Glomerular Disease in Pregnancy

Monica L. Reynolds

Andrea L. Oliverio

INTRODUCTION

Chronic kidney disease (CKD) is estimated to affect 6% of women of reproductive age and 3% of pregnancies globally.¹,²,³ In addition, a growing trend to delay childbirth has led to increasing numbers of women entering pregnancy with chronic disease.⁴ Research surrounding the care of women of reproductive age with glomerulonephritis (GN) has grown substantially in the past two decades, demonstrating commitment to improving maternal and fetal health in this unique population. Strategies that provide coordinated multidisciplinary care to optimize preconception health, meticulous antenatal monitoring, and continued care in the postpartum period appear to be most beneficial.

ADAPTATION TO PREGNANCY

Maternal adaptation to pregnancy includes changes to both kidney anatomy and physiology. Anatomic changes include dilation of the kidney pelvis, calyces, and ureters that peak near 20 weeks of gestation.⁵ Functional hydronephrosis is common, predominantly on the right side because of the acute angle at which the ureter crosses over the iliac and ovarian vessels before entering the pelvis.⁶ With plasma volume expansion, renal vasodilation increases renal plasma flow and leads to a rise in glomerular filtration rate (GFR) by approximately 40%.⁷ Because of decreased tubular protein reabsorption and an associated increase in glomerular basement membrane permeability, a classic cutoff of less than 300 mg/24 h has been accepted as physiologic proteinuria.⁸ However, uncertainty exists surrounding the appropriate diagnostic threshold and may differ depending on factors such as chronic hypertension or twin gestation.⁹,¹⁰

PRECONCEPTION COUNSELING

Beginning in adolescence, women with GN should be asked frequently about their plans for starting or growing their family. Questions such as, “Would you like to become pregnant in the next year?” may open up the conversation for further discussion on timing and risk modification.¹¹ Pregnancy planning can be anxiety-provoking for both the patient and provider, because historically, women with GN were reported to have low live birth rates and high rates of complications.¹² However, qualitative work has shown that women can feel traumatized when providers aggressively counsel against pregnancy.¹³ Education regarding women’s health topics within nephrology may also be lacking. In a survey of nephrologists from Canada and the United States, only one-third (34%) of those surveyed felt confident counseling on the optimal timing of pregnancy in women
with GN, and a similar low percentage (32%) felt confident managing nephrotic syndrome in pregnancy. Reasons cited for lack of confidence included poor knowledge base (40%) and lack of training (53%).¹⁴

TABLE 22.1 Common Obstetric Definitions

Obstetric Outcome	Definition
Chronic hypertension	Hypertension ≥140/90 present before pregnancy or before 20-wk gestation
Gestational hypertension	New onset systolic blood pressure ≥140 and/or diastolic ≥90 after 20-wk gestation on two occasions at least 4 h apart, without proteinuria or severe features of preeclampsia
Preeclampsia	New onset systolic blood pressure ≥140 and/or diastolic ≥90 after 20-wk gestation and proteinuria (≥300 mg/24 h, UPCR > 0.3 g/g, or 2+ dipstick); or if proteinuria absent, new onset hypertension with new onset thrombocytopenia, renal insufficiency, liver transaminase elevation 2× upper limit of normal, pulmonary edema, headache or visual symptoms (ACOG definition),⁹⁶ uteroplacental dysfunction (fetal growth restriction) (ISSHP definition)¹⁰²
Preterm birth	Birth prior to 37 wk of gestation
Low birth weight	An infant weighing 5.5 lbs (2,500 g) or less
UPCR, urine protein to creatinine ratio. ACOG, American College of Obstetrics and Gynecology; ISSHP, International Society for the Study of Hypertension in Pregnancy

