Abstract
Background:
Maternal morbidity and mortality are related to pre-pregnancy hypertensive disease and hypertensive disorders of pregnancy (HDP) including preeclampsia (41.1% of HDP), eclampsia (1.3% of HDP), and/or gestational hypertension (39.9% of HDP). Less information is available on the risk of maternal kidney disease and potential racial/ethnic differences following a hypertensive condition during pregnancy. Our objective was to examine the relationships between HDP and pre-pregnancy hypertension with incident kidney disease subsequent to delivery (up to three, five, and 14 years) with consideration of racial/ethnic differences.
Methods:
In a retrospective cohort study, 391,838 women 12–49 years of age had a live birth in South Carolina between 2004–2016; 35.1% non-Hispanic black (NHB) and 64.9% non-Hispanic white (NHW). Hospitalization, emergency department, and birth certificate data defined pre-pregnancy hypertension and HDP. Hospitalization and death certificate data identified incident kidney disease.
Results:
317,006 (80.8%) women experienced neither condition, 1,473 (0.4%) had pre-pregnancy hypertension, 64,050 (16.3%) had HDP, and 9,662 (2.5%) had both conditions (pre-pregnancy hypertension with superimposed HDP, i.e. preeclampsia). Five years after delivery, incident kidney disease risk was increased for NHB and NHW women with HDP (NHB, HR=2.30, 95% CI: 1.94–2.73; NHW, HR=1.97, 95% CI: 1.64–2.37) and with both conditions (NHB, HR=3.88, 95% CI: 3.05–4.93; NHW, HR=1.86, 95% CI: 1.20–2.87) compared to counterparts with neither condition after adjustment (p-value for race/ethnicity interaction=0.003).
Conclusions:
Increased kidney disease risk five years after delivery was observed for women with HDP and with both compared to neither condition, with associated risk higher in NHB than NHW women.
Keywords: Hypertensive disorders of pregnancy, kidney disease, maternal outcomes, racial differences
Summary:
Women with HDP and/or pre-pregnancy hypertension were at increased risk of fatal and nonfatal kidney disease within three, five, and 14 years after delivery, with risks higher for non-Hispanic black than non-Hispanic white women.
INTRODUCTION
Pre-pregnancy hypertension incidence is estimated to be 3–5% whereas up to 10% of pregnancies are impacted by hypertensive disorders of pregnancy (HDP) including preeclampsia, eclampsia, gestational hypertension, and chronic hypertension.1, 2 Hypertensive disorders of pregnancy have been associated with maternal mortality and morbidity, including end organ damage.3–7 Several studies have also demonstrated an association between HDP and end stage kidney disease (ESKD).8–10 Women with and without HDP were followed for the development of ESKD a mean of 6.3 years10 and a maximum of 11 years (median=9 years),11 respectively, by two Taiwanese studies. Women with up to three pregnancies were followed even longer by a Norwegian study with 17±9 years mean (±standard deviation) follow-up after the initial singleton birth between 1967–1991.8
A recent meta-analysis by Barrett et al. (2020) involving four cohort studies and one case-control study assessed the association of HDP and maternal chronic kidney disease (CKD) and ESKD.12 The authors reported associations of preeclampsia with the risk of maternal ESKD based on five studies (pooled adjusted risk ratio [aRR]= 4.90, 95% CI: 3.56–6.74), and with the risk of CKD based on three studies (aRR=2.11, 95% CI: 1.72–2.59).12 Preeclampsia superimposed on chronic hypertension (aRR=44.72, 95% CI: 22.59–88.52) and gestational hypertension (aRR=3.64, 95% CI: 2.34–5.66) were also related to ESKD with findings based on only one study each. In addition to the above mentioned studies by Vikse and Wu et al., the meta-analysis included a retrospective cohort study conducted in Denmark among all woman with one or more livebirth or stillbirth between 1978–2005 (n=1,072,330) with an average of 18.6 person years of follow-up13 and a Canadian retrospective cohort study of women with hospital deliveries (n=1,598,043) that had a median follow-up for women with HDP of 185 months and 194 months for those without HDP.14 The U.S. nested case-control study that included largely white women (37/44 ESKD cases, 87/88 controls) as well as 7/44 ESRD nonwhite cases and 1/88 nonwhite controls adjusted for race but was unable to compare potential racial differences.15
The aforementioned studies were limited by the inclusion of homogeneous populations that did not include women of minority groups. They were also unable to investigate the effect of pre-pregnancy hypertension on ESKD although Wang et al. considered post-pregnancy hypertension during the follow-up period. Although the association of HDP and risk for kidney disease long-term has been established in homogenous populations, few studies have evaluated this association in the early period, within the first five years, post-delivery in diverse populations.
It is well-known that black women experience HDP, particularly preeclampsia and chronic hypertension, at higher rates than white women.16 Racial differences have also been observed in the incidence and progression of kidney disease. The incidence of ESKD is 2–4 times higher among blacks compared to whites.17 However, there are few studies that have evaluated racial differences in the association of HDP and maternal kidney disease. To better understand the relationship between hypertensive disease in pregnancy and maternal kidney disease, we aimed to evaluate the associations between HDP and pre-pregnancy hypertension with incident kidney disease subsequent to delivery (up to three, five, and 14 years) evaluating racial/ethnic differences in a large diverse cohort in the United States (U.S.). We hypothesized that women with the presence of HDP and/or pre-pregnancy hypertension will have higher incidence of fatal and nonfatal kidney disease subsequent to delivery.
METHODS
The data used for this study cannot be shared due to policies of the South Carolina (SC) Revenue and Fiscal Affairs (RFA) Office, Health and Demographics Section; and the SC Department of Health and Environmental Control (DHEC).
