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Pregnancy Complications and Long-Term Mortality in a Diverse Cohort

Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.122.062177Circulation. 2023;147:1014–1025

Abstract

Background:

Pregnancy complications are associated with increased risk of development of cardiometabolic diseases and earlier mortality. However, much of the previous research has been limited to White pregnant participants. We aimed to investigate pregnancy complications in association with total and cause-specific mortality in a racially diverse cohort and evaluate whether associations differ between Black and White pregnant participants.

Methods:

The Collaborative Perinatal Project was a prospective cohort study of 48 197 pregnant participants at 12 US clinical centers (1959–1966). The Collaborative Perinatal Project Mortality Linkage Study ascertained participants’ vital status through 2016 with linkage to the National Death Index and Social Security Death Master File. Adjusted hazard ratios (aHRs) for underlying all-cause and cause-specific mortality were estimated for preterm delivery (PTD), hypertensive disorders of pregnancy, and gestational diabetes/impaired glucose tolerance (GDM/IGT) using Cox models adjusted for age, prepregnancy body mass index, smoking, race and ethnicity, previous pregnancies, marital status, income, education, previous medical conditions, site, and year.

Results:

Among 46 551 participants, 45% (21 107 of 46 551) were Black, and 46% (21 502 of 46 551) were White. The median time between the index pregnancy and death/censoring was 52 years (interquartile range, 45–54). Mortality was higher among Black (8714 of 21 107 [41%]) compared with White (8019 of 21 502 [37%]) participants. Overall, 15% (6753 of 43 969) of participants had PTD, 5% (2155 of 45 897) had hypertensive disorders of pregnancy, and 1% (540 of 45 890) had GDM/IGT. PTD incidence was higher in Black (4145 of 20 288 [20%]) compared with White (1941 of 19 963 [10%]) participants. The following were associated with all-cause mortality: preterm spontaneous labor (aHR, 1.07 [95% CI, 1.03–1.1]); preterm premature rupture of membranes (aHR, 1.23 [1.05–1.44]); preterm induced labor (aHR, 1.31 [1.03–1.66]); preterm prelabor cesarean delivery (aHR, 2.09 [1.75–2.48]) compared with full-term delivery; gestational hypertension (aHR, 1.09 [0.97–1.22]); preeclampsia or eclampsia (aHR, 1.14 [0.99–1.32]) and superimposed preeclampsia or eclampsia (aHR, 1.32 [1.20–1.46]) compared with normotensive; and GDM/IGT (aHR, 1.14 [1.00–1.30]) compared with normoglycemic. P values for effect modification between Black and White participants for PTD, hypertensive disorders of pregnancy, and GDM/IGT were 0.009, 0.05, and 0.92, respectively. Preterm induced labor was associated with greater mortality risk among Black (aHR, 1.64 [1.10–2.46]) compared with White (aHR, 1.29 [0.97–1.73]) participants, while preterm prelabor cesarean delivery was higher in White (aHR, 2.34 [1.90–2.90]) compared with Black (aHR, 1.40 [1.00–1.96]) participants.

Conclusions:

In this large, diverse US cohort, pregnancy complications were associated with higher mortality nearly 50 years later. Higher incidence of some complications in Black individuals and differential associations with mortality risk suggest that disparities in pregnancy health may have life-long implications for earlier mortality.

Clinical Perspective

What Is New?

  • This article fills a critical data gap in the field of the long-term implications of adverse pregnancy outcomes, in which much of the previous literature has been limited to primarily White populations, by utilizing a diverse cohort and examining for potential heterogeneity in associations by race.

  • Those with common pregnancy complications of preterm delivery, hypertensive disorders of pregnancy, or gestational diabetes/impaired glucose tolerance had a higher mortality risk in the ≈50 years after pregnancy.

  • Black pregnant participants had an increased risk for some pregnancy complications, and in some instances, the mortality risk conferred from pregnancy complications was higher in Black compared with White individuals.

