those with preexisting cardiovascular or kidney disease. Both the duration and severity of hypertension, as well as the lack of systemic therapy prepregnancy, are correlated with perinatal morbidity and preeclampsia risk. The presence of baseline proteinuria increases the risk of preterm delivery and IUGR but not preeclampsia per se. The diagnosis of preeclampsia superimposed on chronic hypertension can be difficult. In the absence of underlying kidney disease, the new onset of proteinuria (>300 mg/day) or sudden worsening hypertension may indicate superimposed preeclampsia. The presence of other signs and symptoms of preeclampsia, such as headache, visual changes, epigastric pain, pulmonary edema, and laboratory derangements (e.g., thrombocytopenia, new or worsening kidney insufficiency, and elevated liver enzymes), also should prompt consideration of preeclampsia and, when present, are an indication of preeclampsia severity. Furthermore, an angiogenic ratio (sFLT1:PlGF ratio of <38) may also be reassuring that these changes are less likely to relate to evolving preeclampsia. These markers have been shown to be normal in the presence of all stages of CKD where preeclampsia is not present but the number of women in these studies was small.

Gestational hypertension (GH) is defined as the new onset of hypertension without any evidence of end organ damage (e.g., proteinuria and abnormal liver function tests) after 20 weeks’ gestation that resolves within 3 months postpartum where there was no evidence of preexisting hypertension before pregnancy. GH likely represents a mix of several underlying etiologies. A subset of women with GH has previously existing chronic hypertension that is undiagnosed. In such cases, if the woman presents for medical care during the second-trimester nadir in BP, it may be inappropriately presumed to be previously normotensive. In such a circumstance, the diagnosis of chronic hypertension is established postpartum when BP fails to return to normal.

GH can progress to overt preeclampsia. The earlier the GH is diagnosed, the greater the likelihood of preeclampsia developing. However, even if GH is diagnosed after 36 weeks’ gestation, women have an approximately 10% chance of developing preeclampsia. Although GH was considered a milder version of preeclampsia, it is a major contributor to maternal and neonatal morbidity and mortality. When GH is severe, it carries similar risks for adverse outcomes similar to preeclampsia, even in the absence of proteinuria.

The goals of therapy for women with GH are similar to those in women with chronic hypertension. The target for BP management is BP <135/85 mm Hg. There is low quality and little data on the timing of birth in women with stable GH.

Pregnancy-associated acute kidney injury (PR-AKI) reflects AKI occurring during pregnancy, labor, delivery, and/or postpartum. PR-AKI is a leading cause of maternal mortality and reflects the tip of the iceberg of inequitable access to CKD screening, reproductive health care, antenatal care, and potentially preventable pregnancy-related morbidity. ^,

PR-AKI incidence may be underestimated due to challenges in detection (as serum creatinine is usually not routinely measured in pregnancy) and definition (as standard AKI criteria are not applicable due to physiologic changes in creatinine and GFR). PR-AKI is often defined as needing acute dialysis in pregnancy, a doubling of serum creatinine from baseline or first measure in pregnancy, oliguria, or a combination.

PR-AKI is most commonly caused by volume depletion; reduced kidney perfusion; acute tubular or cortical necrosis (septic abortion, puerperal sepsis, hyperemesis gravidarum or obstetric hemorrhage, placental abruption); intrarenal pathology (preeclampsia, HELLP syndrome); and medication toxicities. ^, Obstructive uropathy, glomerular diseases, and multisystem conditions such as HUS/TTP and AFLP are rarer but important causes of PR-AKI. The timing of the PR-AKI can be an important clue to causation and must always be considered ( Fig. 58.9 ).

Causes of pregnancy-associated acute kidney injury according to health setting, disease type, and gestational age.

OHSS, Ovarian hyperstimulation syndrome.