In recent decades, improvement in perinatal care and increased knowledge of pregnancy risks in women with GN has improved the ability to counsel and care for these women. From data gathered mostly in women with Immunoglobulin A (IgA) nephropathy and lupus nephritis, it is established that those who enter pregnancy with well-controlled disease, including normal serum creatinine, minimal proteinuria (eg, spot urine protein to creatinine ratio [UPCR] < 0.5 g/g) and normal blood pressure, have high live birth rates and often deliver between 37 and 39 weeks.¹⁵ Conversely, women with elevated preconception serum creatinine (>1.2 mg/dL), hypertension, and nephrotic proteinuria experience the greatest risk for adverse maternal and fetal outcomes.¹⁶,¹⁷ In advanced CKD, including those with GFR less than 60 mL/min/1.73 m2, anticipated complications include preeclampsia, preterm birth, and low-birth-weight infants (see Table 22.1, for common obstetric definitions). In a contemporary retrospective study of 178 women with CKD stages 3 to 5 in the United Kingdom, over 50% of women delivered preterm (<37 weeks) and greater than 25% delivered prior to 34 weeks.¹⁸ Notably, in this population, the live birth rate was 98%, and chronic hypertension was the strongest predictor of delivery less than 34 weeks. Among women with chronic hypertension, a gestational fall in serum creatinine less than 10% compared to prepregnancy values was associated with a 2.67-fold increased risk of delivery less than 34 weeks (95% confidence interval [CI] 1.00-7.09; P = .049). Women with proteinuria greater than or equal to 0.5 g prior to pregnancy or before 20 weeks’ gestation had 2.5 times the risk of delivering a baby with a birth weight below the 10th percentile.¹⁸ Concisely summarizing pregnancy outcomes in CKD can be challenging
because of small sample sizes and heterogeneity of data and definitions over time; however, three contemporary cohorts have examined the outcomes of preterm delivery and progression of CKD by prepregnancy CKD stage¹⁸,¹⁹,²⁰; findings which may be used to support counseling are compiled in Table 22.2.

TABLE 22.2 Summary of Risks of Adverse Pregnancy Outcomes in Patients with CKD

Risk Factor	Notes on Maternal and Fetal Outcomes
CKD stages 1-2>	In 3 cohorts¹⁸,¹⁹,²⁰ with total N = 543, preterm delivery occurred in 23%-29% and progression of CKD in 6%-10%.
CKD stage 3	In 3 cohorts (total N = 217), preterm delivery occurred in 40%-78% of pregnancies and 16%-35% had progression of CKD. The effect of pregnancy resulted in eGFR decline equivalent to 1.7 and 2.1 yr of additional prepregnancy kidney disease in those with CKD 3a and 3b, respectively.¹⁸
CKD stages 4-5	In 3 cohorts (total N = 42), preterm delivery occurred in 88%-100% and 20%-86% had progression of CKD. The effect of pregnancy resulted in eGFR decline equivalent to 4.9 yr of additional prepregnancy kidney disease in those with CKD 4-5.¹⁸
Chronic hypertension in CKD	Increases odds of preterm delivery <34-wk gestation (unadjusted OR 16.5).¹⁸
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; OR, odds ratio.

In addition to obstetric risks, the risk of pregnancy-associated CKD progression should be reviewed during preconception counseling. From the above study in CKD stages 3 to 5, the authors found that a gestational fall in serum creatinine of less than 10% was the most significant predictor of kidney function decline postpartum. Furthermore, this was significantly associated with chronic hypertension but not with maternal age, ethnicity, or GN diagnosis.¹⁸ Independently, proteinuria appears to hasten progression. In a prospective study of women with CKD, those with greater than 1 g proteinuria and estimated glomerular filtration rate (eGFR) less than 40 mL/min/1.73 m² experienced a faster GFR decline after delivery and a shorter dialysis time than those with less than 1 g proteinuria.²¹

Given the bidirectional influences of GN on pregnancy outcomes and pregnancy on GN and CKD, as well as the implications in medication management, contraception, and fertility, nephrologists must recognize their pivotal role in family planning counseling early and often in the disease course and consider preconception consultation with an obstetric provider with knowledge of GN in pregnancy.

