Chronic kidney disease represents a heterogeneous group of disorders characterized by alterations in the structure and function of the kidney. Its manifestations are largely dependent on the underlying cause and severity of the disease, but typically include decreased function, hypertension, and proteinuria, which can be severe. Etiologies are many, but examples of renal disorders common in young women include glomerular diseases (ie, immunoglobulin A nephropathy, minimal change disease, and focal segmental glomerulonephritis), vascular diseases (ie, thrombotic microangiopathies), tubulointerstitial diseases (ie, nephrolithiasis and reflux nephropathy), and cystic diseases (ie, polycystic kidney disease). Further, systemic diseases including diabetes, vasculitis, and systemic lupus erythematous often involve the kidneys. As such, the global prevalence of chronic kidney disease has been recently estimated to be approximately 13.4%, with a higher prevalence in women compared with men.1 Although the prevalence of chronic kidney disease in women of childbearing age seems relatively low, with estimates on the order of 0.1–4%,2 the implications of pregnancy in the context of chronic kidney disease are many and can be severe.
RENAL ANATOMIC AND PHYSIOLOGIC CHANGES ASSOCIATED WITH PREGNANCY
The maternal physiologic adaptation to pregnancy plays a fundamental role in the development of a healthy pregnancy. At the level of the kidney, there are important anatomic and physiologic alterations that are not only critical for an optimal pregnancy outcome, but also have important clinical implications (Fig. 1). Cognizance of the expected pregnancy-associated physiologic changes are necessary to assist with the proper identification and interpretation of worsening kidney dysfunction and proteinuria as well as to aid in the diagnosis of common complications such as preeclampsia.
Anatomic changes include dilatation of the renal collecting system (calices, renal pelvis, and ureters), which peaks by 20 weeks of gestation.3 These changes occur as a result of the effect of progesterone, which reduces ureteral tone, peristalsis, and contraction pressure even early in pregnancy, as well as mechanical compressive forces that occur as the ureters cross the pelvic brim as pregnancy progresses. Hydronephrosis is seen predominantly on the right side, attributed to the crossing of the right ureter over the iliac and ovarian vessels at an angle before entering the pelvis. In contrast, the left ureter travels at a less acute angle in parallel with the ovarian vein.4 Kidney length increases by approximately 1–1.5 cm,5 and kidney volume increases up to 30%.6 Therefore, the diagnosis of true obstruction can be difficult, and, in women at risk (eg, obstructive or reflux nephropathy), surveillance ultrasound scans can be helpful. Further, this dilatation is responsible for the increased risk of pyelonephritis after asymptomatic bacteriuria, and regular screening for urinary tract infection is recommended in at-risk patients (eg, advanced chronic kidney disease, chronic immunosuppression).7
Owing to alterations in the hormones that govern vasodilation and vasoconstriction, several important hemodynamic changes also occur during pregnancy, most notably a decrease in systemic vascular resistance. This in turn leads to a decrease in mean arterial pressure, which typically begins in the first trimester with a nadir at 18–24 weeks of gestation, returning to baseline close to term.8 As such, women with mild hypertension may be able to discontinue medication in the early stages of pregnancy. In contrast, poorly controlled hypertension preconception and in early pregnancy portends a particularly poor prognosis,9,10 and hypertension needs to be managed before an attempt at conception.
Renal vasodilatation increases renal plasma flow, and hence the glomerular filtration rate (GFR). Glomerular hyperfiltration is the most significant physiologic change associated with normal pregnancy, presenting clinically as a decrease in the serum creatinine level. An estimation of the GFR is important in the diagnosis and management of kidney dysfunction during pregnancy. Methods to estimate GFR include creatinine-based estimating equations and creatinine clearance by 24-hour urine collection. Unfortunately, GFR equations cannot be recommended for clinical use in pregnancy because they commonly overestimate or underestimate GFR,11,12 and creatinine clearance by 24-hour urine collection, the current standard, is cumbersome and hampered by the urinary retention that accompanies the dilated collecting system. As such, trends in the serum creatinine level typically are used clinically to assess for deterioration in kidney function. Of note, the inverse hyperbolic relationship between serum creatinine and GFR is blunted at the higher range of the GFR, which typifies pregnancy. In a study that measured GFR by proper clearance methodology in women with preeclampsia and in healthy gravid controls, a comparison of the serum creatinine level with the GFR revealed a profound depression in kidney function in women with preeclampsia that could not be easily appreciated by evaluation of the serum creatinine level.13 Although statistically different, the serum creatinine level remained in the normal range for preeclamptic and healthy women, with respective values of 0.85±0.22 and 0.60±0.10 mg/dL, despite a loss of GFR in excess of 50% in the women with preeclampsia, underscoring the need to pay very close attention to even small increases in the serum creatinine level during pregnancy.
Modification in tubular function also occurs in normal pregnancies, with alterations seen in the tubular handling of glucose, amino acids, and uric acid. The most clinically relevant adaptation is the alteration in protein excretion, wherein increased proteinuria is often attributed to hyperfiltration. Throughout pregnancy, the value for significant protein excretion is that which exceeds 300 mg in a 24-hour period (double the upper limit of normal in healthy adult). However, it should be highlighted that this upper limit has not been well-studied. One of the largest studies established 24-hour urinary excretion of total protein in 270 healthy pregnancies, reporting that mean 24-hour protein excretion was 116.9 mg with an upper 95th CI of 259.4 mg.14 Because convincing evidence for significant glomerular leakage of protein in a normal pregnancy is insufficient, significant proteinuria should not necessarily be attributed to the hyperfiltration of pregnancy and requires assessment.
WHAT IS THE EFFECT OF PREGNANCY ON KIDNEY DISEASE?
One of the most important considerations in the management of pregnancy in the context of chronic kidney disease is the potential for pregnancy to hasten disease progression and decrease the time to end-stage renal disease (ESRD). Unfortunately, chronic kidney disease has variable definitions in the literature (Table 1), so counseling on the potential for progression is challenging. Older studies typically used a serum creatinine level, which has significant potential for overestimation or underestimation of true GFR; newer studies now use a creatinine clearance or a calculated GFR and describe the degree of dysfunction by the stage of chronic kidney disease. However, staging is not always based on a preconception measure of renal function, which can result in misclassification due the aforementioned renal physiologic changes that accompany the gravid state. Irrespective, renal function may potentially decline as a consequence of pregnancy, and the degree and persistence of this decline is typically determined by the severity of the underlying renal disease (Table 2).
