Pregnancy and Chronic Kidney Disease

Medical Problems During Pregnancy

Geena Joseph¹, Sarah L. Housman² and Melanie P. Hoenig³

(1)

Nephrology and Obstetrical Medicine, McMaster University, 73 Water Street North, Suite 601, Cambridge, ON , N1R 7L6, Canada

(2)

Department of Medicine, MGH Women’s Health Associates Massachusetts General Hospital Yawkey 4, 32 Fruit Street, Boston, MA 02114, USA

(3)

Renal Division, Harvard Medical School, , Beth Israel Deaconess Medical Center, 171 Pilgrim Road, Boston, MA 02215, USA

Geena Joseph

Email: geena.joseph@gmail.com

Sarah L. Housman

Email: shousman@bidmc.harvard.edu

Melanie P. Hoenig (Corresponding author)

Email: mhoenig@bidmc.harvard.edu

Keywords

Chronic kidney diseaseEstimated glomerular filtration rateHypertensionPreeclampsiaKidney transplantBreastfeedingProteinuriaImmunosuppressionIntrauterine growth restriction

Abbreviations

ACR

Albumin-to-creatinine ratio

Blood pressure

CNI

Calcineurin inhibitor

CKD

Chronic kidney disease

ESRD

End-stage renal disease

eGFR

Estimated glomerular filtration rate

GFR

Glomerular filtration rate

Urine PrCr

Urine protein-to-creatinine ratio

Case 1

A 34-year-old nulliparous woman with a history of chronic kidney disease and hypertension presents for preconception counseling. Her reduced renal function was secondary to reflux nephropathy and a congenital single kidney (baseline creatinine 1.4–1.6 mg/dL). At the age of 12, the patient had surgical ureteral reimplantation. Her blood pressure is well controlled with lisinopril and hydrochlorothiazide. Discussions regarding pregnancy began when she transitioned to adult care, and more in-depth counseling regarding the risks and potential complications of pregnancy was addressed when she and her spouse began to consider pregnancy more seriously. The patient decides to proceed with pregnancy planning; she begins prenatal vitamins, and lisinopril was switched to labetalol with good blood pressure control.

Laboratory studies included a creatinine 1.4 mg/dL, uric acid 8.0 mg/dL, and urine protein-to-creatinine ratio (urine PrCr) = 0.4 mg/mg.

One year later, she becomes pregnant. She begins low-dose aspirin and a high-calcium diet. During pregnancy, she is monitored by both maternal fetal medicine and nephrology, and her creatinine remains stable at 1.4 mg/dL. While pregnant, she requires only labetalol 100 mg twice daily, and her average blood pressure is 130/80. Her blood pressure increases to 140/85 by 37-week gestation. Her pregnancy is complicated by intrauterine growth restriction (IUGR), and her urine protein-to-creatinine ratio increases from 0.4 to 0.8 g/g. Given the poor fetal growth over this period and the fact that the fetus is in the breech position, she has an elective cesarean section at 37 weeks and 5 days. She delivers a 2275 g baby girl (5–10th percentile). Apgar scores are 8 and 9. The infant requires care in the neonatal intensive care unit for 2 days due to hypoglycemia but then thrives and achieves age-appropriate milestones.

The mother is monitored closely postpartum. Her blood pressure is well controlled on labetalol and hydrochlorothiazide 6.25 mg while lactating. Her creatinine increases over the subsequent 8 months postpartum to 1.9 mg/dL, and her urine protein-to-creatinine ratio remains 0.8 mg/mg.

Renal Physiology in Normal Pregnancy

The physiology of normal pregnancy leads an increase in glomerular filtration rate (GFR) (Fig. 1). This increase is related to several factors, which include an increase in cardiac output, a decrease in peripheral vascular resistance, and an increase in total body water, which ultimately lead to an 80 % increase in renal plasma flow. These changes begin shortly after the first missed period and continue to midtrimester such that in 20 weeks, the GFR may be up to 50 % above baseline. The serum creatinine falls commensurate with the increase in the GFR. Normally, the GFR declines slightly during the third trimester and returns to prepregnancy levels with delivery or up to 3 months postpartum [2]. In the setting of chronic kidney disease (CKD), the physiologic increase in GFR (and fall in serum creatinine) may not occur.

Fig. 1

Normal physiologic changes in pregnancy (Adapted using data from Ueland and Metcalfe [1], Davison and Dunlop [2], Hytten and Paintin [3])

Blood pressure typically decreases by 15–20 mmHg during the first 20 weeks of pregnancy. A decreased sensitivity to vasoconstrictive agents such as angiotensin II and an increased production of vasodilators such as nitric oxide appear to contribute to a significant reduction in systemic vascular resistance and enhance placental perfusion [4, 5]. The blood pressure then increases toward baseline during the third trimester.

Under normal circumstances, in the nonpregnant state, there is a small amount of proteinuria, and this is typically absorbed in the proximal tubules, which normally function at near maximum capacity for reabsorption of albumin, the predominant protein in blood. The net result under normal circumstances is that there is very little proteinuria. In the setting of a physiologic increase in renal blood flow and consequently GFR, as with normal pregnancy, there may be a small increase in proteinuria up to 200–300 mg/day by the third trimester. In twin pregnancies, there is a greater increase in cardiac output and often a greater increase in proteinuria; however, this increase would still result in very mild proteinuria normally under 0.5 g/day [6]. In patients with proteinuria at baseline, the physiologic changes from pregnancy can commonly cause an increase in proteinuria even without a decline in renal function or worsening of the underlying renal disorder.

Uric acid, a product of purine metabolism, is filtered and reabsorbed in the proximal tubule. It may be elevated in the setting of reduced renal function and in volume depletion when there is increased proximal sodium reabsorption. Serum uric acid levels are also increased in preeclampsia; this finding is consistent with the likely pathogenesis of preeclampsia whereby ischemic injury to the kidney occurs in the setting of endothelial damage. In addition, some have postulated that the hyperuricemia can also contribute to endothelial damage [7]. Uric acid levels typically decrease during pregnancy by 25–30 % because of plasma volume expansion and the increase in GFR. Since uric acid can be elevated in CKD, this marker is harder to interpret in the setting of reduced renal function and is not recommended to predict which patients will develop preeclampsia; however, the trend in serum uric acid levels can be useful.