Study Design
This retrospective cohort study is based on administrative billing data including hospital discharge records and emergency department (ED) visit encounters for South Carolina (SC) were obtained from the SC Revenue and Fiscal Affairs (RFA) Office, Health and Demographics Section. We also obtained birth and death certificate data from the SC Department of Health and Environmental Control (DHEC). A retrospective statewide cohort was created from these data for the purpose of this study in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. We received institutional review board approval from the Medical University of South Carolina.
Study Population
In-hospital live births that took place in SC were identified using birth certificate data. Maternal procedure and diagnosis codes were available from hospitalization and ED visit data. Death certificate data included the primary or underlying cause of death and comorbid causes of death for women. Maternal hospitalization data and birth certificate data were able to be linked successfully for 97.5% of the cohort using a unique identifier from the SC RFA Office.
Inclusion and Exclusion Criteria
Birth certificate-reported hospital deliveries in SC included single, liveborn infants born between 2004–2016 for which matched hospitalization/ED visit data was available. Mortality and hospitalization/ED visit data were obtained through 2017 providing one to 14 years of follow-up. Women were categorized into non-Hispanic white (NHW), non-Hispanic black (NHB), Hispanic, or other race/ethnicity based on self-reported race and ethnicity. Inclusion and exclusion criteria for the study are displayed in Fig 1. Exclusions included newborn deaths on the day of delivery as the study was limited to live births, as well as women with an out-of-state delivery, a kidney or other transplant, or pre-existent kidney disease. Because of data accuracy concerns and small numbers, women with a pre-pregnancy weight of <92 or >320 lbs, pre-pregnancy BMI of <16.0 or >52.8 kg/m2, negative time to death or invalid data on previous pregnancies, as well as deliveries with implausible size for gestational age18 and birth weights of <500 or >6000 g were excluded. Hispanic and women of other racial/ethnic groups were excluded as they only made up 11.8% of the study population and had a small number of events.
Fig. 1.
Construction of the analytic dataset. After exclusions, the dataset consists of 391,383 women with singleton births beween 2004 and 2016 in South Carolina
Definitions
Birth certificate data included information on maternal race/ethnicity, education, payer, smoking pre-pregnancy and during pregnancy, BMI (kg/m2) pre-pregnancy and at delivery, pre-pregnancy and gestational hypertension, and pre-pregnancy and gestational diabetes. Race/ethnicity was self-reported on the birth certificate. The Revised-Graduated Prenatal Care Utilization Index (R-GINDEX) which incorporates the gestational age of the newborn as well as the total number of prenatal care visits and the trimester prenatal care began, was used to measure prenatal care adequacy.19, 20 Table S1 shows the outcome, exposure, and covariates as defined using International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification (ICD-9-CM/ICD-10-CM) diagnosis and procedure codes (please see http://hyper.ahajournals.org). Death certificate and hospitalization incident/ED visit data (ICD-9/10-CM: 403, 584, 585.x, 586, N17, N18.x, N19) were used to define the outcome of maternal incident kidney disease which referred to fatal and nonfatal acute kidney failure, kidney failure, ESKD, and unspecified kidney disease failure. A broad definition was used to avoid missing any cases.
There were four exposure groups: 1) women with preeclampsia superimposed on pre-pregnancy (chronic) hypertension referred to as pre-pregnancy hypertension with HDP (“both condition”), 2) women with HDP without pre-pregnancy hypertension (“HDP”), 3) women with pre-pregnancy hypertension who did not experience superimposed HDP (“pre-pregnancy HTN”), as well as 4) women without pre-pregnancy hypertension or HDP (“neither condition”). HDP was defined based on birth certificates (gestational hypertension, preeclampsia, and eclampsia) or ICD-9/10-CM diagnosis codes for HDP (642.3–642.7; O11, O13-O16). Pre-pregnancy hypertension and pre-pregnancy hypertension with superimposed HDP were similarly defined based on birth certificates by self-report or based on ICD-9/10-CM codes at delivery (642.0–642.2; O10.0 and 642.7; O11.x, O12.x, O14.x, O15.x, respectively). The first pregnancy with HDP and/or pre-pregnancy hypertension in the dataset was considered to be the index pregnancy among exposed women with one or more pregnancy. For example, a multiparous women would be classified into the HDP exposure group if she experienced HDP during any of her pregnancies, even if she had a prior pregnancy without HDP. The first pregnancy in the dataset was considered the index pregnancy for unexposed women who had neither condition in every pregnancy in the dataset (whether one or more).
Statistical Analysis
Analysis of variance (ANOVA) was used to assess group differences for continuous variables and the Chi-Square test was used for categorical variables. The association between HDP and/or pre-pregnancy hypertension and incident kidney disease within three, five and up to 14 years after delivery was estimated using Cox proportional hazards models including time from delivery to the event or death. Women with neither condition (pre-pregnancy hypertension nor HDP) served as the reference group. Schoenfeld residuals were used to evaluate the proportional hazards assumption, which was valid. Sociodemographic characteristics (maternal age at delivery, race/ethnicity, education, urban/rural residence, median household income per year, payer during pregnancy, WIC [Special Supplemental Nutrition Program for Women, Infants, and Children (WIC)] eligibility during pregnancy) were adjusted for by the models in addition to behavioral (pre-pregnancy smoking, smoking during pregnancy) and clinical characteristics (pre-pregnancy BMI, change in BMI after delivery, pre-pregnancy or gestational diabetes, gestational age at delivery, size for gestational age, mode of delivery (cesarean section or vaginal including forceps, spontaneous, vacuum), previous cesarean section, and quality of prenatal care (R-GINDEX).