PR-AKI incidence is dependent on geographic location, resource setting, and definitions used, resulting in great variability in the published literature. ^, The PR-AKI incidence and associated mortality, especially due to septic abortion and obstetric hemorrhage, has fallen overall including in some lower-resource settings. This is driven by improved availability of safe and legal abortion, widespread antibiotic use, easy access to kidney function testing, access to good antenatal care, prompt treatment, and access to dialysis. Even so, PR-AKI has not entirely disappeared in high-income countries and may be increasing due to rises in pregnancy age and comorbidities such as diabetes, as well as pregnancies complicated by hypertension and preeclampsia. In high-resource settings, most cases of AKI in pregnancy are mild and self-limited but do increase health care utilization, although AKI requiring dialysis is rare, affecting approximately 1:10,000 pregnancies.

The PR-AKI landscape is vastly different in lower-resource settings of Asia, Africa, and South America, where it remains unacceptably high, constituting 2% to 15% of all AKI cases. ^{, ,} Historically, PR-AKI in these settings was due to sepsis and hemorrhage, but preeclampsia is emerging as a predominant cause. Septic abortion remains a major issue where safe termination of pregnancy is illegal or not accessible. PR-AKI contributes to high rates of dialysis requirement (up to 25% of dialysis referrals in some regions), ongoing kidney failure (3%–9% of survivors, in some regions up to 40%), and maternal mortality (ranging 3%–34%). The fetal outcomes are also comparatively worse, with high rates of fetal demise, preterm birth, and complications. The PR-AKI incidence and outcomes in these countries reflect the level of maternal and obstetric care, with many women presenting late with oliguric/anuric AKI, receiving inadequate prenatal and antenatal care, with lower awareness and ability to detect and manage PR-AKI.

The diagnostic work-up and management of PR-AKI are similar to AKI in the general population, and specific treatments are dependent on the underlying causes (see Fig. 58.9 ). However, gestational age, the fetal condition, and likelihood of delivery will guide decision making. For example, kidney biopsy becomes higher risk after 25 weeks (see section “ Kidney Biopsy in Pregnancy ”). In the third trimester, expedient timing of delivery may occur in conjunction with maternal AKI management.

Women with PR-AKI require planned follow-up to ensure kidney recovery and monitor for hypertension and CKD. However, in low-resource settings, up to a third of women do not recover baseline kidney function by time of discharge, and up to 50% will not get further kidney function testing, leaving a large cohort of women where kidney recovery may be unknown. This has important implications for the next pregnancy and future CKD and cardiovascular risk.

Acute tubular necrosis can be caused by any condition in pregnancy causing volume depletion, vasodilation, hypotension, and circulatory shock. Cortical necrosis is a rare, severe form of vasoconstrictive ischemic injury of uncertain pathogenesis. It is most commonly associated with pregnancy, particularly septic abortion, puerperal sepsis, eclampsia, and placental abruption. Global improvements in maternal and kidney survival have led to reduced incidence of cortical necrosis (<5% of PK-AKI), but this remains an important cause of long-term kidney failure in PR-AKI in many regions. The classical presentation is AKI with prolonged anuria. Cortical necrosis can involve the entire renal cortex (diffuse) or may be incomplete (patchy). CT imaging characteristically demonstrates a hypodense subcapsular rim. Kidney biopsy demonstrates ischemic necrosis of all cortical components.

Treatment of ATN and cortical necrosis is supportive with restoration of circulating volume, correction of underlying precipitants, consideration of expedient delivery, and commencement of dialysis. Kidney survival is usually poor in diffuse cortical necrosis even in the modern era using MRI to define disease extent. Incomplete cortical necrosis may have a protracted period of oligoanuria, followed by variable return of kidney function.

The presence of thrombotic microangiopathy (TMA) with PR-AKI may reflect certain pregnancy syndromes that share pathogenic and pathologic features, with a common final outcome of endothelial injury and microvascular thrombosis. Clinical patterns and diagnostic tests help distinguish between these entities (see Table 58.4 ), but in some cases the diagnosis may remain unclear. Advances in knowledge of mechanisms underlying pregnancy TMAs have led to significant improvements in clinical and therapeutic approaches.