The Management of Hypertension in Pregnant Patients with CKD

Hypertension in the setting of pregnancy is classified as chronic hypertension, gestational hypertension, or preeclampsia (Table 1). This case highlights the management of chronic hypertension in pregnant patients with CKD. Hypertension guidelines for the general CKD, nonpregnant population recommend a target blood pressure of <140/90 mmHg and advocate for a lower target of <130/90 mmHg for patients with proteinuria [8, 9]. These guidelines are based on large randomized controlled studies in thousands of patients that addressed the risks of overall mortality, cardiovascular and renal morbidity, stroke, coronary interventions, and end-stage renal disease (ESRD). During pregnancy, the goals for blood pressure treatment differ from goals in the general population. Instead of long-term goals, the goals are short term and directed at avoiding immediate end-organ damage to the mother and fetus while limiting the risks of altered uteroplacental perfusion which might ultimately affect fetal growth and development [10].

Table 1

Classification of hypertension in pregnancy

Chronic hypertension	Gestational hypertension	Preeclampsia^a
A diagnosis of hypertension before pregnancy	Hypertension in patients at >20-week gestation without a prior diagnosis of hypertension	New onset hypertension on two occasions after 20-week gestation (usually in third trimester after 37-week gestation)
Hypertension during the first 20 weeks of pregnancy	Absence of preeclampsia	Proteinuria (>0.3 g/24 h or urine protein/creatinine > 0.3 mg/mg)^b
Hypertension that persists beyond 12 weeks postpartum	Hypertension resolves postpartum	End-organ damage^c

Hypertension is defined as >140/90 mmHg

^aAs defined by the American College of Obstetricians and Gynecologists, 2013

^bThe urine protein-to-creatinine ratio (urine PrCr) on a random urine specimen approximates the amount of proteinuria in grams. Although this has not been rigorously tested in pregnancy, this test allows clinicians to follow proteinuria without regularly measuring 24-h urine collections

^cEnd-organ damage is defined as platelet count <100,000/μl, serum creatinine >1.1 mg/dL or doubling of the serum creatinine, AST/ALT to twice-normal concentrations, pulmonary edema, new cerebral or visual symptoms

Strict blood pressure targets in pregnancy have been extensively studied as a potential strategy to lower the risk of preeclampsia and pregnancy complications, but results have been disappointing. Several meta-analyses including a 2014 Cochrane review showed that treatment of mild to moderate hypertension during pregnancy does not decrease the risk of preeclampsia, neonatal death, preterm birth, or small-for-gestational-age babies [11].

Given the lack of definitive evidence, guidelines differ on the appropriate blood pressure target in pregnancy. The National Institute for Health and Clinical Excellence guidelines recommend a target blood pressure of <150/100 mmHg during pregnancy, whereas the American College of Obstetricians and Gynecologists recommends a target of <160/110 mmHg [12, 13]. There is strong evidence to suggest that severe hypertension ≥160/110 mmHg is associated with severe complications of maternal stroke and fetal abruption; therefore, severe hypertension should always be treated. Care of patients with hypertension and CKD adds a layer of complexity, and some advocate for slightly lower target of <140/90 mmHg although there is no data to support this recommendation [14].

In the largest study to date, 987 pregnant women with hypertension were randomized to either strict blood pressure control with a target diastolic blood pressure (DBP) of <85 mmHg vs. a target DBP <100 mmHg. Both groups had the same rates of pregnancy loss, need for high-level neonatal care, and maternal complications. The group randomized to less tight control had higher rates of severe maternal hypertension. Overall, this study showed no significant difference in the rates of serious maternal complications and major adverse perinatal outcomes with less tight versus tight control of blood pressure in pregnancy [15]. Of note, none of the patients enrolled in the study had CKD.

Ideally, hypertension management should begin before conception. Many women with CKD take angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blockers (ARBs) as they are recommended for patients with proteinuric CKD to decrease proteinuria and slow progression of kidney disease [16, 17].

In pregnancy, however, ACE inhibitors cross the placenta in pharmacologically significant amounts and have a well-documented pattern of fetal risks with second- and third-trimester exposure. These fetotoxic effects include renal tubule dysplasia, renal agenesis, and other fetal abnormalities including oligohydramnios, hypoplastic lungs, hypocalvaria, and neonatal hypotension, likely stemming from a decrease in fetal angiotensin or an increase in fetal bradykinin [18]. It is generally assumed that ARBs will lead to similar complications, although published data is limited [19, 20]. The Food and Drug Administration (FDA) has labeled ACE inhibitors as contraindicated in the second and third trimesters since 1986; however, first-trimester exposure has been controversial, making prepregnancy counseling and management of young women with chronic kidney disease less straightforward. The evidence for first-trimester risk of congenital abnormalities with ACE inhibitor exposure is conflicting: a retrospective study linked first-trimester prescriptions for ACE inhibitors to a significantly greater risk of serious fetal abnormalities [21], whereas a large cohort study and systematic review did not show an increase in risk [20, 22]. It is possible that this discrepancy is related to characteristics of the hypertensive pregnant population such as undiagnosed diabetes, maternal obesity, or hypertension itself. In the general population, the decision to stop ACE inhibitors prior to conception and control blood pressures with pregnancy-safe medications is obvious. In chronic kidney disease patients, especially with significant proteinuria, the decision is more difficult since ACE inhibitors appear to slow the progression of disease in those with significant proteinuria. Increasingly, experts in the field recommend a more tailored approach to the use of ACE inhibitors in women who are considering pregnancy [23, 24]. In the patient who is able to work closely with her care team and is at high risk for progression without an ACE inhibitor, such as those with proteinuria of >1 g/day, it may be reasonable to continue the ACE inhibitor until pregnancy is confirmed in the first trimester, particularly when conception may take months to years. Yet, the decision to conceive on an ACE inhibitor requires a careful discussion with the patient regarding potential risks and benefits. If a woman chooses to conceive on an ACE inhibitor, she is instructed to discontinue the drug when she obtains a positive pregnancy test to limit exposure and arrange to be seen promptly to confirm pregnancy. At that time, if necessary, pregnancy-safe antihypertensive agents can be used and be prescribed. In patients who are less likely to identify pregnancy early or those whose blood pressure may not be readily controlled without ACE inhibitors, a preconception change in regimen is more appropriate.

Methyldopa, labetalol, and nifedipine are considered first-line agents in pregnant patients or patients with hypertension who are trying to conceive as they have been studied in pregnancy and appear to be the safest [25–27], though methyldopa is used less often because it commonly causes nausea and fatigue and may increase liver enzymes. Thiazide diuretics are considered second-line treatment but are likely to be safe [28]. Patients with chronic hypertension should be seen in the office every 2–4 weeks in the first two trimesters, and visit frequency should be increased as needed, depending on the clinical course. Some suggest that women with chronic hypertension also monitor their blood pressure at home. In patients whose measurements correlate with office measurements, this can be a helpful adjunct to care but would not replace office evaluation of blood pressure. During office visits, urine protein should also be measured.