Racial/ethnic group-stratified models including interaction terms were carried out with NHW and NHB women with neither condition, respectively, serving as the reference groups. A p-value of <0.05 indicated the presence of an interaction between HDP and/or pre-pregnancy hypertension and racial/ethnic groups in the association between HDP and/or pre-pregnancy hypertension and maternal incident kidney disease within five years of delivery and up to 14 years after delivery. SAS Version 9.4 was used to conduct all analyses.21 We also used Stata Version 16 to check the proportional hazards assumption and to create graphs.22
RESULTS
The current analysis involved 391,838 women among the 461,558 births that occurred in SC between 2004 and 2016. Of the women, 64.9% were NHW and 35.1% were NHB. Approximately 81% did not experience either condition during the study period while 0.4% experienced pre-pregnancy hypertension alone, 16.3% experienced HDP alone, and 2.5% experienced both conditions. Of the women with HDP, 41.1% had preeclampsia, 39.9% had gestational hypertension, and 1.3% had eclampsia; these were not mutually exclusive. The control group consisted of women with neither condition during all of the pregnancies noted in the dataset. Characteristics of mothers at the index pregnancy are presented in Table 1. Compared to neither condition, women with HDP and/or pre-pregnancy hypertension were more likely to be older, NHB, reside in a rural area, and have a lower annual household income, Medicaid, higher pre-pregnancy BMI, and pre-pregnancy or gestational diabetes. The change in BMI from pre-pregnancy to delivery was more likely to be higher in women with HDP and with neither condition than women with both conditions or with pre-pregnancy hypertension alone. Women from the three exposure groups were less likely to have graduated from college or smoke during pregnancy than women with neither condition.
Table 1.
Sociodemographic, behavioral, and clinical characteristics at index pregnancy of mothers in South Carolina from 2004–2016 overall and by hypertensive disorders of pregnancy (HDP) and pre-pregnancy hypertension (HTN) status *, †, ‡
| Total | Neither HDP nor pre-preg HTN | Pre-preg HTN | HDP | Both pre-preg HTN and HDP | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| N=391,838 | N=317,006 (80.8) | N=1,473 (0.4) | N=64,050 (16.3) | N=9,662 (2.5) | ||||||
| Characteristic | n (%), mean ±SD | n (%), mean ±SD | n (%), mean ±SD | n (%), mean ±SD | n (%), mean ±SD | |||||
| Age (years) | 27.2 | ±6.0 | 27.0 | ±6.0 | 30.0 | ±6.3 | 27.2 | ±6.1 | 30.1 | ±6.2§ |
| <20 | 39,567 | (10.1) | 32,563 | (10.3) | 63 | (4.4) | 6,515 | (10.1) | 426 | (4.6)§ |
| 20–24 | 104,813 | (26.7) | 85,687 | (27.0) | 263 | (18.2) | 17,419 | (27.1) | 1,444 | (15.7) |
| 25–29 | 110,874 | (28.3) | 90,152 | (28.5) | 369 | (25.6) | 17,980 | (27.9) | 2,373 | (25.8) |
| 30–34 | 86,614 | (22.1) | 69,806 | (22.0) | 381 | (26.4) | 13,821 | (21.5) | 2,606 | (28.3) |
| 35–39 | 40,800 | (10.4) | 31,795 | (10.0) | 275 | (19.0) | 6,931 | (10.8) | 1,799 | (19.5) |
| 40+ | 9,170 | (2.3) | 6,808 | (2.1) | 93 | (6.4) | 1,704 | (2.6) | 565 | (6.1) |
| Race/ethnicity | ||||||||||
| Non-Hispanic white | 254,377 | (64.9) | 211,816 | (66.9) | 716 | (49.6) | 37,643 | (58.5) | 4,202 | (45.6)§ |
| Non-Hispanic black | 137,461 | (35.1) | 104,995 | (33.1) | 728 | (50.4) | 26,727 | (41.5) | 5,011 | (54.4) |
| Education | ||||||||||
| Less than high school | 57,000 | (14.5) | 45,802 | (14.5) | 206 | (14.3) | 9,861 | (15.3) | 1,131 | (12.3)§ |
| High school graduate | 98,696 | (25.2) | 78,715 | (24.8) | 389 | (26.9) | 17,119 | (26.6) | 2,473 | (26.8) |
| Some college | 104,900 | (26.8) | 84,010 | (26.5) | 418 | (28.9) | 17,852 | (27.7) | 2,620 | (28.4) |
| ≥College graduate | 131,242 | (33.5) | 108,284 | (34.2) | 431 | (29.8) | 19,538 | (30.4) | 2,989 | (32.4) |
| Urban/rural (based on RUCA by zipcode of residence) | ||||||||||
| Urban | 288,612 | (73.7) | 233,865 | (73.8) | 1,045 | (72.4) | 47,056 | (73.1) | 6,646 | (72.1)§ |
| Rural | 103,226 | (26.3) | 82,946 | (26.2) | 399 | (27.6) | 17,314 | (26.9) | 2,567 | (27.9) |
| Annual household income | ||||||||||
| Less than $36,000 | 108,160 | (27.6) | 85,356 | (26.9) | 522 | (36.1) | 19,010 | (29.5) | 3,272 | (35.5)§ |
| $36,000 to <$54,000 | 184,824 | (47.2) | 148,738 | (46.9) | 540 | (37.4) | 31,381 | (48.8) | 4,165 | (45.2) |