• Preeclampsia is the most common cause of TMA and AKI in pregnancy (see “ Preeclampsia Epidemiology and Risk Factors ” earlier). In patients with severe preeclampsia and HELLP syndrome, the incidence of AKI ranges from 10% to 25% in various studies. ^, Preeclampsia may promote AKI and future CKD via endothelial damage, podocyte destruction, and vascular injury. AKI in the setting of preeclampsia or HELLP syndrome is generally an indication for delivery.

Maternal long and medium-chain fatty acid oxidation decreases in normal pregnancy, and serum fatty acid levels rise. In at-risk women, fatty acids may be hepatotoxic. Acute fatty liver of pregnancy (AFLP) is a rare but potentially fatal condition, affecting about 1 in 10,000 pregnancies, with a 2% to 10% maternal mortality rate and up to 20% fetal loss. The incidence may be increasing due to earlier detection of milder presentations. Risk factors for AFLP include multiple gestations, fetal fatty acid oxidation disorders (long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency ), and occurrence in past pregnancies.

AFLP presents in later pregnancy with features of multiorgan fatty infiltration, predominantly with liver manifestations of elevated serum aminotransferase levels, hyperbilirubinemia, hyperammonemia, hypoglycemia, and coagulopathy. The Swansea Criteria may be used to diagnose AFLP and predict mortality risk. ^, Hemolysis and thrombocytopenia are not prominent features of AFLP (see Table 58.4 ). Liver biopsy is rarely performed. The resultant AKI is due to prerenal factors, plus direct fatty infiltration, hemorrhagic complications, and effects of hepatorenal syndrome.

Management of AFLP includes usual supportive care of AKI, liver failure and coagulopathy, and delivery of the fetus. Plasmapheresis has been used, but further clinical trials are required. Follow-up testing for fatty acid disorders is recommended.

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathic (TMA) condition caused by acquired or inherent severe deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13), which cleaves von Willebrand factor. TTP is characterized by ADAMTS13 activity <10%, thrombocytopenia, hemolysis, and microthrombi formation. At least half of all acute episodes of TTP are in women of childbearing age. Declining ADAMTS13 levels in the second and third trimesters may contribute to TTP risk. Clinical distinction from preeclampsia/HELLP and HUS is important, and ADAMST13 activity has aided accurate diagnosis and TTP classification in the recent era (see Table 58.4 ). AKI is less common and severe than in other pregnancy-TMA conditions. Nearly 50% of TTP episodes in pregnancy are de novo cases, and one-third may be congenital TTP. ^, Pregnancy can precipitate relapse in women with a history of TTP.

TTP in pregnancy has high mortality (90%) if untreated. Plasma exchange with glucocorticoid therapy is beneficial in TTP but not in preeclampsia or HELLP syndrome. Excellent fetal survival is possible with treatment, ^, but intrauterine fetal death rate is high, especially for women presenting before 30 weeks’ gestation.

The landscape of pregnancy-HUS has changed due to advances in understanding complement dysregulation and genetics. Pregnancy-HUS now falls under the umbrella of complement-mediated HUS rather than secondary HUS. HUS is due to a hereditary or acquired deficiency of complement regulatory proteins, leading to activation of the alternative complement pathway. Pregnancy-HUS is a rare cause of TMA and AKI, occurring usually in primiparous women, in the peripartum or early postpartum period. Kidney manifestations typically predominate, with the vast majority requiring dialysis and more than half eventually reaching end-stage kidney failure. Pregnancy-HUS may coexist with preeclampsia/HELLP, which in themselves are not clearly linked to complement activation. Therefore delivery plus management of HUS may both be required, and plasma exchange may be ineffective. More than half of women with pregnancy and postpartum HUS have been identified to have complement gene mutations, mainly CFH mutation (30%–45%), CFI mutation (9%), and C3 mutation (9%). Complement-blockade with eculizumab has emerged as a highly promising and potentially lifesaving therapeutic intervention in many reported cases.