What Are the Clinical Implications?

  • An important piece of this research is extending the concept of lifelong health implications of pregnancy complications to include Black participants, for whom a greater risk for major pregnancy complications and earlier mortality is present.

  • Greater efforts are needed to alleviate racial disparities in cardiovascular and diabetes screenings among individuals with a history of pregnancy complications.

Major progress has been made in understanding the implications of pregnancy complications for the long-term health of pregnant women. In 2021, the American Heart Association (AHA) released a statement that adverse pregnancy outcomes, such as hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, small-for-gestational-age delivery, pregnancy loss, and placental abruption, should be considered when evaluating the cardiovascular disease risk in patients with a pregnancy history.1 However, much of the focus has been on later cardiovascular health, even though there is some additional evidence suggesting that pregnancy complications are associated with increased risk of other chronic diseases, including diabetes and kidney disease, with mixed findings for dementia.2–9 Additionally, few studies have had long-term follow-up, limiting outcomes to those that develop in midlife rather than later in life, as well as mortality.

There remains a substantial racial disparity in the research related to adverse pregnancy outcomes and long-term health. As noted in the AHA statement, most of the evidence base related to cardiovascular health is from studies comprising 80% to 95% White individuals.1,10 Although race is a social construct, and there are no biological hypotheses to suggest that the effects of pregnancy complications differ between White and non-White patients, there may be differences in health care access, treatment, and monitoring, leading to differential effect sizes, which, in turn, may contribute to the racial disparities in chronic diseases and related mortality.11,12 Additionally, non-White pregnant individuals are at increased risk for developing pregnancy complications and have a higher burden of chronic disease(s) and early mortality than White pregnant individuals.10,13 Yet, only a few studies have evaluated whether adverse pregnancy complications differentially contribute to the greater incidence of chronic disease and earlier mortality observed in historically marginalized populations. For instance, in studies from the Women’s Health Initiative, conducted mostly on White (62–82%) participants, there was no difference by race in the associations between adverse pregnancy outcomes and cardiovascular end points, although inferences of the findings were hindered by the small number of non-White participants.14,15 In another report from the California Child Health and Development Studies, gestational hypertension was associated with an increase in the risk for cardiovascular disease among Black participants only.16 Nonetheless, there is clearly an unmet level of representation of non-White participants in research on the long-term health implications of pregnancy complications.

Through analysis of a large, well-characterized cohort that included approximately half Black and half White pregnant participants, our study aimed to investigate common pregnancy complications in association with total and cause-specific mortality >50 years after the index pregnancy.

Methods

Setting

The Collaborative Perinatal Project (CPP) was a prospective cohort study of 48 197 pregnant participants, with 58 760 pregnancies at 12 US clinical centers from 1959 to 1966. Details of the cohort are described previously.17–19 For the 8772 (18.2%) participants who had >1 pregnancy recorded in study records, the last pregnancy in the CPP was considered the index pregnancy for this analysis, as it represented the latest point of follow-up for each participant. In 2017, the CPP Mortality Linkage Study was conducted to ascertain vital status of participants as of December 31, 2016.20 Vital status was ascertained through linkages to the National Death Index (NDI) and the Social Security Death Master File (SSDMF).

There were no institutional review boards or rules for use of human subjects at the CPP inception during the late 1950s, but a general informed consent for participation was obtained. Institutional review board approval was obtained for the CPP Mortality Linkage Study by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Emmes Corporation, which performed the abstraction of identifying information from historic CPP records and facilitated the linkages. CPP data are publicly available at https://www.archives.gov/research/electronic-records/nih.html (National Archives Identifier: 606622). Because of privacy concerns, mortality data were not publicly available. Researchers interested in the linked mortality data should contact the Eunice Kennedy Shriver National Institute of Child Health and Human Development for data-sharing agreement details.