| $54,000 or more | 91,300 | (23.3) | 75,899 | (24.0) | 251 | (17.4) | 13,427 | (20.9) | 1,723 | (18.7) |
| WIC eligibility during pregnancy | 197,453 | (50.4) | 156,478 | (49.4) | 791 | (54.8) | 35,042 | (54.4) | 5,142 | (55.8)§ |
| Primary payer during pregnancy | ||||||||||
| Medicaid | 192,998 | (49.3) | 153,648 | (48.5) | 737 | (51.0) | 33,955 | (52.7) | 4,658 | (50.6)§ |
| Private | 165,126 | (42.1) | 134,364 | (42.4) | 619 | (42.9) | 26,203 | (40.7) | 3,940 | (42.8) |
| Self-pay | 8,965 | (2.3) | 7,768 | (2.5) | 17 | (1.2) | 1,029 | (1.6) | 151 | (1.6) |
| Other | 22,274 | (5.7) | 18,992 | (6.0) | 51 | (3.5) | 2,833 | (4.4) | 398 | (4.3) |
| Pre-pregnancy smoking | 65,388 | (16.7) | 53,535 | (16.9) | 231 | (16.0) | 10,265 | (15.9) | 1,357 | (14.7)§ |
| Smoking during pregnancy | 50,527 | (12.9) | 41,584 | (13.1) | 172 | (11.9) | 7,740 | (12.0) | 1,031 | (11.2)§ |
| Pre-pregnancy BMI (kg/m2) | 27.3 | ±6.9 | 26.5 | ±6.4 | 31.9 | ±8.0 | 30.2 | ±7.6 | 33.5 | ±7.9§ |
| Change in BMI at delivery | 4.9 | ±3.0 | 4.8 | ±2.9 | 4.4 | ±3.3 | 5.1 | ±3.4 | 4.5 | ±3.4§ |
| Gestational age at delivery | 38.4 | ±2.0 | 38.6 | ±1.8 | 37.8 | ±2.5 | 37.7 | ±2.4 | 37.0 | ±2.8§ |
| <28 weeks | 2,230 | (0.6) | 1,460 | (0.5) | 18 | (1.2) | 600 | (0.9) | 152 | (1.6)§ |
| 28 to <34 weeks | 7,809 | (2.0) | 4,137 | (1.3) | 64 | (4.4) | 2,849 | (4.4) | 759 | (8.2) |
| 34 to <37 weeks | 27,418 | (7.0) | 18,023 | (5.7) | 151 | (10.5) | 7,804 | (12.1) | 1,440 | (15.6) |
| ≥37 weeks | 354,161 | (90.4) | 292,999 | (92.5) | 1,210 | (83.8) | 53,091 | (82.5) | 6,861 | (74.5) |
| Size for gestational age | ||||||||||
| Appropriate for gestational age | 313,320 | (80.0) | 256,165 | (80.9) | 1,101 | (76.2) | 49,132 | (76.3) | 6,922 | (75.1)§ |
| Small for gestational age | 42,835 | (10.9) | 32,143 | (10.1) | 176 | (12.2) | 9,091 | (14.1) | 1,425 | (15.5) |
| Large for gestational age | 35,448 | (9.0) | 28,300 | (8.9) | 166 | (11.5) | 6,118 | (9.5) | 864 | (9.4) |
| Mode of delivery | ||||||||||
| Cesarean section | 135,537 | (34.6) | 100,618 | (31.8) | 666 | (46.1) | 29,247 | (45.4) | 5,006 | (54.3)§ |
| Vaginal | 256,289 | (65.4) | 216,184 | (68.2) | 778 | (53.9) | 35,120 | (54.6) | 4,207 | (45.7) |
| Induced labor | 59,097 | (15.1) | 43,772 | (13.8) | 231 | (16.0) | 13,274 | (20.6) | 1,820 | (19.8)§ |
| Previous cesarean section | ||||||||||
| Yes | 21,316 | (5.4) | 15,790 | (5.0) | 124 | (8.6) | 4,622 | (7.2) | 780 | (8.5)§ |
| No | 161,804 | (41.3) | 130,146 | (41.1) | 538 | (37.3) | 27,510 | (42.7) | 3,610 | (39.2) |
| Unknown | 208,718 | (53.3) | 170,875 | (53.9) | 782 | (54.2) | 32,238 | (50.1) | 4,823 | (52.3) |
| Previous preterm birth | 10,421 | (2.7) | 7,518 | (2.4) | 89 | (6.2) | 2,296 | (3.6) | 518 | (5.6)§ |
| Prenatal care, measured by R-GINDEX | ||||||||||
| Inadequate | 68,370 | (17.4) | 57,664 | (18.2) | 190 | (13.2) | 9,473 | (14.7) | 1,043 | (11.3)§ |
| Intermediate | 91,352 | (23.3) | 76,133 | (24.0) | 284 | (19.7) | 13,405 | (20.8) | 1,530 | (16.6) |
| Adequate | 6,594 | (1.7) | 5,192 | (1.6) | 25 | (1.7) | 1,230 | (1.9) | 147 | (1.6) |
| Intensive | 117,872 | (30.1) | 89,823 | (28.4) | 516 | (35.7) | 23,355 | (36.3) | 4,178 | (45.3) |
| No care | 2,854 | (0.7) | 2,263 | (0.7) | 11 | (0.8) | 506 | (0.8) | 74 | (0.8) |
| Missing | 104,796 | (26.7) | 85,736 | (27.1) | 418 | (28.9) | 16,401 | (25.5) | 2,241 | (24.3) |
| Pre-pregnancy or gestational diabetes | 25,549 | (6.5) | 16,246 | (5.1) | 305 | (21.1) | 7,021 | (10.9) | 1,977 | (21.5)§ |
Abbreviations: BMI, body mass index; HDP, Hypertensive disorders of pregnancy; HTN, hypertension; pre-preg, pre-pregnancy; R-GINDEX, Revised-Graduated Prenatal Care Utilization Index; RUCA, Rural-Urban Commuting Area; WIC, Women, Infants, and Children.
Data includes person-level diagnostic codes at the time of discharge or birth certificates. Hypertensive disorders of pregnancy (HDP) were defined as pre-eclampsia, eclampsia, or gestational hypertension (International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification [ICD-9/10-CM]: 642.3–642.7; O11-O16) based on hospitalization/emergency department (ED) visit data, or gestational hypertension as reported on the birth certificate. Pre-pregnancy hypertension was based on hospitalization/ED visit data (ICD-9/10-CM: 642.0–642.2, 642.7; O10) or birth certificates.