In this vignette, blood pressure variations mirrored the normal trends in blood pressure during pregnancy. The patient’s blood pressure medication requirement decreased during the first half of pregnancy, and then her blood pressure increased toward her baseline during the third trimester. This normal trend is worth noting so that it is not mistaken for the onset of preeclampsia.

Classification of CKD in Pregnancy

The classification of CKD in pregnancy has traditionally differed from the classification of CKD in the general population. This is a reflection of the fact that these considerations preceded the newer “stages” of CKD that have been embraced by the National Kidney Foundation. The latter uses estimated GFR (eGFR) rather than the serum creatinine, whereas, in pregnancy, risk is separated into three categories: mild, moderate, and severe based solely on the value of the serum creatinine prior to conception. These categories are also defined slightly differently in various publications, which make it more difficult to counsel patients. More recent publications have begun to consider pregnancy risk in the context of the estimated GFR and also consider proteinuria [29]. See Fig. 2 for a summary of risks by classification.

Fig. 2

Risks of maternal and fetal complications during pregnancy in CKD (For references, see associated text)

For the general population, formulas such as the Cockroft-Gault or the Modification of Diet in Renal Disease (MDRD) equation are used to estimate GFR. These formulas are used when the renal function is stable and include the serum creatinine and additional factors such as age, weight, gender, ethnicity, blood urea nitrogen, and serum albumin. None of these formulas perform well when the renal function is close to normal or when there is acute kidney injury. Importantly, these formulas also have not been validated for pregnant women [30]. The performance of MDRD equation in pregnancy may substantially underestimate GFR in pregnancy compared to GFR measured by inulin clearance [31]. Reliance on the MDRD formula during pregnancy is not recommended because of this discrepancy. Nevertheless, these estimates have become the standard for measurement of eGFR in the nonpregnant population and therefore are readily available and can be useful in preconception counseling. For comparison, a 30-year-old nonpregnant woman whose serum creatinine is 1.4 mg/dL would have an eGFR of approximately 50 ml/min/1.73 m²using several different formulas.

The degree of proteinuria plays a very important role in determining renal prognosis for patients with CKD who are not pregnant. In fact, this characteristic is so important that the Kidney Disease: Improving Global Outcomes guidelines recommend classifying patients based on both eGFR and level of albuminuria [32]. Those with the most albuminuria are the most likely to have a further decline in renal function. It is likely that significant proteinuria also increases the risk of adverse pregnancy outcomes for women [29, 33]. The gold standard for measuring proteinuria remains the 24-h urine collection (with measurement of the urinary creatinine to assure a complete collection). Significant proteinuria in pregnancy is defined as proteinuria ≥0.3 g/day. Yet this test is difficult to do repeatedly because the sample sometimes requires refrigeration and its collection is cumbersome and time consuming. Instead, a random urine specimen that measures protein and creatinine can be used to calculate the urine protein-to-creatinine (urine PrCr) ratio. This value approximates the number of grams per day of urinary protein. Normal urine PrCr is < 0.2 mg/mg (20 mg/mmol) so a ratio of >0.3 mg/mg (0.30 mg/mmol) represents significant proteinuria in singleton pregnancy [34]; a threshold up to 0.4 mg/mg (40 mg/mmol) may be more appropriate in multiple pregnancy [35, 36].

A urinary albumin-to-creatinine ratio (ACR) can also be used since albumin is the major protein in blood and, therefore, the major protein in urine when there is proteinuria from altered glomerular hemodynamics or glomerular disease. The ACR was initially popularized to detect minute amounts of urinary albumin, too small to be detected by the urinary dipstick, and the units of measurement are three orders of magnitude smaller than the urine protein-to-creatinine ratio. Normal ACR is <30 mcg/mg creatinine. The urinary dipstick typically turns positive at approximately 300 mcg/mg creatinine. The sensitivity and specificity for both the ACR and urine PrCr are excellent when the urinary protein is very low [37]. Although the urinary ACR test has not been validated in pregnancy, it is recommended for screening nonpregnant diabetic patients and routinely used instead of 24-h urine collections to assess proteinuria in patients with CKD. Thus, either the urine PrCr or the urinary ACR can be used to follow patients who have CKD and are pregnant. Although these “spot” tests are less accurate than the 24-h collection, they are clearly more accurate than the urinary dipstick alone since the latter is dependent on the concentration of the urine.

CKD in Pregnancy: Complications

All women with underlying kidney disease are at increased risk of both maternal and fetal complications in pregnancy [38]. A systematic review of pregnancy outcomes in chronic kidney disease revealed that women with CKD appear to have at least a twofold higher risk of developing adverse maternal outcomes (gestational hypertension, preeclampsia, eclampsia, and maternal mortality) compared with women without CKD. Similarly, premature births occurred at least twice as often in women with CKD compared with women without CKD. Other fetal outcomes such as IUGR, SGA, neonatal mortality, stillbirths, and low birth weight were all higher in women with CKD compared to women without CKD; however, the rates vary depending on the study [39].

The risk of complications in pregnancy depends on many factors including baseline kidney function, proteinuria, type of renal disease, disease activity, scarring on kidney biopsy, and hypertension. The literature suggests that the strongest predictors of complications are baseline kidney function and severity of hypertension.

Mild CKD

Mild CKD has traditionally been classified as a prepregnancy serum creatinine less than 1.5 mg/dL(133umol/l), which would represent an estimated GFR of 50 ml/min/1.73 m² or greater for women over 21 years of age. These patients typically do relatively well during pregnancy. Most of the available studies suggest that renal function is generally preserved among patients with mild CKD. Less than 10 % of women with mild CKD who also have minimal proteinuria (<1 g/24 h) and well-controlled blood pressure will develop permanent, significant renal impairment, and greater than 90 % of patients will have successful pregnancy outcomes defined as having a live birth in the absence of preeclampsia, premature delivery, and IUGR [40, 41]. Hypertension appears to be the main predictor of pregnancy outcome for patients with mild CKD, as uncontrolled hypertension (defined as MAP >105 mmHg) in this population carries a higher risk for pregnancy complications [41].

Moderate CKD

Moderate CKD is traditionally classified as a prepregnancy serum creatinine range of 1.5–2.5 mg/dL (132–221umol/L). This includes a wide range of renal function that would reflect a preconception range of estimated GFR from 25 to 50 ml/min/1.73 m^2..

In patients with moderate CKD, up to 30 % will experience significant deterioration of renal function that will persist postpartum [42, 43]. In addition, there is a 10 % risk of progression to ESRD by 12 months postpartum; this risk is likely to be greater with higher preconception creatinine values and significant proteinuria [42, 44]. Among patients with moderate CKD, although the fetal survival rate exceeds 90 %, greater than 50 % of fetuses will experience IUGR or prematurity (often related to preeclampsia) [33, 42, 43]. Furthermore, a longitudinal multicenter cohort study of 49 pregnant patients with moderate-to-severe kidney disease showed that the combination of prepregnant proteinuria (>1 g/day) and Cr > 2.0 mg/dL predicted postpartum renal decline and worse fetal outcomes more than reduced GFR or proteinuria alone [33].