Exposure Ascertainment

At the first pregnancy visit, a physical exam was performed, and information on demographics, medical history, socioeconomic status, and behavior were collected via interviews. Participants were followed throughout pregnancy, providing repeat interviews and physical exams. Upon admission to labor and delivery, a trained observer recorded labor and delivery, postpartum, and neonatal events.

Gestational age was defined according to the date of the last menstrual period. Deliveries ≥20 and <37 completed weeks were classified as preterm. Preterm subtypes were further classified according to the following algorithm: preterm deliveries with recorded spontaneous labor onset were included in the “preterm spontaneous labor” category; preterm deliveries with premature rupture of the membranes (PROM) were included in the “preterm PROM” category; preterm deliveries with recorded induction of labor were included in the “preterm induced labor” category; preterm deliveries without record of spontaneous labor, PROM, or induction that were delivered by cesarean were categorized as “preterm prelabor cesarean”; and all other preterm deliveries were categorized as “preterm unknown reason.”

Hypertensive disorders were classified according to current clinical definitions.21 Chronic hypertension was classified if reported on the past medical history or obstetric diagnostic summary, or if blood pressure at <20 weeks gestation was elevated (ie, ≥2 readings of systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg). Gestational hypertension was classified as new-onset blood pressure elevation at ≥20 weeks gestation. Preeclampsia or eclampsia was classified as the presence of gestational hypertension with any of the following: proteinuria (≥20 weeks gestation dipstick readings of 1+ or recorded on obstetric summary), headache or visual disturbance within 1 week of delivery, pulmonary edema, or eclampsia documented on the delivery report or obstetric diagnostic summary. Superimposed preeclampsia or eclampsia was defined as preeclampsia or eclampsia in the presence of chronic hypertension.

Prepregnancy diabetes (type not specified) was identified from either the past medical history, the obstetric summary, or documented insulin use before pregnancy. Gestational diabetes was defined using any of the following criteria in the absence of prepregnancy diabetes: (1) ≥2 abnormal plasma glucose values on the 3-hour glucose tolerance test during pregnancy according to the currently adopted Carpenter and Coustan criteria22; (2) documented insulin use during pregnancy; or (3) documented severe diabetic conditions, including diabetic coma or ketoacidosis first recognized in pregnancy. Impaired glucose tolerance was defined as any of the following criteria in the absence of prepregnancy diabetes and gestational diabetes: (1) checked box for “diabetes during pregnancy” or “abnormal glucose tolerance test during pregnancy” (without record of the values) documented on the obstetric diagnosis summary; (2) fasting plasma glucose during pregnancy ≥95 mg/dL; (3) any blood glucose during pregnancy ≥200 mg/dL22; or (4) 1, but not 2, abnormal plasma glucose values on the glucose tolerance test during pregnancy. Because few participants met the criteria for gestational diabetes, “any glucose intolerance in pregnancy” was defined by grouping gestational diabetes with impaired glucose tolerance. A glucose tolerance test (63% oral glucose and 37% IV glucose) was performed during pregnancy for 1340 (2.8%) participants.

Outcome Ascertainment

Follow-up time was calculated from the year of the index CPP pregnancy through 2016 or the recorded year of death. Deaths that occurred during pregnancy or immediately postpartum before discharge were recorded on the obstetric forms. All-cause mortality was defined as a death recorded in the NDI, augmented by the SSDMF if there was not a match with the NDI; 89% of the deaths were sourced from the NDI, which is more accurate than the SSDMF.20,23 Participants without death recorded by December 31, 2016, were censored.

