In women with end stage kidney disease, fertility is decreased but the possibility of pregnancy is high enough that it needs to be prevented if not desired and managed carefully by a multidisciplinary team if it does occur. The hypothalamic-pituitary-ovarian axis is deranged, contributing to decreased fertility, loss of libido, and abnormal uterine bleeding.

I. BIRTH CONTROL

A. Indications. Forty percent of women under the age of 55 treated with dialysis menstruate, but periods may be anovulatory or characterized by a shortened luteal phase (Holley, 1997). Infertility is the rule, with pregnancy occurring in 0.3% to 1% per year in women aged 14-44. There is some suggestion that the use of erythropoietin and the increasing intensity of dialysis resulting from increased target Kt/V may have changed the hormonal abnormalities and other factors contributing to infertility in dialysis patients and that the frequency of pregnancy may have increased. A role for increased dialysis in increasing fertility is suggested by the experience of the nocturnal dialysis program at the University of Toronto, where, on average, women are receiving 36 hours of dialysis per week (Nadeau-Fredette, 2013). In this program, conception has occurred in 15% of women of childbearing age. Dialysis patients on standard dialysis regimens occasionally conceive, and when pregnancies occur, patient management is enormously complicated. Birth control is advisable for women who do not wish to conceive. It is difficult to identify women at high risk for pregnancy. Women who become pregnant once on dialysis frequently conceive again. Women who have become pregnant with renal insufficiency prior to starting dialysis, and women with regular menses are at increased risk, but pregnancies have occurred in women treated with dialysis following years of amenorrhea.

B. Methods of contraception. Diaphragms and condoms can be used as in individuals with normal renal function. The incidence of pregnancy with barrier methods is as high as 25%-29% per year in normal women, but would be expected to be much
lower in dialysis patients. Many women may opt for more effective and less cumbersome methods of contraception. Oral contraceptives can be used but are contraindicated in women with a history of thrombophlebitis or severe hypertension. Low-dose estrogen oral contraceptives can be used in patients with lupus who have no history of thrombosis or uncontrolled hypertension. Copper and levonorgesterone containing IUDs (intrauterine devices) can be used in women with diabetes, diabetes with nephropathy, systemic lupus erythematosus, and multiple cardiovascular risk factors, and are good birth control methods for women both on hemodialysis (HD) and peritoneal dialysis (PD). There are no guidelines from the U.S. Medical Eligibility Criteria for Contraceptive Use or from randomized controlled trials. There has been some concern that IUDs might increase the risk of peritonitis in women on PD, but this risk has not been well studied. There has also been concern without information on the effect of estrogen on access patency. The provision of estrogen offers the theoretical benefit of protecting bones from the effects of hypoestrogenemia seen in dialysis patients.

Many women on dialysis have prolonged periods of anovulatory bleeding, associated with the unopposed effect of estrogen on the endometrium. Estrogen-progesterone cycling might reduce the risk of endometrial cancer that is associated with unopposed estrogen. Treatment of infertility has generally not been attempted because pregnancy is dangerous for the mother and the outcome is still poor. The exception is a switch to nocturnal dialysis with higher rates of conception.

II. PREGNANCY

A. Frequency and outcome. Estimates of the frequency of pregnancy in women of childbearing age treated with dialysis range from a high of 1.4% per year in Saudi Arabia to 0.44% in Japan to a low of 0.3% per year in Belgium (Nadeau-Fredette, 2013). The frequency of pregnancy in American women on dialysis is about 0.5% per year (Okundaye, 1998). For reasons that are unclear, conception occurs two to three times more frequently in hemodialysis patients than in PD patients. The likelihood of pregnancy in a dialysis patient resulting in a surviving infant, excluding elective abortions, is about 50%. The chances of success improve once she has reached the second trimester, and then it approaches 60%-70%. There is a further improvement in outcome with intensive dialysis. For women who start dialysis after conception, the likelihood of having a surviving infant is 75%-80%. Of unsuccessful pregnancies, 68% result in spontaneous abortion, 13% in stillbirth, 16% in neonatal death and 3% in therapeutic abortion for life-threatening maternal problems. Approximately 40% of spontaneous abortions occur in the second trimester.