In those with mild renal insufficiency, significant renal function loss is possible though unlikely. However, in those with more advanced chronic kidney disease, the potential for loss of kidney function must be recognized, and its significance not underestimated. In 2015, Piccoli et al reported on the outcomes of 504 pregnancies in women with chronic kidney disease,15 noting that the likelihood for loss of kidney function increased with each successive stage of chronic kidney disease, with 20% of the 10 patients with the most advanced-stage chronic kidney disease requiring dialysis. In contrast to these findings, a recent systematic review evaluated outcomes among pregnancies in women with chronic kidney disease and did not find an association with a decrease in renal function.16 Of the 23 studies identified, eight reported 216 renal outcomes in 1,268 participants. Renal outcomes were defined as doubling of serum creatinine levels, 50% decrement in–creatinine clearance, or ESRD. There was no difference in the renal outcomes of pregnant women with chronic kidney disease compared with those in the control group. However, once again, limited data existed for women with severe renal insufficiency, with only one study including women with decreased renal function before pregnancy. To date, the largest study in women with more advanced disease was conducted in 1996 and included 59 pregnancies in women with moderate renal insufficiency (1.4–2.4 mg/dL) and 15 pregnancies in women with severe renal insufficiency (greater than 2.4 mg/dL), noting significant pregnancy-related loss of kidney function in nearly half of these women either during pregnancy or within 6 weeks postpartum, with 23% of this population progressing to ESRD by 6 months postpartum.17
The degree of renal dysfunction is not the only factor influencing progression in these complicated pregnancies. Concomitant hypertension and proteinuria also contribute to the risk for loss of renal function. Inadequately treated hypertension may contribute to further renal damage, even in women with only moderate renal insufficiency.18 Further, when proteinuria exceeds 1 g/d in combination with significantly compromised GFR (less than 40 mL/min), there is accelerated GFR loss postpartum.19 As such, the greater the baseline degree of compromise in renal function along with the presence of poorly controlled hypertension and proteinuria, the higher the likelihood of loss of renal function during pregnancy, and women must be counseled accordingly. Even in younger age groups, ESRD is associated with significantly increased mortality, and encouraging pregnancy at earlier stages of chronic kidney disease should occur if feasible.
WHAT IS THE EFFECT OF KIDNEY DISEASE ON PREGNANCY?
As important as it is to consider the effect of pregnancy on the course of maternal chronic kidney disease, it is of equal importance to contemplate the effect of chronic kidney disease on pregnancy outcomes, because the degree of renal function impairment in addition to the presence of hypertension and proteinuria are also major determinants of poor maternal and perinatal outcomes. The aforementioned recent systematic review and meta-analysis included 23 studies and examined outcomes in 506,340 pregnancies, with 14 studies included in the assessment of adverse pregnancy outcomes noting greater odds of preeclampsia (odds ratio [OR] 10.4, 95% CI 6.3–17.1), preterm delivery (OR 5.7, 95% CI 3.3–10.0), small for gestational age (SGA) or low birth weight (OR 4.9, 95% CI 3.0–7.8), cesarean delivery (OR 2.7, 95% CI 2.0–3.5), and failed pregnancy (including stillbirth and fetal and neonatal death, OR 1.8, 95% CI 1.0–3.1) in women with chronic kidney disease relative to healthy women in a control group.16
Again, there is a well-described worsening of pregnancy outcomes as women progress through the stages of chronic kidney disease, with even milder disease resulting is significantly increased risks relative to the general population (Table 2). In a large cohort study, the risk of adverse pregnancy outcomes in 504 pregnancies in women with chronic kidney disease was compared with 836 low-risk pregnancies in women without chronic kidney disease.15 Outcomes examined included risk of cesarean delivery, preterm delivery at less than 37 weeks of gestation, early preterm delivery at less than 34 weeks of gestation, SGA, and need for neonatal intensive care unit (NICU) admission. The risk of adverse outcomes increased across stages of chronic kidney disease, with a general combined outcome (preterm delivery, NICU, SGA) of 34% compared with 90% (P<.001) and severe combined outcome (early preterm delivery, NICU, SGA) of 21% compared with 80% (P<.001) for stage 1 compared with stage 4–5 chronic kidney disease, respectively. In those with advanced chronic kidney disease, significantly higher rates of cesarean delivery, preterm delivery at less than 37 and less than 34 weeks of gestation, as well as SGA less than the 10th and less than the 5th percentile have been described.20 Women with more advanced chronic kidney disease also are more likely to have higher rates of concomitant hypertension and proteinuria, which further increases the risk of adverse pregnancy outcomes.15,20
Given the heightened risk for both adverse maternal and neonatal outcomes in women with chronic kidney disease, in particular those with advanced disease, multidisciplinary care that includes nephrologists, maternal–fetal medicine specialists, neonatologists, and a specialized NICU is the ideal. Despite the inherent risks, several management strategies exist to optimize outcomes, beginning with preconception care through delivery and then extending into the postpartum period. These principles of management extend through all stages of chronic kidney disease, including those women on dialysis and posttransplantation (Box 1).
Nephrologic and Obstetric Optimization Strategies for Pregnant Patients With Chronic Kidney Disease
- Safe options
- ○ Methyldopa (maximum 3 g in divided doses)
- ○ Labetalol (maximum 1.2 g in divided doses)
- ○ Nifedipine XL (maximum 90 mg twice/d)
- ○ Hydralazine (50 mg every 6 h)
- Unsafe options
- ○ Angiotensin-converting enzyme inhibitors
- ○ Angiotensin receptor blockers
- Goal less than 140/90 mm Hg
Proteinuria diagnosis and treatment
- Biopsy preconception preferred, but if during pregnancy
- ○ Before 32 wk of gestation
- ▪ For new-onset nephrotic syndrome or renal insufficiency
- ▪ If well-controlled blood pressure and no coagulopathy
- Safe immunosuppression
- ○ Prednisone
- ○ Calcineurin inhibitors
- ○ Azathioprine
- Unsafe immunosuppression
- ○ ? Rituximab—weigh risk–benefit
- ○ Mycophenolate mofetil
- ○ Cyclophosphamide
- Preconception renin-angiotensin-aldosterone system blockade
- ○ Acceptable in select women with no immunologic treatment options
- ○ Must stop at conception and no later than 8 wk of gestation
- Nephrotic syndrome
- ○ Edema
- ▪ Extremity elevation
- ▪ Furosemide (judicious use)
- ▪ Albumin infusions (severe cases)
- ○ Anticoagulation with low-molecular-weight heparin
- ▪ Women with high-grade proteinuria with low serum albumin levels (less than 2.0–2.5 g/dL)
- Low-dose acetylsalicylic acid
- ○ 100–150 mg
- ○ Before 16 wk of gestation
- ○ Stop at 34–36 wk of gestation
- Calcium supplementation
Other chronic kidney disease management
- Avoid nephrotoxins
- ○ Nonsteroidal antiinflammatory drugs
- Dose reduce renally cleared medications
- ○ Cautious use of magnesium sulfate
- Serial biophysical profile, nonstress test or amniotic fluid index, or contraction stress test
- Serial growth assessment
As previously discussed, the presence of hypertension increases the risk of adverse pregnancy outcomes including preeclampsia, preterm delivery, and fetal growth restriction.21 Blood pressure control ideally should be optimized before pregnancy. Several medications compatible with pregnancy exist for management and include, but are not limited to, methyldopa, labetalol, nifedipine, and hydralazine. Angiotensin-converting enzyme inhibitors and angiotensin receptor blocking agents should be discontinued owing to well-established second- and third-trimester teratogenic risks, including renal dysgenesis, perinatal renal failure, oligohydramnios, pulmonary hypoplasia, and hypocalvaria.22 Currently no randomized controlled trials exist to establish optimal blood pressure targets among patients with chronic kidney disease in the context of pregnancy; however, extrapolation from the CHIPS (Control of Hypertension in Pregnancy Study) trial is likely reasonable. This study randomized women to target a diastolic blood pressure of 85 mm Hg (tight control) compared with 100 mm Hg (less tight control) and found no significant difference in risks of adverse pregnancy outcomes between the groups; however, those with less tight control were more likely to develop severe hypertension (greater than 160/110 mm Hg).23 Blood pressure levels of this magnitude may lead to further kidney damage. Thus, a blood pressure target of less than 140/90 mm Hg has been recommended for women with chronic kidney disease during pregnancy.