Pre-pregnancy smoking, smoking during pregnancy, pre-pregnancy BMI, BMI at delivery, gestational age at delivery, mode of delivery, induced labor, previous cesarean section, pre-pregnancy diabetes, and gestational diabetes were available from the birth certificate. Gestational diabetes was also defined using hospitalization/ED visit data based on ICD-9-CM and ICD-10-CM codes.
Variables with >0.1% missing data included: annual household income (n=7,554), primary payer (n=2,475), WIC eligibility in pregnancy (n=5,747), prenatal care as measured by R-GINDEX, (n=104,796). Previous cesarean section is unknown for n=208,718.
p<0.0001
HDP and Pre-pregnancy Hypertension and Incident Kidney Disease Risk
An elevated risk of incident kidney disease was observed in the three years subsequent to delivery for women with both conditions (HR=3.81, 95% CI: 2.96–4.92), with HDP (HR=2.29, 95% CI: 1.95–2.70), and with pre-pregnancy hypertension (HR=2.51, 95%: 1.18–5.33) compared to those with neither condition after controlling for covariates (Table 2). The risk of incident kidney disease attenuated but remained significantly increased for women with both conditions as well as with HDP in the five years subsequent to delivery. A similar pattern was observed up to 14 years after delivery for incident kidney disease among women with both conditions (HR=2.68, 95% CI: 2.36–3.04), with HDP (HR=1.83, 95% CI: 1.69–1.98), and with pre-pregnancy hypertension (HR=1.59, 95% CI: 1.07–2.36) compared to those with neither condition.
Table 2.
Adjusted hazard ratios (HRs) comparing women by exposure status for fatal and nonfatal incident kidney disease within three, five, and up to fourteen years of delivery (the entire study period)
| Incident kidney disease | ||||
|---|---|---|---|---|
| Event | Event Rate * | HR (95% CI)† | ||
| Within 3 years of delivery | ||||
| Neither pre-pregnancy HTN nor HDP | 423 | 0.45 | referent | |
| Pre-pregnancy HTN | 8 | 1.85 | 2.51 | (1.18–5.33) |
| HDP | 277 | 1.44 | 2.29 | (1.95–2.70) |
| Both pre-pregnancy HTN and HDP | 90 | 3.28 | 3.81 | (2.96–4.92) |
| Within 5 years of delivery | ||||
| Neither pre-pregnancy HTN nor HDP | 754 | 0.48 | referent | |
| Pre-pregnancy HTN | 10 | 1.39 | 1.73 | (0.89–3.35) |
| HDP | 458 | 1.43 | 2.14 | (1.89–2.42) |
| Both pre-pregnancy HTN and HDP | 138 | 3.02 | 3.26 | (2.66–3.99) |
| Overall (within 14 years of delivery) | ||||
| Neither pre-pregnancy HTN nor HDP | 2,151 | 0.81 | referent | |
| Pre-pregnancy HTN | 26 | 2.19 | 1.59 | (1.07–2.36) |
| HDP | 1,080 | 2.02 | 1.83 | (1.69–1.98) |
| Both pre-pregnancy HTN and HDP | 328 | 4.22 | 2.68 | (2.36–3.04) |
Abbreviations: CI, confidence interval; HDP, Hypertensive disorders of pregnancy; HR, hazard ratio; HTN, hypertension.
Per 1,000 person-years.
Adjusted for sociodemographic (maternal age, race/ethnicity, education, rural/urban residence, income level, payer, Women, Infants, and Children [WIC]), behavioral (smoking during pregnancy), and clinical characteristics (pre-pregnancy BMI, change in BMI after delivery, gestational age at delivery, size for gestational age, mode of delivery, previous cesarean, adequacy of prenatal care based on the Revised-Graduated Prenatal Care Utilization Index [R-GINDEX], and pre-pregnancy or gestational diabetes).
Presented in Table S2 are model results with additional adjustment for pre-existing systemic lupus erythematosus (SLE) after which little change was observed in the HRs compared to the overall models.
Incident Kidney Disease in HDP and Pre-pregnancy Hypertension by Racial/Ethnic Group
Fig. 2 shows the number of incident kidney disease events and event rates per 1,000 person-years five years subsequent to delivery by exposure status for the entire analytic cohort and by race/ethnicity. Event rates and the risk of incident kidney disease by racial/ethnic group five and 14 years subsequent to delivery are presented in Table 3. Rates appeared to differ by exposure group. NHB women with both conditions experienced the highest incident kidney disease event rates within five (4.65 per 1,000 person-years) and 14 years (5.82 per 1,000 person-years) after delivery while NHW women experienced event rates of 1.10 and 2.22 per 1,000 person-years, respectively. Among those with HDP, incident kidney disease event rates five and 14 years subsequent to delivery were 1.99 and 2.71 per 1,000 person-years for NHB women, and 1.03 and 1.51 per 1,000 person-years for NHW women, respectively.
Fig. 2.
Maternal incident kidney disease event rates (per 1,000 person-years) five years after delivery by hypertensive disorders of pregnancy (HDP) status for the entire cohort and by race/ethnic group
Table 3.