Severe CKD

The preconception serum creatinine that characterizes severe CKD in pregnancy varies somewhat in the literature, and this is related to the limited number of patients in this category who conceive. Certainly, a serum creatinine greater than or equal to 2.5 mg/dL would be considered severe CKD by most. This value is likely to correlate with an eGFR below 25 mL/min/1.73 m². Since preparations for dialysis or evaluation for renal transplant are appropriate for patients with eGFR below 25 ml/min/1.73 m², the prospect of pregnancy in this setting complicates care considerably. These patients tend to have a difficult time conceiving, and they have the highest risk of maternal and fetal complications. Indeed, combined data from several sources suggest that nearly all women with severely reduced renal function will have a complication during pregnancy and half will experience permanent loss of renal function and may need to start dialysis during pregnancy or postpartum [29]. The risk of prematurity is significant and estimated to be as high as 70–90 % in some studies and IUGR risk of up to 50–65 % [29, 45, 46]. Despite the high risk of complications, approximately 75–90 % of patients will have a live birth. Patients must be counseled about the potential long-term consequences associated with prematurity and the additional stress of potentially caring for a sick child while addressing their own health issues such as initiation of dialysis. Counseling patients about these complex issues is important so that patients can make educated decisions.

Primary Renal Disease and Pregnancy

Although much of the literature on CKD in pregnancy categorizes the clinical course by the preconception creatinine, the underlying renal disease and the disease activity prior to conception can greatly affect outcome. For example, in patients with systemic lupus erythematosus or systemic sclerosis, adverse maternal and fetal outcomes are more likely than in women who have a history of reflux nephropathy. Patients with a history of nephrolithiasis or recurrent pyelonephritis may have specific challenges but tend to do well with pregnancy. Similarly, women who have previously donated a kidney and therefore have reduced renal mass tend to have favorable outcomes during pregnancy but may have a greater risk of gestational hypertension and preeclampsia compared to the general population [47]. In general, renal disease should be treated and well controlled prior to pregnancy to improve outcomes; this is particularly true for lupus nephritis, diabetic nephropathy, and glomerulonephritis.

CKD and Preeclampsia

In the first case, the urine protein-to-creatinine ratio increased during pregnancy from 0.4 mg/mg prepartum to 0.8 mg/mg at delivery. Many patients with CKD have proteinuria and hypertension at baseline, and during pregnancy the proteinuria often increases. This can make it challenging to differentiate between chronic kidney disease and preeclampsia particularly since hypertension and proteinuria are two of the criteria used to make the diagnosis of preeclampsia. If hypertension and proteinuria are preexisting, other clinical signs should be used to diagnose preeclampsia such as placental dysfunction, elevated liver enzymes, low platelets, or clinical symptoms. It is critical that the distinction between CKD and preeclampsia is made since an incorrect diagnosis of preeclampsia could lead to iatrogenic prematurity. To complicate matters, patients with CKD have up to four times higher risk of developing preeclampsia, compared to those without CKD [38]. An evolving understanding of the pathogenesis of preeclampsia may lead to the identification of serum biomarkers to help distinguish between the two entities. Biomarkers such as soluble fms-like tyrosine kinase 1 (sFlt1), an anti-angiogenic factor, are elevated in patients with preeclampsia and lead to a reduction in placental growth factor (PIGF) and vascular endothelial growth factor (VEGF). The dysregulation of these growth factors appears to result in placental endothelial dysfunction and the subsequent clinical manifestations of preeclampsia [48]. Patients with preeclampsia have marked elevations in sFlt1, reductions in PIGF, and a higher sFlt1/PIGF ratio compared to those who do not have preeclampsia but have CKD [49, 50]. Although prospective and longitudinal studies are still needed to define the role of these markers in clinical management, in the future, some combination of measurements of angiogenic factors may provide unique tools for caregivers to predict preeclampsia and differentiate preeclampsia from a change in renal function among pregnant patients with CKD.

Prevention of Preeclampsia

There are no treatments that can reliably prevent the development of preeclampsia. In several large randomized, multicenter trials and meta-analyses, low-dose aspirin appeared to confer some benefit in the general pregnant population though these benefits have not been confirmed in subgroup analyses of high-risk patients or those with CKD [51]. Nevertheless, low-dose aspirin at doses of 75–120 mg taken at bedtime and begun by the 16th week of gestation is broadly recommended by major relevant societies including the International Society of Hypertension in Pregnancy, the United Kingdom’s National Institute of Health Care Excellence (NICE), and the American Congress of Obstetricians and Gynecologists (ACOG) [52, 53].

In addition, the World Health Organization endorses calcium supplementation before 20-week gestation in populations where calcium intake is low with a goal of 1.5–2 g of elemental calcium intake daily. This recommendation stems from randomized controlled trials that demonstrated a decreased risk of preeclampsia and preterm delivery with calcium supplementation, particularly in those women who had low-calcium diets [54, 55].

Case 2

A 39-year-old nulliparous woman with polycystic kidney disease (PKD) complicated by hypertension presents for prepregnancy evaluation. She is otherwise healthy. She has never had visible hematuria, kidney stones, or urinary tract infections. Her father had PKD and developed ESRD in his late 40s and then died of a heart attack at the age of 61. Her blood pressure has been well controlled on metoprolol sustained release 100 mg daily for several years. Her menstrual cycles are normal, and she is using condoms for contraception. Her blood pressure was 132/87 mmHg. Abdominal examination was notable for palpable kidneys bilaterally. Her creatinine is 2.6 mg/dL (eGFR 22 mL/min/1.73 m²). Old records reveal a creatinine of 1.9 mg/dL 3 years prior and 2.1 mg/dL the year prior to referral.

Despite minimal proteinuria and good blood pressure control, her renal function has declined relatively rapidly. She is counseled about the high risk of pregnancy complications and decides against pregnancy. She has no suitable donors for transplantation and is counseled regarding options for dialysis. She begins oral contraception to prevent an unplanned pregnancy and decides to pursue adoption.

