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American Journal of Kidney Diseases

Blunted Glomerular Hyperfiltration in Pregnancy and Risk of Adverse Perinatal Outcomes

      To the Editor:
      Major physiologic adaptations to the demands of pregnancy include volume expansion and vasodilation, heightened renal plasma flow, and glomerular hyperfiltration.
      • Cheung K.L.
      • Lafayette R.A.
      Renal physiology of pregnancy.
      The accompanying decline in serum creatinine concentration (Scr) occurs by about 16 weeks’ gestation.
      • Park S.
      • Lee S.M.
      • Park J.S.
      • et al.
      Midterm eGFR and adverse pregnancy outcomes: the clinical significance of gestational hyperfiltration.
      A previous study attempted to define the effect of decreases in midpregnancy kidney function on pregnancy outcomes but had few participants, failed to use a validated reference standard for kidney function during pregnancy, and was confounded by sampling bias.
      • Park S.
      • Lee S.M.
      • Park J.S.
      • et al.
      Midterm eGFR and adverse pregnancy outcomes: the clinical significance of gestational hyperfiltration.
      Accordingly, the effect of blunted hyperfiltration on adverse pregnancy outcomes is still largely unknown.
      A retrospective population-based cohort study was completed in Ontario, Canada, where universal health care is available to all residents. All Ontario hospital birth records were identified in administrative health databases, linked to sociodemographic data and physician billing claims using unique encoded identifiers, and analyzed at ICES. Specifics about the study databases are Table S1.
      The current cohort comprised Ontarian women aged 16 to 50 years who had a singleton live birth or stillbirth at 23 or more weeks’ gestation, March 2007 to December 2015. Each participant had at least 1 outpatient Scr within 10 weeks before conception (“preconception”) and a second Scr at 110/7 to 206/7 weeks’ gestation (“in-pregnancy”), the latter corresponding to when the Scr nadir is reached in healthy pregnancies.
      • Harel Z.
      • McArthur E.
      • Hladunewich M.
      • et al.
      Serum creatinine levels before, during, and after pregnancy.
      If there were 1 or more Scr during either period, that closest to the estimated conception date was used. Measuring Scr is not routine in pregnancy care, so it could occur for either a specific condition or general health screening. Women were excluded if Scr was >250 μmol/L, they died during pregnancy, or had kidney failure or kidney transplantation before conception.
      Net glomerular hyperfiltration was defined as the preconception minus in-pregnancy Scr. Modified Poisson regression generated unadjusted and adjusted relative risks (RRs) per 1-SD (8 μmol/L) incremental decline in net glomerular hyperfiltration (ie, blunted glomerular hyperfiltration).
      • Zou G.
      A modified Poisson regression approach to prospective studies with binary data.
      Study outcomes were extreme preterm birth (PTB; <32 weeks' gestation), PTB (<37 weeks), preeclampsia, perinatal mortality (stillbirth or a neonatal death < 28 days after birth), and severe SGA (birth weight < 5th percentile).
      RRs were adjusted for maternal age, rural residence, maternal region of origin at the time of conception; gestational week of in-pregnancy Scr; preconception Scr; and diabetes mellitus, chronic hypertension, and tobacco/illicit drug use in the 4 years before conception. Additional analyses included a subgroup: (1) with urinary protein measured within 4 years before conception, in which proteinuria was further adjusted for, and (2) with and without underlying prepregnancy comorbid conditions of diabetes, chronic hypertension, chronic kidney disease, or proteinuria.
      Analyses were performed using SAS, version 9.4 (SAS Institute Inc). The use of data was authorized under section 45 of Ontario’s Personal Health Information Protection Act, which does not require research ethics board review.
