Association Between Blunted Glomerular Hyperfiltration in Pregnancy and Severe Maternal Morbidity-A Research Letter.

BACKGROUND: Glomerular hyperfiltration is one physiological adaptation to pregnancy, marked by a decline in serum creatinine (SCr) concentration by 16 weeks' gestation. It is not known whether blunted glomerular hyperfiltration leads to adverse maternal outcomes, including severe maternal morbidity (SMM).
OBJECTIVE: To evaluate the association between blunted glomerular hyperfiltration and subsequent SMM or death.
DESIGN: Population-based cohort study.
SETTING: Ontario, Canada, from 2008 to 2019. PARTICIPANTS: Included were births among women who had ≥ 1 SCr measured as an outpatient within 10 weeks before conception ("preconception"), and again, at 110/7 to 206/7 weeks' gestation ("in-pregnancy"). Excluded were women who died before birth, who had end-stage renal disease or kidney transplantation before conception, or whose pre-pregnancy SCr was 125 μmol/L. EXPOSURE: Net glomerular hyperfiltration defined as the preconception minus the in-pregnancy SCr. MEASURES: The primary study outcome was SMM or death arising from 23 weeks' gestation up to 42 days after the index birth.
METHODS: Adjusted relative risks (aRRs) were calculated using Modified Poisson regression per 1-SD net blunting of glomerular hyperfiltration adjusting for important covariates.
RESULTS: A total of 10,323 births met all inclusion criteria. The mean (SD) SCr was 61.7 (11.0) μmol/L preconception, 48.0 (9.2) μmol/L in-pregnancy, and the mean net difference 13.6 (8.2) μmol/L. Among these births, the adjusted RR of SMM or death from 23 weeks' gestation up to 42 days post-partum was 1.16 (95% confidence interval 1.14-1.30) per 1-SD (8.2 μmol/L) net blunting of glomerular hyperfiltration. LIMITATIONS: As SCr assessment is not a routine part of pregnancy care, its measurement could have been for a specific health condition thereby imparting selection bias.
CONCLUSIONS: Blunted glomerular hyperfiltration in pregnancy may identify some women at higher risk of SMM. Further prospective research is needed about the implications of glomerular hyperfiltration in early pregnancy.

Introduction

Glomerular hyperfiltration is one physiological adaptation to pregnancy, marked by a decline in serum creatinine (SCr) concentration by 16 weeks’ gestation. Glomerular hyperfiltration may be abnormally blunted in women with impaired renal vasculature, decreased nephron mass or pre-existing chronic kidney injury. Such blunting may heighten a woman’s susceptibility to preeclampsia and acute kidney injury—both established causes of maternal morbidity.[2-4] Data are lacking on the effect of blunted glomerular hyperfiltration on the risk of severe maternal morbidity (SMM), especially among women without known antecedent kidney disease. The current study evaluated the association between blunted glomerular hyperfiltration and subsequent SMM or death.

Methods

We completed a retrospective population-based cohort study in Ontario, Canada, where universal health care is available. All hospital birth records were identified in administrative health databases, along with sociodemographic data and physician billing claims. These data sets were linked using unique encoded identifiers and analyzed at ICES.[1,4]

The cohort comprised women aged 16 to 50 years, who had a singleton livebirth or stillbirth at ≥23 weeks’ gestation, from August 2008 to October 2019. Each participant had ≥1 SCr measured as an outpatient within 10 weeks before conception (“preconception”), and again, at 110/7 to 206/7 weeks’ gestation (“in-pregnancy”). Excluded were women who died before birth, who had end-stage renal disease or kidney transplantation before conception, or whose pre-pregnancy SCr was >125 μmol/L as more severe kidney disease may be associated with morbidity measures that comprise SMM.

Net glomerular hyperfiltration was determined by the preconception minus the in-pregnancy SCr. The primary study outcome was SMM or death arising from 23 weeks’ gestation up to 42 days after the index birth. SMM is based on a validated composite measure comprising approximately 40 morbidity measures arising in pregnancy, during labor, or postpartum. SMM or maternal death was further analyzed from the index birth up to 42 days postpartum.