The following year, she begins dialysis for symptoms of nausea and vomiting when her creatinine reaches 5.6 mg/dL, but the symptoms persist. Abdominal ultrasound reveals that she is pregnant, and the approximate age of the fetus is 21-week gestation. Her hemodialysis regimen is intensified and she receives 4 h, 6 days per week (total 24 h per week). Her residual urine output is 1.5 L/day so minimal fluid removal is required with dialysis. Her blood pressures remain normal throughout pregnancy without medication. The fetus has mild fetal growth restriction, but ultrasounds demonstrate normal uterine Doppler flow and amniotic fluid throughout pregnancy. At 35-week gestation, spontaneous labor begins and she delivers a 2619 g baby boy (50–70th percentile). Apgar scores are 8 and 9. The infant is monitored in the neonatal intensive care unit for 1 day given prematurity, but is then discharged and achieves age-appropriate milestones.

Preconception Counseling

Caregivers have variable training and experience giving “sad” and “bad news” to patients, and antenatal counseling in the setting of advanced chronic kidney disease provides a particular challenge. First, the statistics available to help patients make an informed decision are limited and of variable quality. Furthermore, since outcomes relate both to the health of the mother and the chance of normal development and survival of the fetus, counseling is typically emotionally charged. In addition to providing data, it is useful to consider a multistep approach not unlike the steps used for counseling regarding a cancer diagnosis or recognition of advanced kidney disease and impending need for renal replacement therapy. These approaches include the creation of a relationship, identification of the patient’s understanding of her health, sharing information regarding the risks, shared decision-making, a response to her emotions, and a thoughtful planning [56, 57].

Preconception counseling is an essential component of the care of women who are of childbearing age with chronic kidney disease. This counseling should begin at entry to care. All women with kidney disease are at increased risk of pregnancy complications; however, the risk varies based on the kidney disease stage, and therefore thoughtful planning in this population is necessary. For example, women with PKD who begin to lose kidney function should be encouraged to consider pregnancy earlier, when kidney function is still relatively preserved. Although it is fortunate that patients with reduced renal function generally feel well until the GFR is so reduced that renal replacement therapy is imminent, (typically when the eGFR is below 10 ml/min/1.73 m²), this also means that women may have difficulty believing that they are at higher risk of complications. In this situation, since women are usually asymptomatic, the risks of pregnancy outlined by caregivers may seem exaggerated. However, if counseling begins early, appropriate preparations can also begin. For patients with advanced CKD who understand the risks and decide against pregnancy, the spectrum of contraceptive options is available with the same risks and concerns as in the general population [58]. For women who decide to proceed with pregnancy, it is important for caregivers to suspend judgment and provide care with the help of a multidisciplinary team.

Advocate for Patients Who Would Like to Parent

In patients who have severely reduced renal function, it is important to remember that counseling against pregnancy is not the same as counseling against motherhood. Individuals with reduced renal function typically feel well (unless comorbid conditions impact their health). In this situation, caregivers should be advocates for parenthood if patients desire this. Women with chronic kidney disease can utilize the help of a gestational surrogate; although this strategy requires navigation of complex issues that range from contractual and financial issues to cultural pressures and ethical dilemmas [59], it allows a couple to have their own genetically related child. Adoption is an additional option for women who choose to forgo pregnancy because of the attendant risks. Women who choose this route may need support from caregivers to confirm that their health is sufficiently stable to ensure the safety, well-being, and permanence of the placement for an adopted child (Child Welfare Information Gateway) [60].

An additional option is for women to wait until they have a renal transplant to become pregnant. This option can be frustrating for women who are older and have a limited number of potential childbearing years or for women whose renal function is deteriorating slowly, and the time that lapses before progression, transplantation, and the requisite posttransplantation wait is daunting.

Although data is limited, a small series that looked at outcomes for children born to mothers with CKD did not find differences in maternal bonding, additional stress in the parent-child relationship, or other difficulties in parenting that might relate to the stress of maternal renal disease and treatment [61]. Additionally, egg or embryo harvesting can preserve fertility for longer.

Care for Patients Who Become Pregnant While on Dialysis or Require Dialysis While Pregnant

Pregnancy is uncommon in ESRD patients on dialysis. There are several reasons for this observation. Many patients with ESRD feel poorly either from comorbid conditions or dialysis treatments and have reduced libido. In addition, irregular and anovulatory cycles are common and felt to be related to a lack of estradiol-stimulated cyclic luteinizing hormone secretion and elevated prolactin levels [62]. Since most ESRD patients have irregular menstrual cycles, in the event that a woman does become pregnant, there may be a delay in the recognition of the pregnancy. ESRD patients who conceive have usually been on dialysis for less than a year. They usually have higher residual renal function and often conception occurs before the initiation of dialysis. The chance of successful pregnancy in women who conceived prior to initiation of dialysis is close to 90 %, much higher than those who conceive on dialysis [63]. There are well-described strategies, for dialysis of a pregnant patient, albeit from a handful of small, published series, that can guide treatment. Intensification of dialysis is the cornerstone of care for successful pregnancy on dialysis. The best outcomes have been observed in centers where the dialysis prescription was more than doubled compared to usual care. In a series from Toronto, Canada, that described six pregnancies in five women, the dialysis time was increased using nocturnal hemodialysis to deliver a mean dose of 48 h weekly. In this series, there were no cases of preeclampsia or severe hypertension and only two babies developed IUGR though 50 % required preterm delivery (defined as delivery before 37 weeks, though only one delivered before 32 weeks) [64]. Buoyed by this positive experience, the same group has now published a larger series of 22 patients who received intensive dialysis and compared these to a series of 77 patients who received less intensive dialysis. In this series, women who received more than 36 h of dialysis weekly had an 85 % chance of a live birth, whereas those who received less than 20 h of dialysis weekly had a live birthrate of only 48 %. Furthermore, women who had more intensive dialysis achieved longer gestational age and greater birth weights [65]. The authors conclude that pregnancy can be safe and feasible for a woman with ESRD who does hemodialysis. Pregnancy is also possible in patients who perform peritoneal dialysis; however, the ability to intensify the amount of dialysis is limited. The growing uterus limits surface area in the peritoneum and the volume that can be instilled. In order to increase dialysis, women who perform peritoneal dialysis with the cycler by night may need to add frequent exchanges to the daytime period or add hemodialysis to her peritoneal dialysis regimen [66].

The patient in the vignette was in optimal condition prior to pregnancy and although her pregnancy was unplanned and the diagnosis delayed, she maintained good residual renal function and with intensified hemodialysis, she had a good outcome.

Case 3

A 36-year-old woman is seen for preconception counseling. She has ESRD secondary to focal and segmental glomerulosclerosis and required dialysis for 1 year before she had a living-related kidney transplant from her brother. Her medications include an extended release formulation of tacrolimus 7 mg daily, prednisone 5 mg daily, and mycophenolate mofetil (MMF) 1000 mg twice daily. She has had stable renal function, since her transplant with a creatinine of 1.0 mg/dL (88 umol/L), a hemoglobin of 11.1 g/dL, and no proteinuria. She has had no complications, rejections, or infections. She never had hypertension.