The degree of proteinuria also has been associated with progression of underlying renal disease during pregnancy19 and adverse pregnancy outcomes.20 Proteinuria should be minimized where possible before conception, and the best approach is determined by the underlying etiology of the renal disease, which is also best determined before conception. Kidney biopsy is feasible in pregnancy but rarely necessary if the woman has received adequate preconception counseling, which typically would include a biopsy for definitive diagnosis. Biopsy is, therefore, typically done only in early gestation, and indications may include new-onset nephrotic syndrome, significant glomerular disease wherein confirmation of diagnosis will affect treatment choice, or a sudden deterioration in renal function. Complication rates of antepartum compared with postpartum biopsies were found to be significantly greater (7% vs 1%, P<.001) in a meta-analysis of 39 studies, though most complications were not severe.24 Beyond approximately 30 weeks of gestation, however, the risks of kidney biopsy may supersede its benefits owing to technical challenges associated with a gravid uterus and the potential for coexistent preeclampsia.
Once a diagnosis is ascertained, options for management include several pregnancy-safe choices for diseases typically treated with immunosuppression (eg, lupus nephritis, vasculitis, membranous nephropathy, minimal change disease) or, alternatively, renin-angiotensin-aldosterone system blockade discontinued before 8 weeks of gestation for diseases without immunologic treatment options (eg, diabetic nephropathy, reflux nephropathy, hypertensive nephrosclerosis). As already mentioned, renin-angiotensin-aldosterone system blockade is teratogenic beyond 8 weeks of gestation22 and, therefore, must be used with extreme caution after women receive individualized counseling to understand the risk–benefit ratio. A number of agents, including captopril and enalapril, have been determined to be negligible in breast milk, so renin-angiotensin-aldosterone system blockade to manage proteinuria can be reinstituted in the early postpartum period.25
Options for safe immunosuppression during pregnancy and breastfeeding include prednisone, azathioprine, and the calcineurin inhibitors.26–28 Side-effect profiles are similar during pregnancy, but earlier screening for gestational diabetes is warranted in women on prednisone, a calcineurin inhibitor, or both. Further, stress doses of short-acting glucocorticoids during labor and delivery are necessary in those maintained on long-term corticosteroids to manage suppression of the hypothalamic-pituitary-adrenal axis. For significant flares of renal disease during pregnancy, pulse steroids followed by combination immunosuppression is a common approach. Although use in pregnancy has been documented, the long-term neonatal effect of rituximab remains to be determined. It is known to cross the placenta29 as well as enter breast milk in small quantities,30 but there have been no reports to date of teratogenicity. However, there is a risk of neonatal B cell depletion and immunosuppression, particularly with third-trimester exposure, resulting in documented infections and complicating vaccination administration.29,31,32
All patients with lupus nephritis should receive hydroxychloroquine during pregnancy. It should be initiated in women not taking the medication and continued in those already on it because discontinuation during pregnancy has been associated with flares and increased use of prednisone.33 Further, hydroxychloroquine is associated with a significantly decreased risk of having an SGA neonate34 as well as a significantly decreased risk of congenital heart block by approximately 50% in mothers who are anti-Sjögren's-syndrome–related antigen A.35
Immunosuppressive agents to avoid in pregnancy and while breastfeeding include mycophenolate mofetil and cyclophosphamide. Mycophenolate mofetil is associated with high rates of spontaneous pregnancy loss (up to 45%) and has been deemed highly teratogenic, with approximately 25–30% of fetuses exposed to mycophenolate mofetil developing congenital anomalies.36 Birth defects include cleft lip and palate, absent auditory canals, hypertelorism, and microtia.37 This medication should be changed to an alternative agent (typically azathioprine) at least 3 months before conception to ensure disease stability. Cyclophosphamide is also associated with an increased risk of fetal loss38 and is highly teratogenic, causing multiple anomalies, including, but not limited to, hypoplasia of the calvarial and facial bones and oligodactyly along with growth issues and impaired neurologic development39; it thus should be avoided in all trimesters of pregnancy.
Treatments beyond immunosuppression often are required to treat women with severe proteinuria causing nephrotic syndrome (proteinuria greater than 3 g with low albumin, edema, and hypercoagulability). Peripheral edema can be incapacitating. Conservative therapy includes the use of compression stockings and elevation of the extremities, but often careful use of loop diuretics (ie, furosemide) is necessary; in extreme cases, albumin infusions also have been used.40 Pregnancy is a prothrombotic state,41 and in patients with severe hypoalbuminemia, there is a significantly increased risk of venous thromboembolic disease.42 No specific guidelines exist for the management of anticoagulation during pregnancy among those with chronic kidney disease and significant proteinuria, but expert opinion suggests that women with severe proteinuria and a serum albumin level of less than 2.0–2.5 g/dL should receive thromboprophylaxis throughout pregnancy and continued for at least 6 weeks postpartum. Anticoagulation also should be considered among those with lesser degrees of proteinuria with additional risk factors, including prolonged periods of immobility, obesity, or kidney diseases with higher risks of thrombosis (eg, membranous nephropathy and vasculitis). The safety of subcutaneous low-molecular-weight heparin is well-established for use in pregnancy.