Adjusted hazard ratios for incident kidney disease within five and up to fourteen years of delivery (the entire study period) among non-Hispanic white (NHW) and non-Hispanic black (NHB) women by hypertensive disorders of pregnancy (HDP) and pre-pregnancy hypertension (HTN) status
| Non-Hispanic White | Non-Hispanic Black) | |||||
|---|---|---|---|---|---|---|
| Incident kidney disease | Event | Event Rate* | HR (95% CI)† | Event | Event Rate* | HR (95% CI)† |
| ≤5 years of delivery ‡ | ||||||
| Neither HDP nor pre-pregnancy HTN | 420 | 0.40 | referent | 334 | 0.64 | referent |
| Pre-pregnancy HTN | <5 | 1.12 | 2.14 (0.80–5.77) | 5 | 1.66 | 1.47 (0.60–3.57) |
| HDP | 193 | 1.03 | 1.97 (1.64–2.37) | 265 | 1.99 | 2.30 (1.94–2.73) |
| Both pre-pregnancy HTN and HDP | 23 | 1.10 | 1.86 (1.20–2.87) | 115 | 4.65 | 3.88 (3.05–4.93) |
| Overall (≤14 years of delivery) § | ||||||
| Neither HDP nor pre-pregnancy HTN | 1,203 | 0.69 | referent | 948 | 1.06 | referent |
| Pre-pregnancy HTN | 11 | 1.92 | 1.98 (1.09–3.59) | 15 | 2.44 | 1.33 (0.78–2.27) |
| HDP | 464 | 1.51 | 1.70 (1.51–1.91) | 616 | 2.71 | 1.96 (1.76–2.18) |
| Both pre-pregnancy HTN and HDP | 77 | 2.22 | 1.97 (1.54–2.52) | 251 | 5.82 | 3.00 (2.57–3.49) |
Abbreviations: CI, confidence interval; HDP, hypertensive disorders of pregnancy; HR, hazard ratio; HTN, hypertension.
Per 1,000 person-years.
Adjusted for sociodemographic (maternal age, race/ethnicity, education, rural/urban residence, income level, payer, Women, Infants, and Children [WIC]), behavioral (smoking during pregnancy), and clinical characteristics (pre-pregnancy BMI, change in BMI after delivery, gestational age at delivery, size for gestational age, mode of delivery, previous cesarean section, adequacy of prenatal care based on the Revised-Graduated Prenatal Care Utilization Index [R-GINDEX], and pre-pregnancy or gestational diabetes).
p-value=0.003 for interaction between HDP and/or pre-pregnancy hypertension and race/ethnic group.
p-value=0.001 for interaction between HDP and/or pre-pregnancy hypertension and race/ethnic group.
The risk of incident kidney disease differed by race/ethnicity within five and 14 years after delivery following covariate adjustment, with significant interactions found (p=0.003 and p=0.001, respectively). Among women with both conditions, the risk of incident kidney disease five years subsequent to delivery was increased 3.88-fold (95% CI: 3.05–4.93) for NHB women and 1.86-fold (95% CI: 1.20–2.87) for NHW women compared to NHW and NHB women with neither condition, respectively. Compared to their counterparts with neither condition, NHB and NHW women with HDP experienced a 2.30-fold (95% CI: 1.94–2.73) and 1.97-fold (95% CI: 1.64–2.37) elevated incident kidney disease risk, respectively.
The risk of incident kidney disease attenuated although remained significantly increased 14 years subsequent to delivery among NHB (HR=3.00, 95% CI: 2.57–3.49) and NHW (HR=1.97, 95% CI: 1.54–2.52) women with both conditions compared to NHB and NHW women with neither condition, respectively. Among NHB (HR=1.96, 95% CI: 1.76–2.18) and NHW (HR=1.70, 1.51–1.91) women with HDP, a similar pattern was observed for incident kidney disease risk within 14 years of delivery. NHW women with pre-pregnancy hypertension were additionally at increased risk of incident kidney disease (HR=1.98, 95% CI: 1.09–3.59).
Presented in Table S3 are model results by race/ethnicity with additional adjustment for pre-existing SLE. Similar to the overall models, the HRs were similar and findings remained the same.
DISCUSSION
Women who experienced both HDP and pre-pregnancy hypertension as well as women who experienced only HDP were found to be at increased risk of incident kidney disease up to three, five, and 14 years subsequent to delivery compared to women with neither condition. The risk of kidney disease was highest among women with both pre-pregnancy hypertension and HDP (3.81-fold increased risk at 3 years attenuated to 2.68-fold increased risk at 14 years, respectively) while in women with HDP, the risk was doubled (2.29-fold increased risk at 3 years attenuated to 1.83-fold increased risk at 14 years, respectively). No significant associations were found between pre-pregnancy hypertension and incident kidney disease five years after delivery although there were few events. Within three and 14 years of delivery, however, an elevated risk of incident kidney disease (2.51-fold increased risk at three years attenuated to 1.59-fold increased risk at 14 years, respectively) was observed for women with pre-pregnancy hypertension. Moreover, at each time point following delivery (except within five years of delivery among women with pre-pregnancy hypertension), the relative risk of incident kidney disease remained significantly elevated, but appeared to attenuate slightly over time. These findings were observed after controlling for sociodemographic, clinical, and behavioral characteristics that included potential confounders in the models. Notably, the higher relative risk of kidney disease within three years of delivery suggests that kidney injury whether acute or chronic may occur early in the life-course.