She is counseled about the risks of pregnancy. She and her partner accept the risks and proceeded with preparation. Her mycophenolate mofetil is switched to azathioprine 125 mg daily and she begins prenatal vitamins. Her renal function remains stable and after 3 months, they try to conceive. Six months later, she conceives spontaneously and begins aspirin 81 mg daily; a high-calcium diet or calcium supplementation 1500 mg daily is also recommended.

She is followed jointly with a high-risk obstetrician and nephrologist. She is seen monthly with regular blood work, and during this time, her serum creatinine and blood pressure decrease with a nadir at 24 weeks. Her hemoglobin and iron studies decrease and she takes iron supplements as recommended. At 30 weeks, her blood pressure increases to 148/98 mmHg consistently, and she begins a long-acting formulation of nifedipine at 30 mg daily. Fetal ultrasound reveals mild fetal growth restriction, but normal umbilical artery Doppler studies were normal throughout the pregnancy. At 38 weeks, spontaneous labor begins, and she vaginally delivers a healthy baby girl who weighs 2922 g (70–90th percentile). Immediately postpartum the creatinine is noted to be higher at 1.29 mg/dL (114 umol/L), maternal blood pressure is normal, and she starts breastfeeding without difficulty. At 3 days postpartum, her blood pressure rises to 150/100 mmHg, and the nifedipine is increased. Eight weeks postpartum, her blood pressure returns to normal, and she no longer requires antihypertensive medication. At 1 year postpartum, the blood pressure is normal, and the creatinine remains stable at 1.2 mg/dL (106umol/L), without proteinuria.

Renal Transplant and Fertility

The first reported successful pregnancy with a renal allograft was in 1958, and since then over 14,000 pregnancies in renal allograft recipients have been documented [67–69]. Patients with advanced renal failure have impaired reproductive function, related to hypothalamic-pituitary-gonadal axis dysfunction [70]. Sexual function and fertility usually improve within months of renal transplantation, though the return of fertility is not guaranteed [69]. In one series, only two-thirds of renal transplant recipients had regular menstrual cycles, and slightly less had ovulation documented by rising progesterone and ultrasound visualization of follicle growth [71]. Pregnancy is estimated to occur in 5–12 % of women who are of childbearing age with a renal transplant, and approximately 50 % of these pregnancies are unplanned [72, 73]. In vitro fertilization has been used successfully in renal transplants; however data is limited [74].

Pregnancy Counseling and Preparation

Discussions regarding pregnancy should begin when women of childbearing age are seen for pretransplant evaluation and continue after transplantation. Emphasis should be placed on the need to continue immunosuppressive therapy during pregnancy. Some women stop medications for fear of adverse effects on baby without understanding that loss of graft function carries a higher risk for the baby than the medications themselves. Pregnancies should be planned in order to decrease the risk of complications and increase the chance of successful pregnancy outcome. Recipients’ care should be optimized prior to conception, and this may include a change in medications to those that are pregnancy safe, good blood pressure control, and a thorough discussion about the risks.

Two major groups, the European Dialysis and Transplantation Association (EDTA) and the American Society of Transplantation (AST), have published guidelines that are used for advising transplant recipients about pregnancy (Table 2) [75, 76]. The general consensus is that pregnancy can be considered in renal transplant recipients who are in good health posttransplant for a minimum of 1 year. Other favorable prognostic factors include creatinine <1.5 mg/dl (133umol/l), proteinuria <500 mg/day, no recent rejection, good blood pressure control, and stable pregnancy-safe immunosuppression. There is growing evidence that recipients may be able to conceive safely within <1 year, recognizing that the window of fertility may be narrow for some women [76, 77].

Table 2

Guidelines for pregnancy in renal transplant recipients

Timing of pregnancy	No rejection in the past year (AST) Good health for about 2 years (EDTA)
Adequate and stable graft function	Creatinine <1.5 mg/dL (AST) Creatinine < 2 mg/dL (177 umol/L) but preferably <1.5 mg/dL (<133 umol/L) (EDTA)
Proteinuria	<0.5 g/day (EDTA)
Maintenance immunosuppression Dosing is stable	Prednisone <15 mg/day CSA and tacrolimus at therapeutic levels MMF and sirolimus are contraindicated (stop 6 weeks before conception)
Additional concerns	Maternal age, rejection within the first year, established noncompliance, comorbid factors

Adapted from both the American Society of Transplantation (AST) Consensus Statements, 2005, and European Dialysis and Transplantation Association (EDTA) Guidelines, 2002

Pregnancy Outcomes in Patients with Kidney Transplant

Various studies have been published in regard to pregnancy outcomes in renal transplant recipients, and the chance of successful pregnancy ranges from 70 to 80 %. A systematic review and meta-analysis published in 2011, which included publications between 2000 and 2010, reported an average live birthrate of 73.5 %, miscarriage rate 14 %, abortion 9.5 %, stillbirth 2.5 %, and ectopic pregnancy 0.6 % [78]. The National Transplantation Pregnancy Registry (NTPR) is a voluntary registry initiated in 1991 in the United States. As of December 31, 2013, they have collected data on 1,687 pregnancies (1,744 outcomes) in 960 kidney transplant recipients. The live birthrate among women treated with the different immunosuppression regimens was 75.5 % (819 pregnancies) cyclosporine based, 71.5 % (385 pregnancies) tacrolimus based, and 83.4 % (377 pregnancies) azathioprine and/or prednisone [79].

Pregnancy with a renal transplant is associated with an increased risk of complications compared to the general population [78, 80, 81]. Women are at increased risk for hypertension, preeclampsia, preterm delivery, fetal growth restriction, low birth weight, and neonatal complications.

Effect of Pregnancy on Kidney Graft Function

A prospective study of creatinine and inulin clearance in renal transplant recipients with preserved renal function (creatinine clearance >50 mL/min) compared to healthy controls demonstrated that renal allografts accommodate normally to pregnancy [82]. In addition, a study of 18 transplanted women who had 25 pregnancies did not find an adverse effect of pregnancy on graft survival compared to graft survival in 26 female controls and 23 male controls. After a mean follow-up of 11.8 years posttransplant and 6.9 years after pregnancy with similar periods of follow-up for the control groups, graft survival is not significantly different in women who had become pregnant compared to both the female and male controls [83]. Since then, several case-control studies comparing graft survival of pregnant renal transplant recipients to matched nonpregnant controls have shown similar results. The majority of recipients in these studies had a creatinine <1.5 mg/dL (133mmo/L) and met pregnancy guidelines. Furthermore, a study from the Australia and New Zealand Dialysis and Transplant Registry matched 120 women with their first live birth to 120 renal transplant controls who never became pregnant; this study demonstrated no difference in the 20-year risk for renal allograft loss based on pregnancy [84].