AKI due to kidney stones and ureteral obstruction is rare, but pregnancy does increase the risk of first-time stone presentation. Pregnancy predisposes to calcium phosphate stones due to an increase in circulating levels of 1,25-dihydroxyvitamin D ₃ , increased intestinal calcium absorption and urinary excretion of calcium, and excessive calcium supplementation. In normal pregnancy, the concomitant increase in urine flow and physiologic dilation of the urinary tract can help protect from stone formation, and stones are also much more likely to pass.

Ultrasonography and MRI are the preferred imaging methods. Because of the physiologic hydronephrosis of pregnancy, particularly on the right side, the diagnosis of true urinary tract obstruction can be challenging.

Stone management is usually conservative, with adequate hydration and analgesia. Stone-related infection should be treated aggressively, followed by antibiotic prophylaxis. Nephrostomy or stent is rarely required but is safe. Lithotripsy is relatively contraindicated during pregnancy. Stone diagnostics work-up is best timed for the postpartum period.

Urinary tract infections (UTIs) are the most frequent urinary tract problems in pregnancy. Pregnant women are predisposed to bacteriuria and ascending pyelonephritis due to physiologic urinary status. Women with vesicoureteric reflux and polycystic kidney disease have further increased risk. Dysuria and urinary frequency are common in later gestation in the absence of infection, due to pressure on the bladder from the gravid uterus; therefore confirmatory urine culture is important. Asymptomatic bacteriuria occurs in 2% to 10% of pregnancies and has increased risk of premature delivery and low birth weight. Untreated asymptomatic bacteriuria can progress to overt cystitis or acute pyelonephritis in up to 40% of patients. Acute pyelonephritis is a serious complication and usually presents between 20 and 28 weeks’ gestation with typical symptoms or sepsis. Screening of women for asymptomatic bacteriuria in each trimester and treatment reduces pyelonephritis risk by 75 % and improves perinatal outcomes.

Organism-targeted treatment should continue for 5 to 7 days with a follow-up culture; pyelonephritis requires aggressive parenteral therapy with drugs that penetrate the kidney parenchyma. Escherichia coli is the most common pathogen. Cephalosporins and penicillins are safe throughout pregnancy; trimethoprim should be avoided in the first trimester; nitrofurantoin can be used until late pregnancy; a single-treatment dose of fosfomycin upon diagnosis is also acceptable. Suppressive therapy with nitrofurantoin or cephalexin is recommended for those patients with bacteriuria that persists after two courses of therapy. Women with risk factors for or history of UTI should receive antibiotic prophylaxis after a single asymptomatic or symptomatic infection in pregnancy.

Reproductive freedom is a fundamental right, but women with CKD remain disadvantaged. Parenthood may be an important goal for many women with CKD, yet it can be fraught with feelings of grief, psychologic strain, and guilt if this aspiration remains unattainable. ^, Evidence-based, overarching principles of ethical counseling include respect for reproductive autonomy and patient-centered, individualized approaches to shared decision making that reflect patient values and perspectives, ^{, ,} as well as perceptions of pregnancy risk ^, ( Table 58.7 ).

Women might not always feel empowered to initiate discussions about pregnancy themselves, often relying on their clinicians to broach the subject. However, nephrologists may feel inadequately prepared to initiate these discussions. ^, Counseling should be led by clinicians with expertise in pregnancy and CKD (nephrologists, obstetricians, maternal-fetal medicine specialists, obstetric physician). ^, Numerous studies show that clinician support, provision of relevant information, and avoidance of negative, judgmental commentary improves the pregnancy counseling experience for women. ^{, , ,} Women may also value written and online information, peer support groups, and discussions with other specialized clinicians (genetics, fertility services, primary care, and psychologists). However, some women report being overwhelmed by information, so an individualized approach is essential.