The importance of preeclampsia prevention cannot be understated, because women with chronic kidney disease are among the highest risk patients for this serious complication. There have been no randomized controlled trials in preeclampsia prevention conducted specifically in the chronic kidney disease population, but options, including aspirin and calcium supplementation, are generally safe.
Because the population with chronic kidney disease is at high risk for the development of preeclampsia, aspirin should be initiated before 16 weeks of gestation, and, with findings from the recent ASPRE (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention) trial, there is the suggestion that perhaps a higher dose (eg, 150 mg) may be more effective.43
Calcium and Vitamin D Supplementation
Calcium and vitamin D supplementation also have been evaluated as preventative strategies for preeclampsia. A systematic review included randomized controlled trials comparing high-dose (at least 1 g daily of calcium) or low-dose calcium supplementation during pregnancy with placebo or no calcium in the prevention of preeclampsia.44 The assessment of high-dose calcium greater than 1 g/d included 13 studies and 15,730 women, noting that the risk of hypertension was reduced with calcium supplementation compared with placebo, along with a significant reduction in the risk of preeclampsia (risk ratio [RR] 0.5, 95% CI 0.3–0.7). The effect was greatest for women with low-calcium diets (eight trials, 10,678 women; RR 0.4, 95% CI 0.2–0.7) and those at high risk for preeclampsia (five trials, 587 women; RR 0.2, 95% CI 0.1–0.4).
More recently, the benefit of vitamin D and calcium supplementation in pregnancy for risk reduction of preeclampsia and gestational hypertension was assessed by a meta-analysis of 27 randomized controlled trials including approximately 28,000 women, noting that calcium, vitamin D, and calcium plus vitamin D could lower the risk of preeclampsia when compared with placebo, with pooled RRs (95% CI) of 0.5 (0.4–0.7), 0.5 (0.2–0.9), and 0.5 (0.3–0.8), respectively.45 The World Health Organization recommends daily supplementation with 1.5–2 g of oral elemental calcium in populations with low dietary intake for the prevention of preeclampsia, but vitamin D supplementation requires further study.
Other Nephrologic and Obstetric Management Considerations in Chronic Kidney Disease
Other general management strategies in chronic kidney disease include avoidance of nephrotoxic agents and renal dosing for commonly used medications as well as management of anemia, bone mineral metabolism, and acid–base and electrolyte imbalances. Several commonly used medications for obstetric indications may be potentially nephrotoxic and, thus, should be avoided. This includes tocolytic agents such as indomethacin in addition to commonly used antimicrobial agents such as gentamicin. The common use of nonsteroidal antiinflammatory medications for postpartum pain control also should be avoided in women with renal dysfunction. Medications that undergo renal clearance (eg, antimicrobial agents) typically require dose adjustments for a GFR less than 30 mL/min. Magnesium, a frequently used medication for eclampsia prevention or fetal neuroprotection, is cleared by the kidneys, and, as such, magnesium toxicity presents a significant risk in women with advanced chronic kidney disease, especially those on dialysis. Thus, regular assessment of serum magnesium concentrations and deep tendon reflexes and a lower constant infusion rate (eg, 1 g/h) are often indicated.
Maternal anemia is common in women with chronic kidney disease, and early institution of oral iron, intravenous iron sucrose, or both in addition to erythropoietin-stimulating agents when necessary is recommended. Hypocalcemia and hyperphosphatemia due to secondary hyperparathyroidism from advanced chronic kidney disease can be treated safely with oral calcium carbonate supplementation, binders, or both as well as vitamin D analogues. Maternal acidosis will result in progressive fetal acidemia, and, as such, maternal serum pH ideally should be maintained at greater than 7.2. This may require initiation of sodium bicarbonate therapy and, in extreme cases, is an indication for dialysis. Women with chronic kidney disease also may have electrolyte abnormalities, and dietary counseling for a low-potassium diet should be initiated first, but binding resins can be used if needed. Again, this may be an indication to initiate dialysis.
Owing to increased risk of adverse pregnancy outcomes, more frequent prenatal assessments to allow for close maternal and fetal monitoring may be necessary. Otherwise, antepartum fetal surveillance should be conducted according to guidelines.46 In most cases, termination of pregnancy will not result in an improvement in renal function, and, in women with advanced chronic kidney disease who demonstrate progression with no evidence of fetal deterioration and controllable hypertension, expectant management with initiation of dialysis may be considered. On the other hand, a significantly rapid and severe decline in renal function is an indication for preterm delivery or termination of pregnancy. In the absence of maternal or fetal compromise, consideration should be given to delivery at or near term, with cesarean delivery reserved for usual obstetric indications.
PREGNANCY AND END-STAGE RENAL DISEASE
In the population of women with ESRD on dialysis, conception and maintenance of pregnancy were historically infrequent and complex events. Fertility rates are typically low in those on hemodialysis and even lower in women on peritoneal dialysis,47 thought to be due to impaired pituitary release of luteinizing hormone contributing to anovulation. However, hemodialysis in the context of pregnancy is becoming more common, potentially influenced by the use of more biocompatible membranes and the increasing use of erythropoietin-stimulating agents, as well as the intensification of dialysis prescriptions, and, in fact, can be considered a reproductive choice for some women when transplantation is not imminent.
To date, the highest documented pregnancy incidence is 15.6% in eligible intensively dialyzed home dialysis patients who conceived between 2001 and 2006,48 and outcomes also have improved, with live birth rates exceeding 80% in centers using intensified dialysis regimens.49 In a recent comparison of intensively dialyzed patients from the Toronto Pregnancy and Kidney Disease Registry (43±6 h/wk) with patients receiving more standard regimens documented in the American Registry for Pregnancy in Dialysis Patients (17±5 h/wk), the live birth rate was 48% in those dialyzed less than 20 h/wk, 75% in those dialyzed 21–36 h/wk, and 85% in those dialyzed more than 36 h/wk.49 These findings were further supported by results of a recent systematic review and meta-analysis of maternal and neonatal outcomes of 574 pregnancies in patients with ESRD, which revealed an overall live birth rate of 82% and a positive relationship between number of hours on dialysis and improved outcomes, with a decreased risk of preterm delivery before 37 weeks of gestation and SGA neonates less than the 10th percentile.50 As such, in those with ESRD and no residual renal function, we currently recommend a minimum of 36 h/wk, but in women with residual renal function, this intensified therapy may not be required, and the dialysis prescription should be personalized to meet specific needs.