      Among 1,241,286 pregnancies in Ontario during the study period, 5,243 (0.4%) met all inclusion criteria and formed the final cohort (Table 1; Fig S1). Mean Scrs preconception and in-pregnancy were 61.4 ± 12.7 and 47.7 ± 10.9 μmol/L, respectively, with a mean difference of 13.7 ± 8.0 μmol/L. The additional analysis included 3,847 women, of whom 1,300 (34%) had proteinuria.
      Table 1Characteristics of Pregnancies With Scr Measured Preconception and In-Pregnancy
      CharacteristicValue
      At the time of conception
      Age, y31.1 ± 5.4
      Maternal region of origin
       Asia949 (18.1%)
       Caribbean/Africa338 (6.5%)
       Hispanic America162 (3.1%)
       Other3,794 (72.4%)
      Residing in the lowest income quintile area1,135 (21.7%)
      Urban residence4,895 (93.4%)
      Parity1 [0-1]
      Prepregnancy weight, kg72.1 ± 19.2
      Comorbid conditions in 4 y before conception
      Diabetes mellitus1,287 (24.6%)
      Chronic hypertension1,135 (21.7%)
      Illicit drug/tobacco use366 (7.0%)
      eGFR < 60 mL/min/1.73 m2258 (4.9%)
      Obstetric conditions during index pregnancy
      Hypertensive disorder of pregnancy476 (9.1%)
      Gestational diabetes mellitus909 (17.3%)
      Kidney function
      Preconception Scr, μmol/L61.4 ± 12.7
      In-pregnancy Scr, μmol/L
      Measured at a mean of 14.0±2.8 weeks’ gestation.
      47.7 ± 10.9
      Scr difference (preconception − in-pregnancy), μmol/L13.7 ± 8.0
      Note: Values for continuous variables given as median [IQR] or mean ± standard deviation; for categorical variables, as count (percent).
      Abbreviation: eGFR, estimated glomerular filtration rate (calculated with CKD-EPI equation).
      a Measured at a mean of 14.0 ± 2.8 weeks’ gestation.
      The adjusted RR of extreme preterm birth was 1.19 (95% CI, 1.02-1.39) per 1-SD blunting of glomerular hyperfiltration, which changed minimally on adjusting for prior proteinuria (1.22; 95% CI, 1.04-1.43; Table 2). Preterm birth and preeclampsia demonstrated a similar pattern (Table 2). Perinatal mortality was not associated with blunting of glomerular hyperfiltration in the main model (RR, 1.28; 95% CI, 0.96-1.70), but was on adjusting for proteinuria (1.39; 95% CI, 1.05-1.82; Table 2). Severe SGA was not associated with blunting of glomerular hyperfiltration (Table 2). A similar pattern was seen in the subgroup with prepregnancy comorbid disease (Table S2).
      Table 2Risk for Preterm Birth, Preeclampsia, and Perinatal Mortality Associated With Blunted Glomerular Hyperfiltration in Pregnancy
      OutcomeNo. (Overall %) With OutcomeRelative Risk (95% CI)
      Adj
      Adjusted for maternal age, rural residence, region of origin (each at time of index conception); gestational week of in-pregnancy Scr; preconception Scr; and diabetes, chronic hypertension, and tobacco/illicit drug (each ≤4 years before conception).
      Adj + Preconception Proteinuria
      Further limited to 3,847 women who had a urinary albumin-creatinine ratio (UACR) or dipstick measurement done within 4 years before conception. Proteinuria was defined as UACR>2 mg/mmol or dipstick positive.
      Extreme preterm birth: <32 wk
      Restricted to 5,211 live births.
      77 (1.5%)1.19 (1.02-1.39)1.22 (1.04-1.43)
      Preterm birth: <37 wk
      Restricted to 5,211 live births.
      549 (10.5%)1.16 (1.08-1.24)1.16 (1.07-1.26)
      Preeclampsia181 (3.5%)1.26 (1.09-1.46)1.19 (1.01-1.41)
      Perinatal mortality47 (0.90%)1.28 (0.96-1.70)1.39 (1.05-1.82)
      Severe SGA: birthweight < 5th percentile282 (5.4%)1.07 (0.93-1.22)0.99 (0.85-1.16)
      Note: Each outcome is in association with a 1-SD (8 μmol/L) blunting in net glomerular hyperfiltration between preconception and in-pregnancy Scr.
      a Adjusted for maternal age, rural residence, region of origin (each at time of index conception); gestational week of in-pregnancy Scr; preconception Scr; and diabetes, chronic hypertension, and tobacco/illicit drug (each ≤4 years before conception).