Management

Management of renal transplant recipients considering pregnancy begins prior conception. This population is considered high risk and requires follow-up by a dedicated team including high-risk obstetrics and transplant nephrology. Patients often require medication changes, and other medical problems should be optimized prior to conception.

Pregnant kidney transplant recipients have the same risk for acute kidney injury as other pregnant and nonpregnant transplant patients [85]. Yet there are a few issues that require special attention in the pregnant transplant population. Urinary obstruction related to growing uterus is a rare complication and easily identifiable by ultrasound if a first-trimester ultrasound is done at baseline for comparison. Calcineurin inhibitor (CNI) toxicity is also possible given dose changes and changes to other medications during pregnancy. Opinions differ on the need or frequency for dose adjustment of immunosuppression [86]. In general, most recommend following CNI levels and adjusting the dose to avoid toxicity or extremely low values [76]. Acute rejection is uncommon after the first year of transplant, and, based on the NTPR, the incidence is only 1–4 % in pregnancy [79]. Renal biopsy should be performed to confirm rejection if suspected. Preeclampsia should be considered after 20-week gestational age and investigated with blood work and fetal surveillance. Hemolytic uremic syndrome can occur with pregnancy or CNI. In the vignette, causes for a decline in renal function were explored, but fortunately, the serum creatinine stabilized so a kidney biopsy was not required.

Hypertension commonly complicates the pregnancies of patients with kidney transplants, and similar to the pregnant CKD population, most suggest a target BP of <140/90 mmHg.

There is normally a mild physiologic fall in hemoglobin values during pregnancy, which is the net result of an increase in red cell mass along with a larger increase in plasma volume. Patients with CKD and those with renal transplants may have only marginal erythropoietin production and are more likely to develop significant anemia during pregnancy. Iron deficiency should be treated, and erythropoietin-stimulating agents may be required to maintain a hemoglobin >10 g/dL.

Immunosuppressive Medications

Potential effects of immunosuppressive medications on the fetus mandate that patients receive extensive counseling around pregnancy [87] (Table 3). Prednisone has been extensively used in pregnancy for many conditions. In the first trimester, <9-week gestation, one study showed an increased risk of cleft palate compared to the general population [88], but a more recent population study from Norway showed no increase risk of orofacial clefts with first-trimester prednisone exposure [89]. Overall, if there is an increased risk, it is small compared to the high risk of adverse fetal outcomes with graft loss, so the benefits of maintenance immunosuppression outweigh the risks.

Table 3

Maintenance immunosuppression in pregnancy

Medication	FDA class	Comments
Prednisone	B	Possible low first-trimester risk of cleft palate Rare cases of fetal adrenal suppression and thymic hypoplasia if dose > prednisolone 15 mg/day close to term
Calcineurin inhibitors
Cyclosporine	C	Increased risk of miscarriage, IUGR, preterm delivery, hypertension
Tacrolimus	C	Increased risk of IUGR, preterm delivery, and diabetes
Antiproliferative agents
Azathioprine	D	Safe based on large cohorts of patients with transplant, SLE, Crohn’s Not converted by fetal liver to active form
Mycophenolate mofetil Mycophenolic acid	D	Teratogenic in first trimester in humans
Rapamycin, sirolimus	C	Limited evidence, mainly case reports of safety

Azathioprine has also been used safely by thousands of pregnant women for various conditions, though it is still labeled category D by the Food and Drug Administration (FDA). This designation is mainly based on malformations seen in animals given parenteral azathioprine in higher doses than used in humans. Azathioprine is considered safe in pregnancy by physicians for many reasons: the lack of evidence of harm in many human case series, radioactive labeling studies in humans that have shown that the majority of azathioprine administered to mothers appears in fetal blood as the inactive metabolite thiouric acid, and the suggestion that fetus lacks the enzyme inosinate pyrophosphorylase needed for conversion of 6-mercaptopurine (MP) to its active form protecting the fetus from azathioprine’s effects [74, 90].

Calcineurin inhibitors (cyclosporine and tacrolimus) are currently the most commonly used maintenance immunosuppressive agents. There has been no indication of congenital malformations; however, there is a risk for fetal growth restriction. These agents also appear to confer a higher risk of hypertension and serum creatinine >1.5 mg/dL. In comparison with cyclosporine, pregnant women taking tacrolimus have a lower incidence of hypertension and hyperlipidemia but higher incidence of developing posttransplant diabetes mellitus. Tacrolimus has also been associated with transient perinatal hyperkalemia in the newborn [74].

Mycophenolate mofetil (MMF) is associated with an increased risk of spontaneous abortions and congenital malformations with exposure between 4- and 9-week gestation. Evidence accumulated since it came into use, and a 2013 study confirmed that the rate of anomalies might be as high as 22–27 %. Malformations seen with MMF include facial deformities (microtia, cleft lip and palate, auditory canal atresia, micrognathia) and limb anomalies (short fingers and hypoplastic nails) [74, 91].

The risk of congenital anomalies with mycophenolate products is serious enough that the FDA has placed a black box warning and the company has instituted a Mycophenolate Risk Evaluation and Mitigation Strategy that requires providers to be educated about the teratogenicity of MMF. Patients should be on birth control while using MMF and switch to azathioprine at least 6–12 weeks prior to conception.

Evidence for mammalian target of rapamycin inhibitors (sirolimus/everolimus) in pregnancy is very limited. Since there are immunosuppressive options with more evidence of safety during pregnancy, there is general reluctance to use this category of drugs during pregnancy. Yet, there are several case reports of successful pregnancies with sirolimus and everolimus [79].

Infections

Transplant patients are immunosuppressed, and pregnancy is also a period when patients may be more susceptible to infections. Urinary tract infections and urinary reflux are common in pregnant renal transplant recipients; therefore, screening for pyuria and treating positive cultures are important to prevent pyelonephritis. Current guidelines endorse monthly screening [75].

Another serious potential posttransplant infectious complication is cytomegalovirus (CMV). Both primary and reactivation CMV infection can be transmitted to the fetus. Congenital infections have been associated with microcephaly, intrauterine growth restriction, sensorineural hearing loss, visual impairment, and developmental disorders, as well as a high mortality rate [92]. Preexisting immunity to CMV appears to reduce the risk to the fetus. Baseline CMV serology should be performed, and then patients should be retested if they develop a mononucleosis-like illness or if a fetal anomaly is identified on prenatal ultrasound that is suggestive of congenital CMV [74]. Maternal infection can be detected by the presence of CMV immunoglobulin M antibodies in maternal blood. Once found, further evaluation is undertaken to assess for congenital CMV infection.