Discussions regarding reproductive options should be initiated early in the care of women with CKD and revisited periodically as the condition progresses, even if immediate pregnancy plans are not in place. These conversations serve to assist women and their health care providers in identifying the most opportune window for pursuing pregnancy, thereby averting the scenario where fertility may decline or pregnancy might exert a more pronounced impact on kidney health.

A summary of key decision points and considerations for pregnancy planning at each CKD stage is shown in Fig. 58.11 , while the main elements for optimizing maternal health before pregnancy are shown in Fig. 58.12 .

A summary of key decision points and elements for pregnancy planning and care through the spectrum of kidney disease.

From Jesudason S, Williamson A, Huuskes B, Hewawasam E. Parenthood with kidney failure: answering questions patients ask about pregnancy. Kidney Int Rep . 2022;7:1477–1492.

Framework for pregnancy preparation in women with kidney disease considers continuation of renin-angiotensin-aldosterone blockade until conception in selected women where benefit outweighs risk.

#Consider biopsy if uncertain.

Fertility in women with CKD falls with increasing maternal age and advancing CKD stage. Uremia disrupts the hypothalamic-pituitary-gonadal axis, with blunted cyclical GnRH secretion and hyperprolactinemia. Anti-Mullerian hormone levels are reduced in women with CKD at every age. Furthermore, exposure to libido-reducing drugs and the cosmetic effects of surgery and dialysis access affect sexual drive. Women with CKD therefore have significant menstrual irregularities, anovulation, early menopause, and sexual dysfunction impacting fertility.

However, fertility may be better than anticipated, and contraception should always be considered for all women of childbearing age. With modern, lower-dose regimens and GnRH analogs for ovarian protection, cyclophosphamide treatment has lower impact on fertility and does not usually cause amenorrhea with 3 to 6 gm cumulative exposure. Uremia is not always contraceptive, especially in well-dialyzed women with treated anemia. At least 30% of dialyzed women menstruate and may ovulate. Transplantation may rapidly restore fertility.

Contraception is a crucial component of navigating to successful pregnancy outcomes in women with CKD and transplants—women should be counseled that unplanned pregnancies may have worse outcomes and should be avoided. ^, Contraception is particularly important where there is teratogenic medication, active primary disease or declining GFR, commencing dialysis, or immediately post-transplant, when fertility may return suddenly. Despite this, contraception remains underutilized in women with CKD, on dialysis, or post-transplant. ^{, ,}

Nephrologists should either prescribe or refer to expert in contraceptive management and regularly confirm that contraception is implemented. Estrogen-based contraceptives may be contraindicated in many women with CKD due to hypertension, proteinuria, and thrombosis risk but may be used in normotensive women with no proteinuria and normal kidney or graft function who have no other contraindications. ^, Progesterone-only oral or implantable contraceptives and intrauterine devices are generally effective and safe options for most women with CKD and post-kidney transplantation. Barrier contraception alone has a high failure rate (up to 5%), so it is not recommended. Emergency contraception strategies can be used in women with CKD as risks outweigh potential benefits of averting an unplanned pregnancy. ^, Access to safe and legal termination of pregnancy is not universally available or acceptable, underscoring the need for effective reproductive counseling and contraception in women with CKD.

Women who enter pregnancy with CKD of any stage are at increased risk for adverse maternal and fetal outcomes. The physiologic increase in renal blood flow and hyperfiltration characteristic of normal pregnancy may place additional load on the damaged kidney, with exacerbation of hypertension and proteinuria. Multiple longitudinal cohort studies have demonstrated that increased risk for adverse pregnancy outcomes and decline in kidney function postpartum is linked to CKD stage, degree of proteinuria (especially >1 g/L), remission or activity of glomerular diseases, presence of chronic hypertension, and degree of BP control. ^{, ,} While the live birth rate is generally excellent (>90%) even in women with kidney failure, rates of preterm birth, growth restriction and low birth weight, perinatal mortality, and neonatal intensive care unit admission are increased. Adaptive responses may be attenuated in CKD and failure of the serum creatinine >10% to drop midpregnancy is associated with worse perinatal and kidney outcomes.