Despite improvement in live birth rates, pregnancy in the context of intensified dialysis is associated with significant risks. Preterm birth, preeclampsia, low birth weight, and fetal growth restriction remain common outcomes, necessitating careful care and follow-up by an interdisciplinary care team. Nephrology management includes, but is not limited to, intensification of dialysis; continuous assessment of volume status and treatment of hypertension to maintain postdialysis blood pressure less than 140/90 mm Hg; maintenance of electrolyte and calcium-phosphate balance, which typically necessitates use of dialysate baths with higher levels of potassium and calcium and even the addition of phosphate; and treatment of anemia, which typically requires intravenous iron and a doubling of the dose of erythropoietin-stimulating agents to avoid the need for transfusion. Details of the dialysis management for these women is discussed in detail elsewhere.51 Obstetric care, on the other hand, focuses on optimization and surveillance of maternal and fetal status starting before conception and continuing into the postpartum period.
Preconception and in early pregnancy, care should be taken to discontinue teratogenic medications, which are frequently used in this patient population (eg, angiotensin-converting enzyme inhibitors, angiotensin receptor blocking agents, and statins), and replace these medications with those compatible with pregnancy. In early pregnancy, the utility of standard first-trimester pregnancy prenatal screening tests is diminished, and results must be interpreted with caution because levels are altered in an unpredictable manner in cases of renal compromise, resulting in increased reliance on nuchal translucency and later anatomic assessments. β-hCG is partially cleared by the kidneys and is inversely related to creatinine clearance.52 Pregnancy-associated plasma protein A is higher in patients on hemodialysis, and levels are further enhanced by the administration of heparin to maintain dialysis circuit patency.53,54 As such, prenatal screening becomes less reliable, and other options may need to be explored, including chorionic villus sampling or amniocentesis, with its inherent risks and limitations. Noninvasive prenatal testing with cell-free fetal DNA can be attempted, though in our experience insufficient fetal fractions have proven an issue. Supplementation of water-soluble vitamins and minerals, including folic acid, is necessary, and we administer a doubling of the usual daily dose of water-soluble vitamins, including a minimum of 5 mg of folic acid in the first trimester, because these nutrients are removed by dialysis. Dietary counseling is important to ensure adequate intake of protein. Recommended daily intake for protein in pregnancy is approximately 1.1 g/kg; however, because 10–15 g of amino acid can be lost daily in the dialysate,55 the recommended intake in pregnancy in the context of ESRD is approximately 1.5–1.8 g/kg daily. Finally, aspirin is recommended for prevention of preeclampsia as previously discussed, though no data exist on the effect of aspirin specifically in women with ESRD.
Surveillance in the latter part of pregnancy focuses on serial assessments of fetal growth and well-being. Consideration should be made for the serial assessment of cervical length, because cervical insufficiency appears to be more common in women with ESRD on hemodialysis.49 Serial monitoring of amniotic fluid volume is also an important component of surveillance. Polyhydramnios may be related to inadequate clearance of uremic toxins (elevated blood urea nitrogen results in fetal diuresis) or may be indicative of volume overload. The development of polyhydramnios should prompt consideration for further intensification of delivered dialysis dose or an increase in ultrafiltration volume. Clearance of urea plays a crucial role in pregnancy success, and there exists a correlation between blood urea levels and gestational age, with urea levels lower than 48 mg/dL being associated with a gestational age of at least 32 weeks.56 Hypertension is a frequent comorbidity in women with ESRD, but concern must arise for superimposed preeclampsia when faced with worsening hypertension after 20 weeks of gestation.
In the absence of evidence of maternal or fetal compromise, induction of labor is considered at term (37–39 weeks of gestation) to avoid spontaneous labor in an anticoagulated woman. Delivery should take place in a center with resources necessary to care for complex maternal and fetal situations. As mentioned, initiation of magnesium sulfate for prevention of eclampsia or fetal neuroprotection in cases of preterm delivery must be prescribed with vigilance. Postpartum, breastfeeding is safe in women undergoing dialysis. Most medications that are compatible with pregnancy are also safe while breastfeeding, but providers also should be attentive to avoid overaggressive ultrafiltration and dehydration, which might impede breast milk supply.
PREGNANCY AND RENAL TRANSPLANTATION
Estimates indicate that the proportion of women with renal transplants who become pregnant is approximately 2–5%.57 Pregnancy rates are significantly lower than in the age-matched general population, and it is not clear whether this represents decreased fertility or counseling practices and patient choice.47,58 At this time, much of the information available to guide practice comes from single-center experiences and systematic reviews and through transplant registries. The recently published Transplantation Pregnancy Registry International 2015 Annual Report includes 1,892 pregnancies in kidney recipients and 109 in kidney–pancreas recipients and is the largest of the available registries providing data on both maternal and fetal outcomes.59 When embarking on a pregnancy, the process for preparation does not differ significantly from women with native kidney chronic kidney disease.
Potential loss of graft function due to the hemodynamic effects of pregnancy presents a significant concern, but most women can be reassured that overall long-term graft function is usually not significantly affected. A study based on data from the Australian and New Zealand Dialysis and Transplant Registry did not detect significant differences in rates of graft loss after 20 years of follow-up in 120 women with renal transplant who had a pregnancy compared with nulliparous women in a control group matched for year of transplantation, duration of transplant, age at transplantation, and graft function.60 However, when allograft function before pregnancy is impaired, there is significant reason for concern because pregnancy may hasten graft loss. In scenarios wherein serum creatinine levels are in excess of 1.5 mg/dL, there is a greater likelihood of postpartum graft dysfunction,61,62 which may be further accelerated by superimposed preeclampsia. Fortunately, episodes of acute rejection are rare in kidney recipients, with rates of only 4.2% reported in a recent meta-analysis63 and even lower rates reported by the Transplantation Pregnancy Registry International of 0.8% and 4.9% in kidney and kidney–pancreas recipients, respectively.59 Rejection is prevented by close surveillance of calcineurin inhibitor levels, which typically decrease during pregnancy, along with dose adjustments when necessary.
Pregnancy outcomes after renal transplantation are generally thought to be superior to those in women undergoing dialysis. Pregnancy complications occur more commonly in renal transplant recipients as compared with the general population, including hypertension (54% vs 5%), preeclampsia (27% vs 3.8%), and gestational diabetes (8% vs 3.9%).63 Additional adverse outcomes include low birth weight, increased risk of cesarean delivery, and admissions to NICU.63 Up to 1 in 10 patients maintained on calcineurin inhibitors and prednisone may require insulin therapy to control blood glucose levels during pregnancy.64 Although never specifically studied in this population, aspirin should be prescribed for prevention of preeclampsia because this is a particularly high-risk population, with rates of preeclampsia greater than 25%59,63 in kidney transplant recipients and 33% in kidney–pancreas transplant recipients.59
The chronically immunosuppressed woman is also at risk for opportunistic infections. The most frequent maternal infection encountered is urinary tract infection, which can result in pyelonephritis. As such, we perform a monthly urine culture and promptly treat asymptomatic bacteriuria.
