Pre-Pregnancy eGFR and the Risk of Adverse Maternal and Fetal Outcomes: A Population-Based Study.

SIGNIFICANCE STATEMENT: Pregnancies in women with CKD carry greater risk than pregnancies in the general population. The small number of women in prior studies has limited estimates of this risk, especially among those with advanced CKD. We report the results of a population-based cohort study in Ontario, Canada, that assessed more than 500,000 pregnancies, including 600 with a baseline eGFR < 60 ml/min per 1.73 m 2 . The investigation demonstrates increases in risk of different adverse maternal and fetal outcomes with lower eGFR and further risk elevation with baseline proteinuria. BACKGROUND: CKD is a risk factor for pregnancy complications, but estimates for adverse outcomes come largely from single-center studies with few women with moderate or advanced stage CKD. METHODS: To investigate the association between maternal baseline eGFR and risk of adverse pregnancy outcomes, we conducted a retrospective, population-based cohort study of women (not on dialysis or having had a kidney transplant) in Ontario, Canada, who delivered between 2007 and 2019. The study included 565,907 pregnancies among 462,053 women. Administrative health databases captured hospital births, outpatient laboratory testing, and pregnancy complications. We analyzed pregnancies with serum creatinine measured within 2 years of conception up to 30 days after conception and assessed the impact of urine protein where available. RESULTS: The risk of major maternal morbidity, preterm delivery, and low birthweight increased monotonically across declining eGFR categories, with risk increase most notable as eGFR dropped below 60 ml/min per 1.73 m 2 . A total of 56 (40%) of the 133 pregnancies with an eGFR <45 ml/min per 1.73 m 2 resulted in delivery under 37 weeks, compared with 10% of pregnancies when eGFR exceeded 90 ml/min per 1.73 m 2 . Greater proteinuria significantly increased risk within each eGFR category. Maternal and neonatal deaths were rare regardless of baseline eGFR (<0.3% of all pregnancies). Only 7% of women with an eGFR <45 ml/min per 1.73 m 2 received dialysis during or immediately after pregnancy. CONCLUSIONS: We observed higher rates of adverse pregnancy outcomes in women with low eGFR with concurrent proteinuria. These results can help inform health care policy, preconception counseling, and pregnancy follow-up in women with CKD.

Longitudinal changes in glucose during pregnancy in women with gestational diabetes risk factors.

AIMS/HYPOTHESIS: Despite recommendations to screen women with diabetes risk factors for hyperglycaemia in the first trimester, criteria for normal glucose values in early pregnancy have not been firmly established. We aimed to compare glucose levels in early pregnancy with those later in gestation and outside of pregnancy in women with diabetes risk factors. METHODS: In pregnant women (N = 123) followed longitudinally through the postpartum period, and a separate cohort of non-pregnant women (N = 65), we performed 75 g oral glucose tolerance tests. All participants had one or more risk factors for diabetes. Using linear regression, we tested for differences in glucose levels between non-pregnant and pregnant women at early (7-15 weeks) and mid-late (24-32 weeks) gestation as well as postpartum, with adjustment for maternal age, parity, marital status and BMI. In a longitudinal analysis using mixed-effects models, we tested for differences in glucose levels across early and mid-late pregnancy compared with postpartum. Differences are expressed as ß (95% CI). RESULTS: Fasting glucose was lower in pregnant compared with non-pregnant women by 0.34 (0.18, 0.51) mmol/l (p < 0.0001) in early pregnancy and by 0.45 (0.29, 0.61) mmol/l (p < 0.0001) in mid-late pregnancy. In longitudinal models, fasting glucose was lower by 0.13 (0.04, 0.21) mmol/l (p = 0.003) in early pregnancy and by 0.16 (0.08, 0.25) mmol/l (p = 0.0003) in mid-late pregnancy compared with the same women postpartum. Early pregnancy post-load glucose levels did not differ from those in non-pregnant women or the same women postpartum. In mid-late pregnancy, compared with non-pregnant women, elevations in 1 h post-load glucose level (0.60 [-0.12, 1.33] mmol/l, p = 0.10) and 2 h post-load glucose (0.49 [-0.21, 1.19] mmol/l, p = 0.17) were not statistically significant. However, in longitudinal analyses, 1 h and 2 h post-load glucose levels were higher in mid-late pregnancy (by 0.78 [0.35, 1.21] mmol/l, p = 0.0004, and 0.67 [0.30, 1.04] mmol/l, p = 0.0005, respectively) when compared with postpartum. CONCLUSIONS/INTERPRETATION: In women with diabetes risk factors, fasting glucose declines in the first trimester. Post-load glucose increases later in pregnancy. These findings may inform criteria for diagnosing hyperglycaemia early in pregnancy.