Underlying causes of death were obtained from the NDI, which defines underlying causes of death in accordance with recommendations of the World Health Organization and the International Conference for the Ninth Revision of the International Classification of Diseases as “(a) the disease or injury which initiated the train of events leading directly to death, or (b) the circumstances of the accident or violence which produced the fatal injury.”24,25 These coding decisions are automated based on international coding rules. Causes of death were coded according to the International Classification of Diseases, 9th revision (ICD-9) codes for deaths occurring between 1979 and 1998 and according to the International Classification of Diseases, tenth revision (ICD-10) codes for deaths occurring between 1999 and 2016 (Table S1). Underlying causes of death were grouped according to ICD-10 codes and comparable ICD-9 codes.26 There were 10 cause-of-death categories26: cardiovascular disease, cancer, diabetes, respiratory disease (pneumonia, influenza, chronic obstructive pulmonary disease, and allied conditions), infections (other than pneumonia or influenza), dementia, kidney disease, chronic liver disease, accidents, suicide, and other causes. The dementia category of death was based on the Centers for Disease Control and Prevention definition of dementia mortality, which includes deaths attributable to Alzheimer disease, unspecified dementia, vascular dementia, and other degenerative diseases of the nervous system, not classified elsewhere.27 Cardiovascular disease was further classified into hypertensive disease, ischemic heart disease, arrhythmia, heart failure, cerebrovascular disease, and atherosclerosis or other diseases of the arteries.26

Covariate Ascertainment

Covariates were collected from participants during study enrollment via in-person interviews and defined based on the index pregnancy and included age, smoking status, race and ethnicity (Black, Puerto Rican, other, or White; self-reported), prepregnancy body mass index (in kg/m2), previous pregnancies (0, 1, 2, 3, or ≥4), marital status (single, married/common law, or other), family income (≤$1999, $2000–3999, $4000–5999, $6000–7999, $8000–9999, or ≥$10 000), education (less than high school, some high school, high school graduate, or some college), previous medical conditions, site, and year. Details on the covariates, their definitions, and functional form are included in Table S2.

Statistical Methods

Participant characteristics at the index pregnancy were compared across categories of diabetes, preterm delivery, and hypertensive disorders in pregnancy using χ2 tests for categorical variables and ANOVA for continuous variables. Missing data on exposures (1–10%), covariates (<1–12%), and causes of death identified by the SSDMF (4%) were multiply imputed using chained equations under the missing at random assumption.28 For each of the 50 imputed data sets, the regression models were estimated, and the results were combined using the Rubin rule.29

Separate models were estimated for each exposure. We previously compared a standard Cox regression model and modified Cox regression with a double-censoring approach that assumed that nonmatched participants could be either right-censored in 2016 (still alive) or left-censored between index pregnancy and 1979 (deceased before 1979), and the results were nearly identical; therefore, the current study utilized a standard Cox regression model.20,30 Cox proportional hazards regressions estimated the hazard ratios (HRs) of mortality in association with each exposure, for which the all-cause and cause-specific hazard models were both fitted. The cause-specific hazard, which accounted for the competing risks of deaths attributable to different causes, is interpreted as the instantaneous risk of dying from the cause of interest among the participants who were alive. The cumulative incidence functions were calculated from all-cause Cox models. Then, risk differences were estimated at 50 years after the index pregnancy by taking the differences of cumulative incidence functions among exposure groups. Risk differences were estimated for all-cause mortality only because, in general, we have less power with risk differences than HRs, and this is exacerbated with the cause-specific associations. Additionally, for preterm birth, we restricted the analysis to pregnancies lasting ≥20 weeks. For all-cause mortality, we utilized inverse probability weights to control for potential selection bias introduced by this restriction.31 Weights included all covariates for the main models.

Effect modification by race was examined and tested by fitting models with the individual exposure category, race, and an interaction term between the exposure of interest and race.12 Only participants who were White or Black were included for these analyses because of small sample sizes in the other groups. A sensitivity analysis examined whether pregnancies affected by hypertensive disorders were delivered preterm (<37 weeks) or at term (≥37 weeks). Statistical significance was defined as P<0.05, and all tests were 2-sided. Analyses were conducted using SAS version 9.4 (SAS Institute) and R.