In patients undergoing cesarean delivery, the obstetrician must be attentive to the location of the transplanted kidney and ureter by reviewing operative summaries as well as ultrasonographic imaging before delivery. Often the ureter is reimplanted at the dome of bladder, and thus a common recommendation is to avoid creation and development of a bladder flap at the time of cesarean delivery.
Many of the aforementioned maternal and fetal complications can be somewhat minimized by carefully timing pregnancy posttransplantation, but the literature does seem to suggest a maternal–fetal tradeoff. A recent assessment of 729 pregnancies from the United States Renal Data System noted that pregnancy in both the first and second posttransplant years was associated with higher rates of allograft failure from any cause censored for death (hazard ratio 1.3, 95% CI 1.04–1.50 and hazard ratio 1.3, 95% CI 1.06–1.50, respectively). Pregnancy in the third posttransplant year was not associated with an increased risk of graft loss.65 On the other hand, live birth rates tend to be higher in the first 2 years posttransplantation. A meta-analysis of outcomes in 4,706 pregnancies in renal transplant recipients indicated a higher live birth rate (80%) with a mean interval between transplant and pregnancy of less than 2 years compared with intervals of 2–3 years, 3–4 years, and more than 4 years (live birth rates 64%, 76%, and 75%, respectively).63 However, for those conceiving less than 2 years posttransplant, higher risks of other adverse pregnancy outcomes, including preeclampsia, gestational diabetes, cesarean delivery, and preterm birth, were reported.63 The American Society of Transplantation Guidelines provides some direction and recommends avoidance of conception in the first year after transplant.66 Pregnancy is deemed safe if there has been no rejection within the past year, adequate and stable graft function as evidenced by serum creatinine levels less than 1.5 mg/dL, no or minimal proteinuria, no acute infections that may affect fetal growth and well-being, and stable maintenance immunosuppression with pregnancy-safe medications. However, there is a complex interplay between maternal age, comorbidities, and transplant status that requires careful, individualized counseling.
In summary, management of pregnancy in the context of chronic kidney disease represents a unique and complex situation with increased risks of adverse maternal and perinatal outcomes. Recognition that even early-stage chronic kidney disease brings associated risks is important, but so is understanding that women with advanced chronic kidney disease and those on dialysis or with a kidney transplant stand especially to benefit from combined care with nephrology specialists along with high-risk obstetricians or maternal–fetal medicine specialists. Access to advanced neonatal care is also critical. Finally, expert knowledge and skill provided by a multidisciplinary team of health care professionals is beneficial for optimizing pregnancy outcomes.
CME FOR THE CLINICAL EXPERT SERIES
Learning Objectives for “Chronic Kidney Disease in Pregnancy”
After completing this learning experience, the involved learner should be able to:
- List some of the heterogeneous group of disorders characterized by alterations in the structure and function of the kidney during pregnancy;
- Discuss markers for the presence and severity of these diseases;
- Enumerate the physiologic changes in renal structure and function brought on by pregnancy; and
- Outline strategies to reduce the risk to mother and fetus when these conditions are present.
Instructions for Obtaining AMA PRA Category 1 CreditsTM
Continuing Medical Education credit is provided through joint providership with The American College of Obstetricians and Gynecologists.
Obstetrics & Gynecology includes CME-certified content that is designed to meet the educational needs of its readers. This article is certified for 2 AMA PRA Category 1 CreditsTM. This activity is available for credit through June 30, 2022.
The American College of Obstetricians and Gynecologists is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
AMA PRA Category 1 Credit(s)TM
The American College of Obstetricians and Gynecologists designates this journal-based CME activity for a maximum of 2 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
College Cognate Credit(s)
The American College of Obstetricians and Gynecologists designates this journal-based CME activity for a maximum of 2 Category 1 College Cognate Credits. The College has a reciprocity agreement with the AMA that allows AMA PRA Category 1 CreditsTM to be equivalent to College Cognate Credits.
Disclosure of Faculty and Planning Committee Industry Relationships
In accordance with the College policy, all faculty and planning committee members have signed a conflict of interest statement in which they have disclosed any financial interests or other relationships with industry relative to article topics. Such disclosures allow the participant to evaluate better the objectivity of the information presented in the articles.
How to Earn CME Credit
To earn CME credit, you must read the article in Obstetrics & Gynecology and complete the quiz, answering at least 70 percent of the questions correctly. For more information on this CME educational offering, visit the Lippincott CMEConnection portal at https://cme.lww.com/browse/sources/196 to register and to complete the CME activity online. A free one-time CME coupon is available to participants by using the coupon code, ONGFREE. Thereafter, ACOG Fellows will receive 50% off by using coupon code, ONG50.
Hardware/software requirements are a desktop or laptop computer (Mac or PC) and an Internet browser. This activity is available for credit through June 30, 2022. To receive proper credits for this activity, each participant will need to make sure that the information on their profile for the CME platform (where this activity is located) is updated with 1) their date of birth (month and day only) and 2) their ACOG ID. In addition, participants should select that they are board-certified in obstetrics and gynecology.
The privacy policies for the Obstetrics & Gynecology website and the Lippincott CMEConnection portal are available at http://www.greenjournal.org and https://cme.lww.com/browse/sources/196, respectively.
Questions related to transcripts may be directed to firstname.lastname@example.org. For other queries, please contact the Obstetrics & Gynecology Editorial Office, 202-314-2317 or email@example.com. For queries related to the CME test online, please contact firstname.lastname@example.org or 1-800-787-8985.
1. Hill NR, Fatoba ST, Oke JL, Hirst JA, O'Callaghan CA, Lasserson DS, et al. Global prevalence of chronic kidney disease—a systematic review and meta-analysis. PLoS One 2016;11:e0158765.
2. Piccoli GB, Alrukhaimi M, Liu ZH, Zakharova E, Levin A; World Kidney Day Steering Committee. What we do and do not know about women and kidney diseases; questions unanswered and answers unquestioned: reflection on World Kidney Day and International Woman's Day. Physiol Int 2018;105:1–18.