Pregnancy and End-Stage Renal Disease.

Pregnancy is uncommon in women with end-stage renal disease (ESRD). Fertility rates are low in women on dialysis, and physicians still frequently counsel women with ESRD against pregnancy. Advancements in the delivery of dialysis and obstetric care have led to improved live birth rates in women on dialysis, so pregnancy for young women with ESRD is now more feasible and safer. However, these pregnancies remain high-risk for both maternal and fetal complications, necessitating experienced multidisciplinary care. In this article, we review fertility issues in women with ESRD, discuss pregnancy outcomes in women on dialysis, and provide an approach for management of pregnant women with ESRD.

Pregnancy Outcomes after Clinical Recovery from AKI.

The effect of clinically recovered AKI (r-AKI) on future pregnancy outcomes is unknown. We retrospectively studied all women who delivered infants between 1998 and 2007 at Massachusetts General Hospital to assess whether a previous episode of r-AKI associated with subsequent adverse maternal and fetal outcomes, including preeclampsia. AKI was defined as rise in serum creatinine concentration to 1.5-fold above baseline. We compared pregnancy outcomes in women with r-AKI without history of CKD (eGFR>90 ml/min per 1.73 m2 before conception; n=105) with outcomes in women without kidney disease (controls; n=24,640). The r-AKI and control groups had similar prepregnancy serum creatinine measurements (0.70±0.20 versus 0.69±0.10 mg/dl; P=0.36). However, women with r-AKI had increased rates of preeclampsia compared with controls (23% versus 4%; P<0.001). Infants of women with r-AKI were born earlier than infants of controls (37.6±3.6 versus 39.2±2.2 weeks; P<0.001), with increased rates of small for gestational age births (15% versus 8%; P=0.03). After multivariate adjustment, r-AKI associated with increased risk for preeclampsia (adjusted odds ratio [aOR], 5.9; 95% confidence interval [95% CI], 3.6 to 9.7) and adverse fetal outcomes (aOR, 2.4; 95% CI, 1.6 to 3.7). When women with r-AKI and controls were matched 1:2 by age, race, body mass index, diastolic BP, parity, and diabetes status, r-AKI remained associated with preeclampsia (OR, 4.7; 95% CI, 2.1 to 10.1) and adverse fetal outcomes (OR, 2.1; 95% CI, 1.2 to 3.7). Thus, a past episode of AKI, despite return to normal renal function before pregnancy, associated with adverse outcomes in pregnancy.

Longitudinal Changes in the Relationship Between Hemoglobin A1c and Glucose Tolerance Across Pregnancy and Postpartum.

OBJECTIVE: To characterize the relationship between hemoglobin A1c (HbA1c) levels and glucose tolerance across pregnancy and postpartum. DESIGN AND PARTICIPANTS: In a longitudinal study of pregnant women with gestational diabetes risk factors (N = 102), we performed oral glucose tolerance testing (OGTT) and HbA1c measurements at 10-15 weeks of gestation, 24-30 weeks of gestation (N = 73), and 6-24 weeks postpartum (N = 42). Complete blood counts were obtained from clinical records. We calculated HbA1c-estimated average glucose levels and compared them with mean OGTT glucose levels (average of fasting, 1- and 2-hour glucose levels). Linear mixed effects models were used to test for longitudinal changes in measurements. RESULTS: Mean OGTT glucose increased between 10-15 and 24-30 weeks of gestation (ß = 8.1 mg/dL, P = .001), while HbA1c decreased during the same time period (ß = -0.13%, P < .001). At 10-15 weeks of gestation and postpartum the discrepancy between mean OGTT glucose and HbA1c-estimated average glucose was minimal (mean [standard deviation]: 1.2 [20.5] mg/dL and 0.16 [18.1] mg/dL). At 24-30 weeks of gestation, the discrepancy widened (13.2 [17.9] mg/dL, ß = 12.7 mg/dL, P < .001, compared to 10-15 weeks of gestation, with mean OGTT glucose being higher than HbA1c-estimated average glucose). Lower hemoglobin at 24-30 weeks of gestation was associated with a greater discrepancy (ß = 6.4 mg/dL per 1 g/dL lower hemoglobin, P = .03 in an age- and gestational age-adjusted linear regression model). CONCLUSIONS: HbA1c accurately reflects glycemia in the 1st trimester, but underestimates glucose intolerance in the late 2nd trimester. Lower hemoglobin level is associated with greater underestimation. Accounting for gestational age and maternal hemoglobin may improve the clinical interpretation of HbA1c levels during pregnancy.

Metabolic and Hypertensive Complications of Pregnancy in Women with Nephrolithiasis.