CONTRACEPTION

In the United States, nearly half of all pregnancies are unintended (mistimed or undesired).²² In women with CKD, an unintended pregnancy may increase the risk of potentially modifiable maternal and fetal morbidity. Correct and consistent use of contraception along with proactive family planning is recommended to
optimize preconception health. Sexual activity and contraception use should be included in the review of systems at each outpatient nephrology visit.

In women with systemic lupus erythematosus, use of oral contraception did not increase the risk of flare in those with stable disease (Visual Abstract 22.1). However, in women with active GN, estrogen-containing contraception is generally not advised because of the increased risk of thrombosis as well as exacerbation of underlying hypertension and proteinuria.²³,²⁴,²⁵ As such, progesterone-only options may be safest for women with GN. Of these, long-acting reversible contraception (LARC) options such as the intrauterine device (IUD) and the subdermal implant may be best suited for women who do not desire pregnancy in the near term. Historically, it was thought that immunosuppressive medications might render IUD inactive or that the IUD increased the risk of infections or tubal infertility, but this has not been substantiated.²⁶,²⁷ LARC use is increasing in the U.S. general population and may be among women with GN as well.²⁸,²⁹,³⁰ The progesterone-only pill is an option as an oral daily medication but notably has a narrow therapeutic window. If a pill is taken more than 3 hours late, a backup barrier method is recommended for the next 48 hours.³¹ Barrier options are also subject to user error, and overall, are less effective at pregnancy prevention with typical use. They do, however, prevent sexually transmitted infections. Emergency contraception, such as high-dose progestins or IUDs can be safely prescribed in women with CKD.³²

FERTILITY

Disease activity and therapies may influence fertility rates in women with GN. Women with glomerular disease are often advised to delay pregnancy until the disease is well controlled, potentially contributing to an older maternal age. In addition, treatment with cyclophosphamide has been associated with premature ovarian failure in both an age- and dose-dependent manner.³³,³⁴ Studies of women with lupus nephritis confirm that sustained amenorrhea occurs at higher rates in women 30 years and older with cumulative doses greater than 8 g/m².³³,³⁵,³⁶ This is clinically significant as early menopause has been associated with increased risk for both ischemic cardiovascular disease and increased mortality.³⁷ Given the reduction in cumulative cyclophosphamide dose over the past two decades, largely because of the implementation of the Euro-Lupus regimen³⁸ or mycophenolate-based regimen for lupus nephritis as well as the increased use of rituximab in other glomerular diseases, more contemporary data are needed to assess for premature ovarian failure risk in these women.

Temporary ovarian suppression obtained by administering gonadotropin-releasing hormone agonists (GnRHa) during cyclophosphamide therapy has the potential to preserve ovarian function in premenopausal patients. In a meta-analysis of GnRHa for ovarian preservation in women receiving chemotherapy, GnRHa use was associated with a 68% increased rate of preserved ovarian function compared to nonusers (summary relative risk = 1.68, 95% CI, 1.3-2.1).³⁹ Immediately after GnRHa administration, pituitary GnRH receptors are stimulated and there is a transient increase in luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estrogen, which potentially increases ovarian sensitivity to cyclophosphamide; thus, the optimal timing of a GnRHa is 1 to 2 weeks prior to therapy. However, as cyclophosphamide is often urgently required in treating GN, an alternative strategy is to give GnRHa between the first and second doses of cyclophosphamide.³⁹ Associated menopausal symptoms of GnRHa generally resolve within 12 weeks after cessation, and resumption of menses occurs within 12 to 24 weeks of withdrawal.