RESULTS

The CPP cohort included 48 197 pregnant participants. Those who died during the index CPP pregnancy were excluded (n=9) to focus on postpregnancy mortality. Participants without identifiable information who were unable to be submitted for vital status linkage were excluded from the analysis (n=1637 [3.4%]). The final analysis included 46 551 participants (Figure S1).

The majority of study participants were either Black (45%) or White (46%; Table 1). Black participants were younger than White participants at the index pregnancy, less likely to have had a previous pregnancy, more likely to have obesity, more likely to be single, had lower incomes, less attained education, and were more likely to have cardiovascular conditions before pregnancy than White participants. Detailed distributions of the participant characteristics across pregnancy complications are shown in Tables S3 to S5.

Table 1. Participant Characteristics of the Collaborative Perinatal Project Mortality Linkage Study

Characteristic at index pregnancyOverall
(n=46 551)
Black (n=21 107 [45%])White (n=21 502 [46%])Puerto Rican (n=3462 [7%])Other*
(n=480 [1%])
Age, y24.5±6.224.0±6.425.1±6.023.7±5.425.8±5.5
Previous pregnancies
 012 372 (27)5346 (26)5921 (29)935 (27)170 (36)
 19590 (21)4057 (20)4612 (23)807 (23)114 (24)
 27115 (16)3103 (15)3338 (16)606 (18)68 (15)
 35102 (11)2359 (11)2311 (11)399 (12)33 (7)
 ≥410 986 (24)5916 (28)4294 (21)694 (20)82 (18)
Prepregnancy body mass index
 <18.5 kg/m23838 (9)1713 (9)1754 (10)298 (10)73 (18)
 18.5–24.9 kg/m228 212 (69)12 848 (65)12 992 (72)2099 (69)273 (69)
 25.0–29.9 kg/m26336 (15)3505 (18)2285 (13)514 (17)32 (8)
 ≥30.0 kg/m22761 (7)1680 (9)911 (5)152 (5)18 (5)
Marital status
 Single6953 (15)5487 (26)1167 (5)257 (7)42 (9)
 Married/common law35 539 (76)13 305 (63)18 733 (87)3099 (90)402 (84)
 Other4054 (9)2313 (11)1599 (7)106 (3)36 (8)
Smoking
 Nonsmoker24 030 (53)11 958 (58)9395 (46)2371 (69)306 (66)
 <1 pack/day14174 (32)7212 (35)6006 (30)843 (25)113 (24)
 ≥1 pack/day6728 (15)1599 (8)4871 (24)213 (6)45 (10)
Annual income
 ≤$19995935 (14)4013 (21)1681 (9)185 (6)56 (13)
 $2000–399918 465 (44)9703 (51)6345 (34)2254 (68)163 (39)
 $4000–599910 187 (24)3622 (19)5737 (30)700 (21)128 (31)
 $6000–79994443 (11)1268 (7)2949 (16)172 (5)54 (13)
 $8000–99991584 (4)362 (2)1189 (6)21 (<1)12 (3)
 ≥$10 0001127 (3)157 (<1)959 (5)7 (<1)4 (1)
Education
 Less than high school8093 (18)3900 (19)2638 (13)1487 (44)68 (15)
 Some high school17 319 (39)9590 (47)6254 (32)1353 (40)122 (27)
 High school graduate13 259 (30)6027 (29)6641 (34)518 (15)73 (16)
 Some college5453 (12)1056 (5)4169 (21)47 (1)181 (41)
Previous medical conditions
 Cardiovascular diseases5414 (12)2894 (14)2283 (11)186 (5)51 (11)
 Respiratory diseases3463 (8)1489 (7)1545 (7)369 (11)60 (13)
 Renal diseases3961 (9)1813 (9)2041 (10)77 (2)30 (6)
 Neurologic diseases§4572 (10)1657 (8)2676 (13)192 (6)47 (10)
 Cancer and tumors#1767 (4)655 (3)1064 (5)38 (1)10 (2)
 Diabetes742 (2)191 (<1)524 (3)23 (<1)4 (<1)
Delivery**
 Elective or spontaneous abortion700 (2)268 (1)385 (2)41 (1)6 (1)
 Preterm spontaneous labor5688 (13)3704 (18)1405 (7)540 (17)39 (9)
 Preterm PROM298 (<1)153 (<1)125 (<1)18 (<1)2 (<1)
 Preterm induced labor149 (<1)50 (<1)90 (<1)8 (<1)1 (<1)
 Preterm prelabor cesarean delivery252 (<1)55 (<1)179 (<1)8 (<1)1 (<1)
 Preterm reason unknown366 (<1)183 (<1)142 (<1)37 (<1)4 (<1)
 Term36 516 (83)15 875 (78)17 637 (88)2617 (80)387 (88)
Hypertensive disorders of pregnancy
 Normotensive41 966 (91)18 749 (89)19 396 (93)3365 (97)456 (96)
 Chronic hypertension1776 (4)1164 (6)579 (3)28 (<1)5 (1)
 Gestational hypertension775 (2)291 (1)462 (2)18 (<1)4 (<1)
 Preeclampsia/eclampsia453 (1)201 (1)232 (1)18 (<1)2 (<1)
 Superimposed927 (2)642 (3)253 (1)25 (<1)7 (1)
Diabetes
 Normoglycemic44 608 (97)20 589 (98)20 152 (96)3403 (98)464 (98)
 Prepregnancy diabetes742 (2)191 (1)524 (3)23 (<1)4 (<1)
 Gestational diabetes, impaired glucose tolerance540 (1)263 (1)242 (1)29 (<1)6 (1)