BACKGROUND AND OBJECTIVES: Kidney stones are associated with future development of hypertension, diabetes, and the metabolic syndrome. Our objective was to assess whether stone formation before pregnancy was associated with metabolic and hypertensive complications in pregnancy. We hypothesized that stone formation is a marker of metabolic disease and would be associated with higher risk for maternal complications in pregnancy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective cohort study of women who delivered infants at the Massachusetts General Hospital from 2006 to 2015. Women with abdominal imaging (computed tomography or ultrasound) before pregnancy were included in the analysis. Pregnancy outcomes in women with documented kidney stones on imaging (stone formers, n=166) were compared with those of women without stones on imaging (controls, n=1264). Women with preexisting CKD, hypertension, and diabetes were excluded. RESULTS: Gestational diabetes and preeclampsia were more common in stone formers than nonstone formers (18% versus 6%, respectively; P<0.001 and 16% versus 8%, respectively; P=0.002). After multivariable adjustment, previous nephrolithiasis was associated with higher risks of gestational diabetes (adjusted odds ratio, 3.1; 95% confidence interval, 1.8 to 5.3) and preeclampsia (adjusted odds ratio, 2.2; 95% confidence interval, 1.3 to 3.6). Infants of stone formers were born earlier (38.7±2.0 versus 39.2±1.7 weeks, respectively; P=0.01); however, rates of small for gestational age offspring and neonatal intensive care admission were similar between groups (8% versus 7%, respectively; P=0.33 and 10% versus 6%, respectively; P=0.08). First trimester body mass index significantly influenced the association between stone disease and hypertensive complications of pregnancy: in a multivariable linear regression model, stone formation acted as an effect modifier of the relationship between maximum systolic BP in the third trimester and body mass index (P interaction <0.001). CONCLUSIONS: In women without preexisting diabetes, hypertension, and CKD, a history of nephrolithiasis was associated with gestational diabetes and hypertensive disorders of pregnancy, especially in women with high first trimester body mass index.

Risk of Preeclampsia and Pregnancy Complications in Women With a History of Acute Kidney Injury.

An episode of clinically recovered acute kidney injury (r-AKI) has been identified as a risk factor for future hypertension and cardiovascular disease. Our objective was to assess whether r-AKI was associated with future preeclampsia and other adverse pregnancy outcomes and to identify whether severity of AKI or time interval between AKI and pregnancy was associated with pregnancy complications. We conducted a retrospective cohort study of women who delivered infants between 1998 and 2016 at Massachusetts General Hospital. AKI was defined using the 2012 Kidney Disease Improving Global Outcomes laboratory criteria with subsequent clinical recovery (estimate glomerular filtration rate, >90 mL/min per 1.73 m2 before conception). AKI was further classified by severity (Kidney Disease Improving Global Outcomes stages 1-3) and time interval between AKI episode and the start of pregnancy. Women with r-AKI had an increased rate of preeclampsia compared with women without previous r-AKI (22% versus 9%; P<0.001). Infants of women with r-AKI were born earlier (gestational age, 38.2±3.0 versus 39.0±2.2 weeks; P<0.001) and were more likely to be small for gestational age (9% versus 5%; P=0.002). Increasing severity of r-AKI was associated with increased risk of preeclampsia for stages 2 and 3 AKI (adjusted odds ratio, 3.5; 95% confidence interval, 2.1-5.7 and adjusted odds ratio, 6.5; 95% confidence interval, 3.5-12.0, respectively), but not for stage 1 (adjusted odds ratio, 1.7; 95% confidence interval, 0.9-3.2). A history of AKI before pregnancy, despite apparent full recovery, was associated with increased risk of pregnancy complications. Severity and timing of the AKI episode modified the risk.

Lupus-like Immune Complex-mediated Glomerulonephritis in Patients with Hepatitis C Virus Infection Treated with Oral, Interferon-free, Direct-acting Antiviral Therapy.

Novel, all-oral interferon-free direct-acting antiviral agents have revolutionized the management of hepatitis C virus (HCV) infection by producing exceptional cure rates with minimal adverse events. While provocation or exacerbation of autoimmunity has been reported in HCV-infected patients receiving interferon, this phenomenon has not been reported in patients receiving interferon-free HCV therapy. We report the occurrence of three cases of lupus-like immune complex-mediated glomerulonephritis occurring shortly after exposure to sofosbuvir-based direct-acting antiviral therapies. In all three cases, renal function quickly improved with immunosuppression. However, two of the three patients developed infectious complications of immunosuppression and died. This is the first report of a lupus-like immune complex mediated glomerulonephritis occurring in the context of HCV eradication with all-oral direct-acting antiviral therapies.