Our results differ from the Prevention of Renal and Vascular End Stage Disease (PREVEND) Study that found no difference in incident CKD among Dutch women with (n=977) and without HDP (n=1,805) (HR=1.04, 95% CI: 0.79–1.37).23 While ESRD was not diagnosed over the study’s 11-year median follow-up period, a significant decline in the estimated glomerular filtration rate (eGFR), a measure of kidney function, was observed among women with HDP compared to those without, supporting our findings that women with HDP have a higher risk for kidney disease. Moreover, our findings of a higher risk of kidney disease in women with HDP are consistent with Barrett et al.’s recent meta-analysis evaluating the relationships between HDP with maternal CKD and ESKD that found an increased risk of CKD with preeclampsia (aRR=2.11, 95% CI, 1.72–2.59) and gestational hypertension (aRR=1.49, 95% CI: 1.11–2.01) as well as an increased risk of ESKD with preeclampsia (aRR=4.90, 95% CI: 3.56–6.74) and gestational hypertension (aRR=3.64, 95% CI: 2.34–5.66).12 In addition, a U.S. case-control study of ESKD conducted in Minnesota reported a significant association between preeclamptic pregnancy and ESKD after adjustment for race that attenuated after further adjustment for obesity.15 The study was limited by small numbers and the inability to examine race in analysis limited to European studies of largely white populations. Our study had a sufficient sample size to adjust for pre-pregnancy BMI and gestational weight gain (as reflected by change in BMI from pre-pregnancy to delivery) as well as to evaluate the association with race up to five and 14 years after delivery.
We observed stark differences in maternal kidney disease risk among NHB and NHW women in our study. NHB women experienced the highest event rates and risks of incident kidney disease at both time points after delivery regardless of exposure. Specifically, compared with having neither condition, NHB women with both pre-pregnancy HTN and HDP had 3.88-fold increased risk of incident kidney disease within five years of delivery and triple the risk within 14 years of delivery. Among NHB women with HDP, the risk of incident kidney disease was elevated 2.30-fold within five years of delivery and 1.96-fold within 14 years than NHB women with neither condition. NHW women with both conditions experienced 1.86-fold the risk of incident kidney disease within five years of delivery and 1.97-fold the risk within 14 years than NHW women with neither condition. Among NHW women with HDP, the risk of incident kidney disease was elevated 1.97-fold within five years of delivery and 1.70-fold within 14 years compared to NHW women with neither condition. Social determinants of health such as economic instability and poor access to quality health care, as well as systemic racism and unconscious bias have perpetuated racial inequities in kidney health. Genetic ancestry has also been implicated in racial differences in both HDP and kidney disease. High-risk maternal-fetal Apolipoprotein L1 (APOL1) genotypes have been associated with preeclampsia and are implicated in kidney disease progression.17, 24 Further studies are needed to identify key factors contributing to racial disparities in the risk for kidney disease among younger women.
More recently, a U.S. study (California) in 2020 by Ton et al. adjusted for maternal race and ethnicity and found an increased risk of acute renal failure within the first year after delivery among women with mild preeclampsia (relative risk [RR]=3.61, 95% CI: 3.44–3.79) and with severe preeclampsia (RR=12.84, 95% CI: 12.51–13.19) compared to women without preeclampsia.25 Our study observed approximately double the risk of incident kidney disease in HDP with incident kidney disease within three, five, and 14 years of delivery, which included fatal as well as nonfatal acute and chronic kidney disease. However, we were not able to examine severity of preeclampsia given our data sources and did not consider events within one year of delivery due to small numbers.
Hypertension is a known risk factor for the development of ESKD.26–29 Less is known about the impact of pre-pregnancy hypertension with HDP on later renal function. It is unclear whether women with pre-pregnancy (i.e., chronic) hypertension may have some degree of subclinical kidney dysfunction that could be accelerated by HDP or whether HDP may cause further kidney injury. Preeclampsia, one of the most well studied HDP, has been characterized by imbalances in angiogenic and anti-angiogenic factors which may potentiate kidney injury, resulting in podocyte damage and vascular injury. Kidney disease subsequent to preeclampsia could also be related to underlying kidney disease masked by preeclampsia30 or may be a risk marker of preeclampsia.8 Compared to women who never experienced preeclampsia, one study reports those with a history of preeclampsia received an earlier diagnosis of kidney disease and at a younger age.31 Preeclampsia, cardiovascular disease, and renal disease have some similar risk factors, including hypertension.32, 33 Kidney injury has been found to worsen due to the effect of preeclampsia-related blood pressure regardless of the presence of renal disease in preeclampsia animal models.34, 35
In summary, given the maternal morbidity and mortality associated with HDP as well as with kidney disease, more research is needed to further explore long-term effects of HDP and subsequent kidney disease, compare potential subgroup differences in the relationship (e.g., race/ethnicity, preeclampsia severity), and to elucidate potential mechanisms for post-pregnancy kidney disease. There is also an important need for future studies evaluating kidney outcomes that also include outpatient visits such as follow-up with maternal fetal medicine, obstetrics, primary care physician, or other specialists. Additionally, CKD takes time to develop and many individuals with early kidney disease may be asymptomatic so rates may actually be higher than what was captured if patients did not seek care.
Strengths and Limitations
Our study had some limitations including the exclusion of Hispanic women and women of other racial/ethnic groups due to small numbers in SC and the rarity of kidney disease as an outcome. Power may be reduced as there were a small number of events in the group of women with pre-pregnancy hypertension; kidney disease risk was not able to be evaluated within three years of delivery by racial/ethnic group. As our study involved ED visit encounters, hospitalizations, and mortality data, inclusion of more severe cases of maternal incident kidney disease including acute kidney injury is likely. Thus, women with subclinical, asymptomatic, or undiagnosed kidney disease pre-conception or during pregnancy who were not hospitalized or did not visit the ED would have been missed. In our study, the prevalence of pre-pregnancy hypertension was 2.8% in pregnant women aged 12–49 years (0.4% of women with pregnancy hypertension and 2.4% of women with both conditions, i.e. pre-pregnancy hypertension and HDP). Our study’s low prevalence of pre-pregnancy hypertension may be due to underreporting in the birth certificate/ICD-9/10-CM diagnosis codes at the time of delivery, which may misclassify diagnosis overall and by racial/ethnic group.