B. Diagnosis. A high index of suspicion is required to make a timely diagnosis of pregnancy. Amenorrhea is common, and symptoms of early pregnancy such as nausea are often attributed to metabolic or gastrointestinal problems. A bloodbased pregnancy test (serum levels of the β subunit of HCG) should be done prior to radiographic studies for abdominal complaints. Urine pregnancy tests are not reliable even if the patient is not anuric. Even with blood tests, false positives and false negatives occur. The small amounts of HCG produced by somatic cells may be excreted slowly enough in renal failure for blood levels to be borderline positive for pregnancy. Occasionally, these borderline results have led to cancellation of elective surgery. During pregnancy, β-HCG levels are more elevated than expected for gestational age, so gestational age is best assessed by ultrasound. Failure to appreciate the high β-HCG levels has led to mistaken diagnosis of a hydatidiform mole and the mistaken belief that a pregnancy was not viable when no fetal heart beat was found when high levels of β-HCG led doctors to think the pregnancy was more advanced than it was (Potluri, 2011). The reasons for false negative tests are unclear. Similarly, serum tests of α-fetoprotein done to screen for Down’s syndrome may be falsely elevated in pregnant dialysis patients, and amniocentesis with karyotyping should be done to confirm abnormal results.

C. Management of hypertension during pregnancy. The major maternal risk associated with pregnancy in dialysis patients is severe hypertension. Eighty percent of pregnant dialysis patients have some degree of hypertension (BP >140/90 mm Hg). Forty percent have severe hypertension with diastolic blood pressures greater than 110 mm Hg or systolic blood pressures greater than 180 mm Hg. Seventy-five percent of severe hypertension occurs before the third trimester. Intensive care unit admissions for control of accelerated hypertension are required in 2% to 5% of pregnant dialysis patients. Patients should be taught to take their blood pressure on nondialysis days and report any increases in blood pressure promptly. Monitoring of blood pressure should continue for 6 weeks postpartum. Hypertension, even when severe, may not require the termination of pregnancy. The first step toward blood pressure control as in the nonpregnant patient is to make sure that the woman is euvolemic.

1. Drug therapy. If the blood pressure remains higher than 140/90 mm Hg when the patient is euvolemic, there are several first line drugs than can be used safely, including α-methyldopa, labetalol, and calcium channel blockers. There is less experience with β-blockers and clonidine, but, with the exception of atenolol, these are probably safe. Hydralazine can be added to any of these first line drugs, but it does not work as a single agent when given orally. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are contraindicated in pregnancy. In
animal studies, they have been associated with a fetal loss rate of 80%-93%. In humans, their use has been associated with an ossification defect in the skull, dysplastic kidneys, neonatal anuria, and death from hypoplastic lungs. One report that noted an increase in congenital anomalies with first trimester exposure to ACE inhibitors has driven practice away from first trimester use (Cooper, 2006) despite contradictory data in other studies.

2. Superimposed preeclampsia and hypertensive crisis. Women treated with chronic dialysis are at increased risk for superimposed preeclampsia, but the diagnosis is difficult to make in the absence of findings of the HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelets) syndrome such as thrombocytopenia, elevated liver enzymes, or microangiopathic hemolytic anemia.

There appears to be some benefit of low-dose aspirin in preventing preeclampsia in women at high risk for the disease. Although dialysis patients have not been specifically studied, they constitute an extremely high-risk group and can be given 75 mg daily of aspirin.

a. Antihypertensive drugs. Intravenous hydralazine is the drug of first choice for hypertensive crisis in pregnant women and should be given in doses of 5-10 mg every 20-30 minutes. Labetalol is a good alternative. It can be given as a 20-mg bolus repeated every 30 minutes to a maximum of 220 mg or as a continuous infusion with 1 to 2 mg/min followed by 5-10 mg/hr to a maximum of 300 mg.

b. Magnesium. Magnesium is superior to other anticonvulsants for seizure prophylaxis in women with preeclampsia, but it must be used with extreme caution in dialysis patients. A loading dose can be given safely. Additional magnesium should not be given until after dialysis or until after a drop in the serum magnesium level has been demonstrated. Magnesium potentiates the hypotensive effects of calcium channel blockers, and any calcium channel blocker should be stopped if magnesium is required.

D. Dialysis regimen during pregnancy

1. Dialysis modality. In direct comparisons of dialysis modalities, there is no difference in outcome of pregnancy between hemodialysis patients and peritoneal dialysis patients, as measured by either infant survival or mean gestational age of live-born infants (Okundaye, 1998). However, it is easier to increase the amount of dialysis delivered with hemodialysis. The higher success rates reported in more recent studies have been achieved in hemodialysis patients. Although dialysis modality should not be changed because of pregnancy, it may be easier to start hemodialysis in a pregnant woman than peritoneal. If peritoneal dialysis is elected, placement of a peritoneal catheter is possible at any stage of pregnancy, but immediate use and
increased intra-abdominal pressure may increase the risk of leaking around the catheter. There have been instances of mechanical problems with peritoneal catheters with changes in fetal position. Some nephrologists have elected to supplement peritoneal dialysis with hemodialysis when pregnancy is near term.