Maternal morbidity is also more common, particularly the need for induced and operative delivery, hypertensive disorders of pregnancy, and decline in kidney function. Maternal mortality is rare in high-income settings, but kidney disease remains an important global cause of maternal death. The primary cause of kidney disease usually has less impact on outcomes than CKD stage; however, some conditions have specific problems in pregnancy. Women with nephrotic syndrome, diabetic kidney disease, and systemic lupus erythematosus (SLE) have additional risks (see section on these diseases later). Vesicoureteric reflux is associated with a higher risk of HDP and adverse outcomes. Women with ADPKD may be at risk of UTI and liver cyst progression in pregnancy and may be considered for preimplantation genetic diagnosis. Women with IgA nephropathy generally have lower risks compared with women with other glomerular diseases but exhibit outcomes similar to other women with CKD.

It is important to note that women with underlying kidney disease but only mild kidney impairment, normal BP, and no proteinuria are most likely to experience excellent maternal and fetal outcomes, with little risk for CKD progression; however, this risk is not negligible and remains higher than women without CKD. ^{, ,} As CKD stage advances, the risks of adverse pregnancy outcomes, as described earlier, rise. In CKD stages 3 to 5, the majority of babies are likely to be born preterm—this may be driven by fetal condition, maternal comorbidity, and clinical reluctance to prolong gestation beyond 36 to 37 weeks due to diminishing fetal benefit and rising risks. Preeclampsia rates approach 40% in women with more advanced CKD, and more than two-thirds will have cesarean delivery. Although rates of commencing dialysis during pregnancy are <10% in women with CKD stages 3 to 5, data from the UK suggest up to 46% of women will have a sustained drop GFR of >25% or CKD stage shift or need to start dialysis after pregnancy.

An overall approach to preconception preparation and antenatal care of women with CKD is shown in Figs. 58.12 and 58.13 . The principles of care are focused on optimizing maternal health, careful maternal and fetal vigilance, and determining the best point for delivery. ^{, ,} Each pregnant woman should have access to a multidisciplinary team including nephrologist, obstetrician, maternal-fetal medicine, nursing, and allied health. A schedule for antenatal visits, laboratory testing, medication management, and fetal monitoring should be established. BP control (see “ Hypertensive Disorders of Pregnancy ” earlier for management) and aspirin for preeclampsia prophylaxis are critical elements of care. Women may need to relocate from rural areas to access specialized care. In many countries, there may be a financial burden associated with high-risk pregnancy. Emotional and psychological support should also be considered.

A framework for antenatal care in women with kidney disease.

This care plan should be determined preconception and revised at conception and regularly as the pregnancy progresses. The frequency of monitoring and visits will be individualized according to chronic kidney disease stage and pregnancy risk. SLE, Systemic lupus erythematosus; UTI, urinary tract infection.

Kidney biopsy as part of the preconception work-up may be highly informative regarding diagnosis, disease activity, and fibrosis indicative of renal reserve. Kidney biopsy may be indicated during pregnancy where there is clinical suspicion of glomerular disease or transplant rejection. Biopsy is warranted only where the disease is severe enough to impact pregnancy and the establishment of a pathologic diagnosis is likely to change management within the time frame of the pregnancy. Where delivery is likely before treatment can take effect, it is better to deliver and then biopsy. Many studies on kidney biopsy in pregnancy were from the preultrasound era. A 2013 review of 243 kidney biopsies performed during pregnancy and 1236 kidney biopsies performed during the postpartum period revealed kidney biopsies performed during pregnancy had a higher complication rate than biopsies performed after pregnancy (7% vs. 1%). Only four cases of major bleeding occurred, all in women who were biopsied between 23 and 26 weeks’ gestation. This led to recommendations to avoid kidney biopsy after 23 to 26 weeks’ gestation. More recent series have revealed a low rate of complications but high rate of diagnosis and change of management in pregnancy following biopsy up to 30 weeks. Transplant biopsy may be lower risk due to location and may have greater risk-to-benefit ratio, where there may be risk of graft loss. Overall, biopsy should be used judiciously in pregnancy. Follow-up is essential: Postpartum biopsy usually has a high diagnostic yield.