COMORBIDITY OPTIMIZATION

As in the general population, optimization of comorbid risk factors, including obesity, hypertension, and diabetes, may lead to improved pregnancy outcomes for women with GN. Elevated preconception blood pressure among healthy women has been associated with pregnancy loss⁴⁰ and preeclampsia.⁴¹ Blood pressure should be well controlled in women with GN attempting to conceive. Preconception management of hypertension should include transitioning to medications compatible with pregnancy, including labetalol, nifedipine, or methyldopa as first-line agents (Table 22.3). Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers are contraindicated in the second and third trimesters of pregnancy because of potential teratogenicity.⁴² However, preconception ACEi should be considered in those with proteinuria who may experience disease progression while off the medication. This avoids a prolonged period of inadequate treatment while awaiting conception, which may be particularly important in older women. In a recent analysis using Medicaid data, maternal ACEi use in the first trimester had a risk profile similar to other antihypertensives with
regard to malformations in live-born offspring. The authors concluded that the previously reported increased risk of malformations associated with ACEi use in the first trimester⁴³ was likely because of underlying hypertension and other confounding factors.⁴⁴ In this situation, women should be instructed to complete monthly urine pregnancy tests and stop the medication at any positive test or missed menstrual period. Following a positive pregnancy test, substitution with a pregnancy-compatible blood pressure medication should be quickly instituted to maintain optimum control.

TABLE 22.3 Pregnancy-Compatible Antihypertensive Medications

Drug^a	Dose	Comments
Labetalol	200-2,400 mg/d in two to three divided doses	First-line agent. Avoid in asthma, bradycardia, decompensated heart failure
Nifedipine	30-120 mg/d, extended-release preparation	First-line agent. Utilize immediate release for severe, acutely elevated blood pressure
Methyldopa	500-3,000 mg/d in two to four divided doses	Adverse effects may include sedation, dizziness, depression
Hydrochlorothiazide	12.5-50 mg daily	Prior concern for oligohydramnios is not supported by data
Hydralazine	30-300 mg/d in three to four divided doses	Adverse effects may include reflex tachycardia, hypotension, headaches, palpitations, and flushing
Clonidine	0.2-0.9 mg/d in two to three divided doses; 0.1-0.3 mg patch per week	Avoid abrupt withdrawal because of the risk of rebound hypertension
Amlodipine	2.5-10 mg daily	May continue in those controlled on amlodipine prior to pregnancy
Diltiazem	120-360 mg/d in three to four divided doses; 120-480 mg ER daily	Potential antiproteinuric benefit, although data are very limited
^aAngiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists are contraindicated because of potential teratogenicity. For closely monitored patients with progressive proteinuric kidney disease, may consider continuing ACE inhibitors until positive pregnancy test and/or missed menses, as fetal toxicity is greatest with second and third trimester exposures (refer to section “Comorbidity Optimization”).

DISEASE QUIESCENCE AND MEDICATION TRANSITION

For women with GN, disease quiescence while on pregnancy-compatible immunosuppression or no immunosuppression for a minimum of 3 to 6 months prior to pregnancy is recommended. This generally includes stable or low-level proteinuria (eg, <0.5 g via 24 hour or spot UPCR), stable GFR, and inactive urine sediment. A repeat kidney biopsy may be considered to assess for disease activity and chronicity.⁴⁵

Immunosuppressive medications that may be initiated preconception and continued in pregnancy include azathioprine, tacrolimus, cyclosporine, and prednisone (Table 22.4). Mycophenolate mofetil has been associated with pregnancy loss as well as congenital malformations (including to the external ear, cleft lip and palate, distal limbs, heart, esophagus, and kidney) and should be stopped at least 6 to 12 weeks prior to conception.⁴⁶,⁴⁷ The use of cyclophosphamide in girls and women of childbearing age must be accompanied by counseling regarding its potential risk for decreased fertility and the utility of fertility preservation options.³³,⁴⁸ First-trimester use of cyclophosphamide has been associated with fetal loss and congenital malformations and should be avoided.⁴⁹,⁵⁰ Data on rituximab are limited, but thus far it has not been shown to be teratogenic. In a small cohort of women with multiple sclerosis receiving maintenance rituximab at 500 mg every 6 months, no increase in adverse pregnancy outcomes was observed when infusions were given preconception or in the first trimester.⁵¹ Transient neonatal B-cell suppression and increased risk for infections have been reported, especially when given in the second and third trimesters⁵²,⁵³ as rituximab is an Immunoglobulin G (IgG) that crosses the placenta after 16 weeks’ gestation.

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