      b Further limited to 3,847 women who had a urinary albumin-creatinine ratio (UACR) or dipstick measurement done within 4 years before conception. Proteinuria was defined as UACR > 2 mg/mmol or dipstick positive.
      c Restricted to 5,211 live births.
      Blunted glomerular hyperfiltration in early pregnancy may be associated with increased risk for preterm birth and possibly with perinatal mortality.
      Glomerular hyperfiltration may be viewed as a measure of “global vascular reserve.”
      • Cheung K.L.
      • Lafayette R.A.
      Renal physiology of pregnancy.
      Failure to hyperfilter may reflect the antecedent presence of intraglomerular hypertension due to pre-existing vascular dysfunction, impaired endothelium, and faulty angiogenesis, all associated with underlying comorbid conditions such as chronic kidney disease, hypertension, and diabetes.
      • Conrad K.P.
      • Novak J.
      • Danielson L.A.
      • Kerchner L.J.
      • Jeyabalan A.
      Mechanisms of renal vasodilation and hyperfiltration during pregnancy: current perspectives and potential implications for preeclampsia.
      • Perni U.
      • Sison C.
      • Sharma V.
      • et al.
      Angiogenic factors in superimposed preeclampsia: a longitudinal study of women with chronic hypertension during pregnancy.
      • Di Marco G.S.
      • Reuter S.
      • Hillebrand U.
      • et al.
      The soluble VEGF receptor sFlt1 contributes to endothelial dysfunction in CKD.
      Vascular dysfunction can also lead to the abnormal placental implantation or development, leading to placental dysfunction
      • Maynard S.E.
      • Min J.Y.
      • Merchan J.
      • et al.
      Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.
      and ensuing maternal preeclampsia, a leading cause of provider-initiated preterm birth.
      • Ray J.G.
      • Park A.L.
      • Fell D.B.
      Mortality in infants affected by preterm birth and severe small-for-gestational age birth weight.
      This study used a large diverse cohort of women within a universal health care system and adjusted for some important covariates, including preconception Scr. As a limitation, Scr was ordered on clinical grounds, for which the indication was not known. Conceivably some women studied were at higher risk for adverse perinatal outcomes due to selection bias. Body mass index was not accounted for, which may affect Scr and the ability to hyperfilter. Despite these limitations, our results have biological plausibility.
      Further study into the pathophysiology of intrarenal hemodynamic dysfunction in pregnancy and how it relates to perinatal complications is needed.

      Article Information

      Authors’ Full Names and Academic Degrees

      Ziv Harel, MD, MSc, FRCPC, Alison L. Park, MSc, and Joel G. Ray, MD, MSc, FRCPC.

      Authors’ Contributions

      Research idea and study design: ZH, ALP, JGR; data analysis/interpretation: ZH, ALP, JGR; statistical analysis: ALP; supervision or mentorship: JGR. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate.

      Support

      This study was supported by a Biomedical Grant from the Kidney Foundation of Canada and ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC).

      Financial Disclosure

      The authors declare that they have no relevant financial interests.

      Disclaimer

      Parts of this material are based on data and information compiled and provided by MOHLTC, CIHI, and Immigration, Refugees and Citizenship Canada. The analyses, conclusions, opinions, and statements expressed here are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred.

      Peer Review

      Received November 31, 2019. Evaluated by 3 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form February 7, 2020.

      Supplementary Material

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