In the general pregnant population, primary infection with toxoplasmosis is reported to cause neonatal infection in 25–65 % of exposed infants [90]. Suspected infection in the fetus can be detected by a combination of testing amniotic fluid and fetal blood as well as the finding of brain ventricular enlargement by ultrasound at 20–24 weeks. Treatment with sulfadiazine and pyrimethamine or spiramycin reduces the likelihood of congenital infection by 60 %, so primary infections should be treated even if the mother is not seriously ill. In immunosuppressed patients, congenital infection can occur after reactivation of toxoplasmosis, and consideration should be given to treating seropositive women with rising antibody titers. Pregnant kidney transplant recipients should be screened for toxoplasmosis each trimester [74].

Herpes simplex infection can be serious for the fetus and neonate. Before 20 weeks of gestation, vertical (mother-to-fetus) transmission can lead to spontaneous abortion in up to 25 % of patients. Herpes simplex is usually transmitted during birth, and women are routinely examined during labor for lesions in the birth canal. Cesarean sections are performed if herpes lesions are identified and fetal exposure is likely. Suppression with acyclovir or valacyclovir during the last month of pregnancy may reduce the need for cesarean section because of herpes lesions [74].

Overall, successful pregnancy is possible in women with renal transplants, but is associated with increased risk of complications and requires close follow-up by a dedicated team.

Breastfeeding

Patients with CKD

While ACE inhibitors are contraindicated in pregnancy, short-acting ACE inhibitors (such as captopril and enalapril) are considered safe during lactation as minimal amounts of the medication are transmitted into breast milk [93, 94]. These agents can be used safely after the immediate postpartum period as long as renal function is stable, when babies are ready to leave the hospital. All antihypertensive agents that are safe in pregnancy are considered safe for breastfeeding. Specific data can be found at LactMed, an online database for medications used during lactation [95].

Patients with Renal Transplant

Breastfeeding in transplant recipients is controversial. Although breastfeeding is not recommended on the current labeling of most immunosuppressive medications and most transplant physicians advise against it, the NTPR has recorded an increasing trend in the number of recipients who choose to breastfeed their infants [79] Fig. 3.

Fig. 3

NTPR trend in breastfeeding practices of transplant recipients (Published with permission from National Transplantation Pregnancy Registry (NTPR). 2013 Annual report: Gift of Life Institute. Philadelphia, PA: 2014. Available by request: NTPR@giftoflifeinstitute.org)

Only small amounts of corticosteroids are present in breast milk, at most 0.1 % of the total prednisolone ingested by the mother. The American Academy of Pediatrics (AAP) considers corticosteroids safe for breastfeeding [96].

Cyclosporine and tacrolimus are excreted in breast milk in varying quantities. In a study of 14 transplant recipients using tacrolimus during pregnancy and breastfeeding, maternal blood, breast milk samples, and infant blood samples were studied for up to 72 days postpartum. The highest amount of tacrolimus excreted in breast milk was equivalent to 0.23 % of the maternal dose; this is comparable to other studies which suggest rates of 0.06–0.5 % of maternal dose. Eight of twelve breastfed infants showed the same rapid decline in serum tacrolimus levels after birth as bottle-fed infants, suggesting that patients who take tacrolimus need not be discouraged from breastfeeding [97].

Azathioprine is excreted into breast milk in varying amounts, but the majority of cases have undetectable amounts of azathioprine and 6-mercaptopurine, its active metabolite. Small amounts of 6-mercaptopurine can be detected in breast milk in samples taken within 4 h of administration of azathioprine [98]. Based on available data, an infant who is breastfed would receive 0.0075 mg/kg body weight, less than 1 % of the maternal dose and 1/1000th of the therapeutic dose of 1 mg/kg. Thus breastfeeding during treatment with azathioprine appears safe [96].

There is now long-term data from the NTPR on over 100 transplant recipients who chose to breastfeed their infants while taking immunosuppressive medications. The length of time the children were breastfed ranged from several days to 2 years. At last follow-up, which ranged from 3 weeks to 13 years, there were no specific problems reported in children attributed to breastfeeding [96]. The American Society of Transplantation consensus opinion is that breastfeeding need not be viewed as absolutely contraindicated [76].

Conclusion

When women with chronic kidney disease or a renal transplant consider pregnancy, a dedicated team is required to provide a tailored approach to counseling and care. Successful pregnancy in this patient population is challenging but rewarding. An overview of care is provided in Table 4.

Table 4

Approach to management of pregnancy in patients with CKD and renal transplant

Before pregnancy

Tests for antibodies to rubella, hepatitis B and C, and rubella vaccine if not immune

CBC, electrolytes, urea, creatinine, urine: UA, culture, PrCr, or ACR

24-h urine for protein and creatinine clearance for baseline

Review all medications for safety in pregnancy

Optimize all medical problems

Optimize blood pressure (BP < 140/90)

Consultation with high-risk obstetrician

During pregnancy

Low-dose aspirin (75–120 mg) at bedtime by 16-week gestation and high-calcium diet or calcium supplements (>1000 mg/day)

Ideally, daily home measurements of blood pressure by patient (BP <140/90)

Monitor – biweekly/monthly

Nephrologist and obstetrician visit

CBC, complete metabolic profile, urine: UA, culture, PrCr, or ACR monthly

Ultrasound assessment of fetal well-being from 26-week gestation

Monitor – each trimester

Consider 24-h urine for protein and creatinine clearance

Monitor – last trimester

Biweekly fetal surveillance

Examine for HSV lesion close to delivery and at labor

Peripartum and postpartum

C-section only for obstetric indications

Continue BP monitoring for a minimum of 6–8 weeks postpartum (BP < 140/90)

Assess renal function and proteinuria 1 month and 6 months postpartum

Additional management for patients with renal transplant

Before pregnancy

Rh compatibility of patient and transplant

Tests for antibodies to HSV, CMV, and toxoplasmosis before pregnancy

PCR for CMV and toxoplasmosis before pregnancy

Switch immunosuppression to pregnancy safe (stop MMF, sirolimus, and everolimus 6 weeks before conception. May substitute with azathioprine, cyclosporine, tacrolimus, or prednisone)

During pregnancy

Kidney ultrasound during the first trimester

CNI levels (weekly to monthly)

Each trimester – CMV and toxoplasmosis PCR and/or IgM for seronegative women (optional)

Last trimester – check IgM to HSV for seronegative women

Abbreviations: CBC, complete blood count; PCR, polymerase chain reaction; CMV cytomegalovirus, BP, blood pressure; CNI, calcineurin inhibitor; UA, urinalysis; HSV, herpes simplex virus; MMF, mycophenolate mofetil

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