Proteinuria is more likely to commence or worsen in pregnancy as CKD stage advances or where glomerular disease is not controlled. Serum albumin falls in normal pregnancy due to dilution, but in a proteinuric woman, low serum albumin (<28 g/L) may reflect nephrotic syndrome. Hyperlipidemia and edema are less discriminatory as these may be observed in normal pregnancy. The usual effects of urinary protein loss are observed in nephrotic pregnant women including loss of transferrin (iron deficiency), immunoglobulins (infection), and antithrombin III (venous thromboembolism).

The management of primary glomerular diseases causing nephrotic syndrome is altered in pregnancy, with a focus on steroids, azathioprine, and calcineurin inhibitor (CNI), and potentially rituximab as third-line therapy. BP control is essential. Substantial edema may be managed with diuretics, with monitoring for oligohydramnios and placental perfusion. Venous thromboembolism prophylaxis is recommended, given the prothrombotic risks of nephrotic syndrome and pregnancy, especially with other risk factors (obesity, immobility). Low-molecular-weight heparin dosing should be adjusted for renal function and should continue for 6 weeks postpartum. RAAS blockade should be commenced postpartum. Women with no clear diagnosis should be followed up postpartum and biopsied if proteinuria does not resolve within 6 months. Postpartum biopsy has a high diagnostic yield. Where there may be a genetic basis for nephrotic syndrome (e.g., focal segmental glomerulosclerosis), genetic testing may be considered for mother and baby.

The timing of delivery will be determined by maternal and fetal condition, with a goal for term delivery (over 37 weeks), if the fetal gains of longer gestation continue to outweigh risks of prolonging pregnancy. However, in many women with CKD, preterm delivery will be necessitated due to preeclampsia, worsening maternal BP or kidney function, or declining fetal growth or condition. Therefore timing of delivery should be under constant review. Isolated serum creatinine rises toward the end of pregnancy should not be the sole indication for delivery, as this also occurs in normal pregnant cohorts. CKD or kidney transplant itself does not mandate cesarean delivery; this should occur for obstetric indications only. Vaginal delivery is safe and may be preferred. Transplant anatomy should be defined well ahead of delivery by the obstetric team, with involvement of the transplant surgical team if required.

There should be vigilance intrapartum and postpartum regarding fluid balance, urine output, blood loss, and use of nephrotoxic analgesia (NSAIDs) and antibiotics. Urgent postdelivery transplant imaging for any reduction in function or urine output. Women will require close follow-up in the immediate and short-term postpartum periods.

Breastfeeding should be encouraged in women who wish to do so. Most pregnancy-safe medications are usually also safe in lactation. The Drugs and Lactation Database (LactMed) is an excellent online resource. Studies on transfer of CNIs to the babies of breastfeeding mothers are inconsistent but overall suggest breast milk exposure is much lower than in utero exposure. Monitoring neonatal blood concentrations is not usually necessary. Theoretically, MMF should be safe in breastfeeding because the active metabolite secreted in breast milk, MMA, is not gastrointestinal bioavailable; however, human evidence of safety is limited to a few case reports. There are also insufficient data regarding safe breastfeeding with angiotensin receptor antagonists, statins, SGLT2 inhibitors, fineronone, and mTOR inhibitors. Enalapril and quinapril can be used to reinstate RAAS blockade in proteinuric women.