In addition to carrying out a large retrospective cohort study in SC and the ability to examine potential differences in NHW and NHB women, other strengths are access to individual-level data on sociodemographic and clinical characteristics including smoking status and BMI. Maternal and pregnancy-related information on past births was available from the birth certificate data although we do not have access to pregnancy history, blood pressure control, or possible diagnoses that may have occurred before the index pregnancy such as cardiovascular disease. Data were also not available on post-partum diet or medical treatments. Women with severe hypertension are at higher risk for renal damage. Thus, the initial presentation of HDP or pre-pregnancy hypertension for those with the exposure of interest, or the first pregnancy in the dataset for those without HDP or pre-pregnancy hypertension, was deemed the index pregnancy. Prenatal care was controlled for using the R-GINDEX, but was unavailable for 26.7% of women.
Although kidney disease following HDP has been examined, most studies were unable to compare differences by race/ethnicity or control for multiple covariates due to data limitations.5, 8, 14, 18 We had the ability to consider racial/ethnic differences and to include four exposure groups consisting of women with HDP and pre-pregnancy hypertension separately and together compared to a control group of women without either condition. In our study, differences were observed in the association of HDP and/or pre-pregnancy hypertension with incident risk of maternal kidney disease within three and five years of delivery as well as for the overall study period (up to 14 years), and race was found to modify these differences within five and 14 years of delivery.
CONCLUSIONS
Our study observed an increase in incident kidney disease risk three, five, and 14 years after delivery for women with HDP regardless of pre-pregnancy hypertension as well as women with pre-pregnancy hypertension within three and 14 years after delivery compared to women with neither HDP nor pre-pregnancy hypertension. We also observed variations in incident kidney disease risk and event rates within five and 14 years subsequent to delivery among NHW and NHB women with HDP with or without pre-pregnancy hypertension and for NHW women with pre-pregnancy hypertension up to five years after delivery. Thus, HDP with and without pre-pregnancy hypertension may be related to maternal fatal and nonfatal incident, acute and chronic kidney disease long-term with racial/ethnic differences. As the literature related to disparities and potential racial/ethnic differences in HDP and maternal kidney disease is limited due to inclusion of largely homogeneous populations lack diversity, results from this study will help to fill the knowledge gap with the goal of improving outcomes for women who experience HDP. Our study utilized available data for all NHB and NHW women with a live, singleton birth in a SC hospital between 2004 and 2016. We also had the ability to examine long-term maternal incident kidney disease outcomes of HDP among women with and without pre-pregnancy hypertension. In particular, reducing and preventing pregnancy-related, kidney disease morbidity and mortality through identification of high-risk groups of women could impact public health and clinical practice through primary prevention measures as well as further screening and treatment.
PERSPECTIVES
In a retrospective cohort study in SC, we investigated the relationship between HDP and pre-pregnancy hypertension with subsequent maternal kidney disease within three, five, and 14 years among deliveries occurring between 2004 and 2016, overall and by race/ethnicity. An increased risk of maternal incident kidney disease was observed for the three time points examined among women with HDP and for women with both HDP and pre-pregnancy hypertension. Within five and 14 years of delivery, a significant interaction was present with race/ethnic group. Compared to NHB women and NHW women with neither condition, respectively, NHB women and NHW women with HDP and with both HDP and pre-pregnancy hypertension experienced an increased risk of incident kidney disease within five years of delivery. However, the risk was higher for NHB women with HDP as well as those with both HDP and pre-pregnancy hypertension than NHW counterparts. The models adjusted for sociodemographic, clinical, and behavioral characteristics including potential confounders. Maternal morbidity and mortality are associated with HDP and kidney disease, and findings from our study suggest acute or chronic kidney injury may occur early in the life-course. Therefore, future studies are warranted to further explore the long-term effects of HDP and subsequent maternal kidney disease. Potential differences in the association can also be compared by subgroups such as race/ethnicity and severity of preeclampsia.
Supplementary Material
Pathophysiologic Novelty and Relevance.
What is New?
The association of hypertensive disorders of pregnancy (HDP) and/or pre-pregnancy hypertension with maternal kidney disease was evaluated in a large dataset of 391,838 women.
The cohort was diverse, allowing for evaluation by race/ethnicity.
What is relevant?
Our findings add to general knowledge of the impact of HDP/pre-pregnancy hypertension on subsequent kidney disease overall and by race/ethnic group.
Up to 14 years of follow-up allows evaluation of maternal incident kidney disease.
What are the Pathophysiological Implications?
Understanding the impact of HDP/pre-pregnancy hypertension on maternal kidney disease outcomes could lead to prevention efforts for at-risk populations.
ACKNOWLEDGEMENTS
An abstract based on this work was given as an oral presentation virtually in December 2020 at the Society for Epidemiologic Research (SER) Annual Meeting. The abstract was also accepted as a poster presentation by SER’s sister society, the Society for Pediatric and Perinatal Epidemiologic Research (SPER) Annual Meeting, for a virtual poster presentation in December 2020 although the virtual conference was limited to oral presentations and posters were not presented.
Research reported in this publication was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health (NIH) under Award Number K01HL138273 and the American Kidney Fund Clinical Scientist in Nephrology Program. This project was also supported by the South Carolina Clinical & Translational Research (SCTR) Institute with an academic home at the Medical University of South Carolina through the Clinical and Translational Science Award (CTSA) NIH/National Center for Advancing Translational Sciences (NCATS) grant number UL1 TR001450. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or NCATS.
Nonstandard Abbreviations and Acronyms
- HDP
Hypertensive disorders of pregnancy
- NHB
Non-Hispanic Black
- NHW
Non-Hispanic White
- R-GINDEX
Revised-Graduated Prenatal Care Utilization Index
- RUCA
Rural-Urban Commuting Area
- SC RFA
South Carolina Revenue and Fiscal Affairs Office
- SC DHEC
South Carolina Department of Health and Environmental Control
- WIC
Women, Infants, and Children
Footnotes
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