2. Intensive dialysis. There is growing evidence that the likelihood of a surviving infant is increased with intensive dialysis. The ideal number of hours of dialysis has not been established. There was a marked improvement in outcomes for women dialyzed more than 20 hours per week, with a corresponding decrease in severe prematurity compared with less intense regimens (Hou, 2010). Infant survival was 75% for pregnancies in the group dialyzed more than 20 hours a week compared with 33% and 44% for less intensively dialyzed groups. Mean gestational age for babies born to women dialyzed more than 20 hours a week was 34 weeks compared with 30 weeks in less intensively dialyzed women. Even better outcomes have been seen in women undergoing nocturnal hemodialysis 48 hours weekly with most infants surviving and born close to term (Nadeau-Fredette, 2013). In a comparison of pregnancy results in the United States versus Canada, there was a suggestion of a “dose response” relationship between duration of weekly dialysis and pregnancy outcomes (Hladunewich, 2014). There may be some amount of dialysis between 20 and 48 hours a week that will lead to satisfactory outcomes. Daily dialysis decreases the fluid removal at each treatment, decreasing the risk of hypotension during dialysis. Daily dialysis also allows the patient to eat a high-protein diet to ensure that the needs of pregnancy are met.

Increasing the intensity of dialysis in peritoneal dialysis patients is difficult. Late in pregnancy, women have difficulty with severe abdominal distension, and exchange volume may have to be decreased. It becomes necessary to increase the frequency of exchanges even to maintain the same level of dialysis. A combination of frequent daytime exchanges and nighttime cycler is often necessary.

Some have raised the question whether increased dialysis might have a detrimental effect by causing electrolyte abnormalities or by removing progesterone. Progesterone withdrawal plays a role in the initiation of labor. Measurements of serum progesterone levels during dialysis in pregnant dialysis patients are variable. Brost and colleagues (1999) measured pre- and postdialysis progesterone levels in seven pregnant dialysis patients. Changes in serum progesterone ranged from a 52% decrease in levels to an 8% increase (Brost, 1999). Changes in serum progesterone were not associated with changes in home uterine activity monitoring.

3. Dialysis solution calcium. With the recognition of the risk of soft tissue calcification in long-term dialysis patients, a
2.25 mEq/L (1.125 mM) or 2.5 mEq/L (1.25 mM) calcium concentration has replaced 3.5 mEq/L (1.75 mM) as standard. When a bath containing 2.5 mEq/L (1.25 mM) is used, the patient is usually in positive calcium balance, averaging about 200 mg/treatment. There is some production of calcitriol by the placenta that may increase serum calcium. Predialysis serum calcium levels should be checked weekly. The fetus needs 25 to 30 g of calcium for calcification of the fetal skeleton. With a 2.5 mEq/L (1.25 mM) bath, 25 weeks of dialysis should provide enough calcium, but premature birth is common enough, and calcium flux variable enough, that oral supplementation is advisable. If the woman requires phosphate binders, 1 to 2 g of elemental calcium should be sufficient. Over the long term, dialysate calcium should be low enough to minimize soft tissue calcification, but over the short term of pregnancy, calcium should be sufficient for the fetal skeleton. Skeletal abnormalities have been described in one baby born to a dialysis patient. For women who need phosphate binders, calcium-containing binders are the only group known to be safe in pregnancy. There is no experience with sevelamer or lanthanum carbonate in pregnancy. Lanthanum is neurotoxic in fetal mice.

Some women become hypophosphatemic. Often, phosphate binders are no longer required, and it may be necessary to add phosphorus to the bath (e.g., 4 mg/dL [1.3 mM] phosphorus or higher). For women who do not need phosphate binders, calcium can be provided in a lower dose separate from meals. Experience with cinacalcet in pregnancy is limited to a few case reports of use in primary hyperparathyroidism. Serum calcium and phosphorus should be monitored weekly. Hypercalcemia may suppress the fetal parathyroid glands and cause neonatal tetany.

4. Dialysis solution bicarbonate.

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