3. Cietak KA, Newton JR. Serial qualitative maternal nephrosonography in pregnancy. Br J Radiol 1985;58:399–404.
4. Schulman A, Herlinger H. Urinary tract dilatation in pregnancy. Br J Radiol 1975;48:638–45.
5. Bailey RR, Rolleston GL. Kidney length and ureteric dilatation in the puerperium. J Obstet Gynaecol Br Commonw 1971;78:55–61.
6. Christensen T, Klebe JG, Bertelsen V, Hansen HE. Changes in renal volume during normal pregnancy. Acta Obstet Gynecol Scand 1989;68:541–3.
7. Piccoli GB, Attini R, Cabiddu G. Kidney diseases and pregnancy: a multidisciplinary approach for improving care by involving nephrology, obstetrics, neonatology, urology, diabetology, bioethics, and internal medicine. J Clin Med 2018;7:E135.
8. Chapman AB, Abraham WT, Zamudio S, Coffin C, Merouani A, Young D, et al. Temporal relationships between hormonal and hemodynamic changes in early human pregnancy. Kidney Int 1998;54:2056–63.
9. Zetterström K, Lindeberg SN, Haglund B, Hanson U. Maternal complications in women with chronic hypertension: a population-based cohort study. Acta Obstet Gynecol Scand 2005;84:419–24.
10. Nobles CJ, Mendola P, Mumford SL, Naimi AI, Yeung EH, Kim K, et al. Preconception blood pressure levels and reproductive outcomes in a prospective cohort of women attempting pregnancy. Hypertension 2018;71:904–10.
11. Koetje PM, Spaan JJ, Kooman JP, Spaanderman ME, Peeters LL. Pregnancy reduces the accuracy of the estimated glomerular filtration rate based on Cockroft-Gault and MDRD formulas. Reprod Sci 2011;18:456–62.
12. Cote AM, Lam EM, von Dadelszen P, Mattman A, Magee LA. Monitoring renal function in hypertensive pregnancy. Hypertens Pregnancy;29:318–29.
13. Hladunewich MA, Myers BD, Derby GC, Blouch KL, Druzin ML, Deen WM, et al. Course of preeclamptic glomerular injury after delivery. Am J Physiol Ren Physiol 2008;294:F614–20.
14. Higby K, Suiter CR, Phelps JY, Siler-Khodr T, Langer O. Normal values of urinary albumin and total protein excretion during pregnancy. Am J Obstet Gynecol 1994;171:984–9.
15. Piccoli GB, Cabiddu G, Attini R, Vigotti FN, Maxia S, Lepori N, et al. Risk of adverse pregnancy outcomes in women with CKD. J Am Soc Nephrol 2015;26:2011–22.
16. Zhang JJ, Ma XX, Hao L, Liu LJ, Lv JC, Zhang H. A systematic review and meta-analysis of outcomes of pregnancy in CKD and CKD outcomes in pregnancy. Clin J Am Soc Nephrol 2015;10:1964–78.
17. Jones DC, Hayslett JP. Outcome of pregnancy in women with moderate or severe renal insufficiency. N Engl J Med 1996;335:226–32.
18. Hou SH, Grossman SD, Madias NE. Pregnancy in women with renal disease and moderate renal insufficiency. Am J Med 1985;78:185–94.
19. Imbasciati E, Gregorini G, Cabiddu G, Gammaro L, Ambroso G, Del Giudice A, et al. Pregnancy in CKD stages 3 to 5: fetal and maternal outcomes. Am J Kidney Dis 2007;49:753–62.
20. Piccoli GB, Fassio F, Attini R, Parisi S, Biolcati M, Ferraresi M, et al. Pregnancy in CKD: whom should we follow and why? Nephrol Dial Transpl 2012;27(suppl 3):iii111–8.
21. Bramham K, Parnell B, Nelson-Piercy C, Seed PT, Poston L, Chappell LC. Chronic hypertension and pregnancy outcomes: systematic review and meta-analysis. BMJ 2014;348:g2301.
22. Bullo M, Tschumi S, Bucher BS, Bianchetti MG, Simonetti GD. Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a systematic review. Hypertension 2012;60:444–50.
23. Magee LA, von Dadelszen P, Rey E, Ross S, Asztalos E, Murphy KE, et al. Less-tight versus tight control of hypertension in pregnancy. N Engl J Med 2015;372:407–17.
24. Piccoli GB, Daidola G, Attini R, Parisi S, Fassio F, Naretto C, et al. Kidney biopsy in pregnancy: evidence for counselling? A systematic narrative review. BJOG 2013;120:412–27.
25. Beardmore KS, Morris JM, Gallery ED. Excretion of antihypertensive medication into human breast milk: a systematic review. Hypertens Pregnancy 2002;21:85–95.
26. Moretti ME, Sgro M, Johnson DW, Sauve RS, Woolgar MJ, Taddio A, et al. Cyclosporine excretion into breast milk. Transplantation 2003;75:2144–6.
27. Bramham K, Chusney G, Lee J, Lightstone L, Nelson-Piercy C. Breastfeeding and tacrolimus: serial monitoring in breast-fed and bottle-fed infants. Clin J Am Soc Nephrol 2013;8:563–7.
28. Sau A, Clarke S, Bass J, Kaiser A, Marinaki A, Nelson-Piercy C. Azathioprine and breastfeeding: is it safe? BJOG 2007;114:498–501.
29. Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to rituximab. Blood 2011;117:1499–506.
30. Bragnes Y, Boshuizen R, de Vries A, Lexberg A, Ostensen M. Low level of Rituximab in human breast milk in a patient treated during lactation. Rheumatology (Oxford) 2017;56:1047–8.
31. Hay S, Burchett S, Odejide O, Cataltepe S. Septic episodes in a premature infant after in utero exposure to rituximab. Pediatrics 2017;140:e20162819.
32. Klink DT, van Elburg RM, Schreurs MW, van Well GT. Rituximab administration in third trimester of pregnancy suppresses neonatal B-cell development. Clin Dev Immunol 2008;2008:271363.
33. Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum 2006;54:3640–7.
34. Moroni G, Doria A, Giglio E, Tani C, Zen M, Strigini F, et al. Fetal outcome and recommendations of pregnancies in lupus nephritis in the 21st century: a prospective multicenter study. J Autoimmun 2016;74:6–12.
35. Buyon JP, Kim MY, Guerra MM, Laskin CA, Petri M, Lockshin MD, et al. Predictors of pregnancy outcomes in patients with lupus: a cohort study. Ann Intern Med 2015;163:153–63.
36. Hoeltzenbein M, Elefant E, Vial T, Finkel-Pekarsky V, Stephens S, Clementi M, et al. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet A 2012;158A:588–96.