Data presented as mean±SD for continuous variables or n (%) for categorical variables. Missing data: age (n=2), previous pregnancy (n=1386); prepregnancy body mass index (n=5404), marital status (n=5), smoking (n=1619), income (n=4810), education (n=2427), previous medical conditions (cardiovascular diseases [n=717], respiratory diseases [n=717], renal diseases [n=717], neurological diseases [n=717], cancer and tumors [n=717], and diabetes [n=661]), preterm delivery (n=2592), and hypertensive disorders of pregnancy (n=654). PROM indicates premature rupture of membranes.

* The “other” category includes participants self-reporting race and ethnicity as Asian or “other.”

† Including hypertension, rheumatic fever, and any other cardiovascular diseases.

‡ Including tuberculosis, asthma, other chronic pulmonary diseases, and other conditions requiring thoracic surgery.

ǀǀ Including pyelitis, glomerulonephritis, and other conditions requiring kidney, urinary, or bladder surgery.

§ Including neuromuscular diseases, convulsive disorders, psychosis, alcohol or drug addiction, or other neurological diseases.

# Including any history of cancer, or gastrointestinal, kidney, urinary, bladder, or gynecological tumors.

** Elective and spontaneous abortions, <20 weeks’ gestation; preterm deliveries, 20 to <37 weeks gestation; term deliveries, ≥37 weeks gestation.

The median time between the index pregnancy and death or censoring as of 2016 was 52 years (interquartile range, 45–54), for a total of 2 229 721 person-years. As of 2016, 18 170 (39%) deaths were observed (Table 2). Mortality was higher among Black compared with White participants (41% versus 37%). Across all the race and ethnic groups, the top 2 leading causes of death were cardiovascular disease (27% to 34% of total deaths) and cancer (24% to 34% of total deaths).