Modified Poisson regression generated unadjusted and adjusted relative risks (RR) and 95% confidence interval (CI), modeled per 1-SD net blunting of glomerular hyperfiltration. One additional analysis was limited to women who had urinary protein measured ≤4 years before conception, with proteinuria further added to the regression model. Another analysis explored specific SMM components plausibly affected by impaired hyperfiltration, namely, severe preeclampsia, HELLP syndrome (characterized by hemolysis, elevated liver enzyme levels, and a low platelet count) or eclampsia; acute kidney injury or dialysis; and maternal ICU admission.[4,5]

Analyses were performed using SAS version 9.4 (SAS Institute), with a 2-sided P value < .05 for significance.

Results

A total of 10,323 births met all inclusion criteria. The mean (SD) SCr was 61.7 (11.0) μmol/L preconception, 48.0 (9.2) μmol/L in-pregnancy, and the mean net difference 13.6 (8.2) μmol/L.

Among 10,323 births, the adjusted RR of SMM or death from 23 weeks’ gestation up to 42 days post-partum was 1.16 (95% CI 1.14-1.30) per 1-SD (8.2 μmol/L) net blunting of glomerular hyperfiltration, which changed minimally after adjusting for a history proteinuria (Table 1). The associated risk was higher for severe preeclampsia, and for acute kidney injury or dialysis, but not for maternal ICU admission (Table 1).

Table 1.

Risk of Severe Maternal Morbidity (SMM) or Death, or Specific SMM Components, Each in Association With a Blunting of Glomerular Hyperfiltration in Pregnancy.

Timing of assessment of outcome	Outcome	No. (overall %) with SMM or death	Unadjusted relative risk(95% CI)	Adjusted relative risk(95% CI) a	Adjusted relative risk with proteinuria(95% CI) b
23 weeks’ gestation up to 42 days postpartum	SMM or death	354 (3.43)	1.14 (1.03-1.27)	1.16 (1.04-1.30)	1.20 (1.07-1.36)
	Severe preeclampsia, HELLP syndrome or eclampsia	97 (0.94)	1.18 (0.93-1.51)	1.27 (1.01-1.60)	1.34 (1.03-1.74)
	Acute kidney injury or dialysis	21 (0.20)	1.10 (0.61-2.00)	1.44 (1.02-2.04)	1.57 (1.18-2.10)
	Maternal ICU admission	59 (0.57)	1.13 (0.89-1.45)	0.90 (0.66-1.23)	0.94 (0.68-1.31)
Index birth up to 42 days postpartum	SMM or death	183 (1.77)	1.02 (0.89-1.18)	0.97 (0.83-1.14)	1.03 (0.87-1.21)

Note. Each outcome is expressed per 1-SD (8.2 μmol/L) blunting of the serum creatinine between the preconception and in-pregnancy periods. CI = confidence interval; ICU = intensive care unit.

Adjusted for maternal age, rural residence, income quintile (each at time of index conception); gestational week of in-pregnancy serum creatinine; preconception serum creatinine; and diabetes mellitus, chronic hypertension, and tobacco/illicit drug—each within 4 years before conception.

Further limited to 6992 pregnancies with a urine albumin-creatinine ratio or dipstick measurement done within 4 years before conception, and adjusted for proteinuria (defined as a urine albumin-creatinine ratio > 2 mg/mmol or a urine dipstick positive for protein).

A net blunting of glomerular hyperfiltation was not associated with SMM or death arising from birth to 42 days postpartum (Table 1).

Discussion

These preliminary findings suggest that blunted glomerular hyperfiltration in pregnancy may identify some women at higher risk of SMM.

This study has some limitations. First, as SCr assessment is not a routine part of pregnancy care, its measurement herein could have been for a specific health condition. Second, due to data limitations, we did not account for all important confounders which may affect SCr and the ability to hyperfilter, including body mass index and previous episodes of hypertensive disorders of pregnancy. While the ensuing selection bias may have included women especially at higher risk of SMM, these would also represent women who might benefit from enhanced surveillance and preventive strategies. One example might be aspirin prophylaxis, which decreases the risk of preeclampsia, one major cause of SMM.

Further prospective research is needed about the implications of glomerular hyperfiltration in early pregnancy.