37. Anderka MT, Lin AE, Abuelo DN, Mitchell AA, Rasmussen SA. Reviewing the evidence for mycophenolate mofetil as a new teratogen: case report and review of the literature. Am J Med Genet A 2009;149A:1241–8.
38. Clowse ME, Magder L, Petri M. Cyclophosphamide for lupus during pregnancy. Lupus 2005;14:593–7.
39. Enns GM, Roeder E, Chan RT, Ali-Khan Catts Z, Cox VA, Golabi M. Apparent cyclophosphamide (cytoxan) embryopathy: a distinct phenotype? Am J Med Genet 1999;86:237–41.
40. Sebestyen A, Varbiro S, Sara L, Deak G, Kerkovits L, Szabo I, et al. Successful management of pregnancy with nephrotic syndrome due to preexisting membranous glomerulonephritis: a case report. Fetal Diagn Ther 2008;24:186–9.
41. Liu S, Rouleau J, Joseph KS, Sauve R, Liston RM, Young D, et al. Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada. J Obstet Gynaecol Can 2009;31:611–20.
42. Barbour SJ, Greenwald A, Djurdjev O, Levin A, Hladunewich MA, Nachman PH, et al. Disease-specific risk of venous thromboembolic events is increased in idiopathic glomerulonephritis. Kidney Int 2012;81:190–5.
43. Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017;377:613–22.
44. Hofmeyr GJ, Duley L, Atallah A. Dietary calcium supplementation for prevention of pre-eclampsia and related problems: a systematic review and commentary. BJOG 2007;114:933–43.
45. Khaing W, Vallibhakara SA, Tantrakul V, Vallibhakara O, Rattanasiri S, McEvoy M, et al. Calcium and vitamin D supplementation for prevention of preeclampsia: a systematic review and network meta-analysis. Nutrients 2017;9:E1141.
46. Antepartum fetal surveillance. Practice Bulletin No. 145. American College of Obstetricians and Gynecologists. Obstet Gynecol 2014;124:182–92.
47. Shahir AK, Briggs N, Katsoulis J, Levidiotis V. An observational outcomes study from 1966 to 2008, examining pregnancy and neonatal outcomes from dialyzed women using data from the ANZDATA registry. Nephrology (Carlton) 2013;18:276–84.
48. Barua M, Hladunewich M, Keunen J, Pierratos A, McFarlane P, Sood M, et al. Successful pregnancies on nocturnal home hemodialysis. Clin J Am Soc Nephrol 2008;3:392–6.
49. Hladunewich MA, Hou S, Odutayo A, Cornelis T, Pierratos A, Goldstein M, et al. Intensive hemodialysis associates with improved pregnancy outcomes: a Canadian and United States cohort comparison. J Am Soc Nephrol 2014;25:1103–9.
50. Piccoli GB, Minelli F, Versino E, Cabiddu G, Attini R, Vigotti FN, et al. Pregnancy in dialysis patients in the new millennium: a systematic review and meta-regression analysis correlating dialysis schedules and pregnancy outcomes. Nephrol Dial Transpl 2015;31:1905–34.
51. Tangren J, Nadel M, Hladunewich MA. Pregnancy and end-stage renal disease. Blood Purif 2018;45:194–200.
52. Wehmann RE, Amr S, Rosa C, Nisula BC. Metabolism, distribution and excretion of purified human chorionic gonadotropin and its subunits in man. Ann Endocrinol (Paris) 1984;45:291–5.
53. Coskun A, Bicik Z, Duran S, Alcelik A, Soypacaci Z, Yavuz O, et al. Pregnancy-associated plasma protein A in dialysis patients. Clin Chem Lab Med 2007;45:63–6.
54. Wittfooth S, Tertti R, Lepäntalo M, Porela P, Qin QP, Tynjälä J, et al. Studies on the effects of heparin products on pregnancy-associated plasma protein A. Clin Chim Acta 2011;412:376–81.
55. Ikizler TA, Pupim LB, Brouillette JR, Levenhagen DK, Farmer K, Hakim RM, et al. Hemodialysis stimulates muscle and whole body protein loss and alters substrate oxidation. Am J Physiol Endocrinol Metab 2002;282:E107–16.
56. Asamiya Y, Otsubo S, Matsuda Y, Kimata N, Kikuchi K, Miwa N, et al. The importance of low blood urea nitrogen levels in pregnant patients undergoing hemodialysis to optimize birth weight and gestational age. Kidney Int 2009;75:1217–22.
57. McKay DB, Josephson MA. Pregnancy in recipients of solid organs—effects on mother and child. N Engl J Med 2006;354:1281–93.
58. Gill JS, Zalunardo N, Rose C, Tonelli M. The pregnancy rate and live birth rate in kidney transplant recipients. Am J Transpl 2009;9:1541–9.
59. Coscia LA, Constantinescu S, Carlin FR, McGrory CH, Armenti D, Moritz MJ. 2015 Annual Report for the National Transplantation Pregnancy Registry (issued June 15, 2016). Available at: www.transplantpregnancyregistry.com
. Retrieved March 7, 2019.
60. Levidiotis V, Chang S, McDonald S. Pregnancy and maternal outcomes among kidney transplant recipients. J Am Soc Nephrol 2009;20:2433–40.
61. Kim HW, Seok HJ, Kim TH, Han DJ, Yang WS, Park SK. The experience of pregnancy after renal transplantation: pregnancies even within postoperative 1 year may be tolerable. Transplantation 2008;85:1412–9.
62. Bramham K, Nelson-Piercy C, Gao H, Pierce M, Bush N, Spark P, et al. Pregnancy in renal transplant recipients: a UK national cohort study. Clin J Am Soc Nephrol 2013;8:290–8.
63. Deshpande NA, James NT, Kucirka LM, Boyarsky BJ, Garonzik-Wang JM, Montgomery RA, et al. Pregnancy outcomes in kidney transplant recipients: a systematic review and meta-analysis. Am J Transpl 2011;11:2388–404.
64. Rao S, Ghanta M, Moritz MJ, Constantinescu S. Long-term functional recovery, quality of life, and pregnancy after solid organ transplantation. Med Clin North America 2016;100:613–29.
65. Rose C, Gill J, Zalunardo N, Johnston O, Mehrotra A, Gill JS. Timing of pregnancy after kidney transplantation and risk of allograft failure. Am J Transpl 2016;16:2360–7.
66. McKay DB, Josephson MA, Armenti VT, August P, Coscia LA, Davis CL, et al. Reproduction and transplantation: report on the AST Consensus Conference on reproductive issues and transplantation. Am J Transpl 2005;5:1592–9.