Table 2. All-Cause and Underlying Cause–Specific Mortality by Race and Ethnicity in the Collaborative Perinatal Project Mortality Linkage Study

Overall
(n=46 551)
Black participants
(n=21 107 [45%])
White participants
(n=21 502 [46%])
Puerto Rican participants (n=3462 [7%])Other* participants
(n=480 [1%])
All deaths18 124 (39)8714 (41)8019 (37)1241 (36)150 (31)
Major causes of cause-specific deaths
 Cardiovascular4914 (31)2604 (34)1912 (27)356 (33)42 (31)
 Cancer5094 (32)2325 (30)2455 (34)268 (24)46 (34)
 Diabetes790 (5)435 (6)279 (4)67 (6)9 (7)
 Respiratory1245 (8)401 (5)760 (11)76 (7)8 (6)
 Dementia574 (4)333 (4)171 (2)65 (6)5 (4)
 Infection581 (4)238 (3)304 (4)35 (3)4 (3)
 Kidney348 (2)229 (3)105 (1)11 (1)3 (2)
 Other219 (1)105 (1)73 (1)36 (3)5 (4)
Cardiovascular-specific causes
 Hypertensive diseases485 (3)349 (5)4 (3)41 (4)91 (1)
 Ischemic heart disease2191 (14)1029 (13)18 (13)189 (17)955 (13)
 Arrhythmia287 (2)155 (2)1 (1)14 (1)117 (2)
 Heart failure281 (2)139 (2)3 (2)9 (1)130 (2)
 Cerebrovascular902 (6)522 (7)9 (7)63 (6)308 (4)

Data expressed as n (%). Data reflect pregnancies from 1959 to 1965; vital status ascertainment through 2016.

*“ Other” category included pregnant participants who checked the “other” category as well as those who identified as Asian.

Overall, 15% of pregnancies were delivered preterm (13% preterm spontaneous labor; <1% preterm PROM; <1% induced labor; <1% preterm prelabor cesarean delivery; and <1% preterm reason unknown). The proportion of spontaneous preterm deliveries differed substantially between Black (18%) and White participants (7%); no differences were observed for other preterm deliveries (<1% in both Black and White participants). All preterm deliveries, except for those with an unknown cause, were associated with an increased adjusted all-cause mortality. Compared with term births (≥37 weeks), the adjusted HRs for preterm spontaneous labor, preterm PROM, preterm induced labor, preterm prelabor cesarean delivery, and preterm reason unknown were 1.07 (95% CI, 1.03–1.12), 1.23 (1.05–1.44), 1.31 (1.03–1.66), 2.09 (1.75–2.48), and 0.92 (0.79–1.07), respectively, with corresponding risk differences of 1.5 (−0.6 to 3.6), 4.5 (0.3–8.7), 6.0 (−0.1 to 12.1), 19.1 (13.2–25.1), and −1.7 (−5.1 to 1.7) deaths per 100, respectively (Table 3). The P value for interaction the between Black and White race and preterm delivery was P=0.009 (Table S6). There was no major difference in the HRs for preterm spontaneous labor and preterm PROM, whereas for preterm induced labor, the mortality association was slightly stronger among Black participants, and for preterm prelabor cesarean delivery, the mortality association was stronger for White participants. For participants with a spontaneous preterm delivery, the increased mortality risk was generally because of an increase in cardiovascular disease mortality (HR, 1.18 [1.09–1.28]). For participants with preterm PROM, the increased mortality risk was generally attributable to the increased mortality from cardiovascular disease (HR, 1.37 [1.04, 1.80]) and diabetes (HR, 1.83 [0.98, 3.41]). Comparatively, for participants with preterm induced labor, a heightened mortality risk was observed with kidney disease (HR, 5.22 [2.14, 12.75)], diabetes (HR, 4.20 [2.25, 7.83]), and cardiovascular disease (HR, 1.74 [1.19, 2.54]). For participants with preterm prelabor cesarean delivery, a heightened mortality risk was observed with diabetes (HR, 5.39 [3.41, 8.52]), kidney disease (HR, 3.53 [1.43, 8.68]), cardiovascular disease (HR, 2.80 [2.19, 3.58]), and respiratory disease (HR, 1.80 [1.02, 3.18]).

Table 3. Associations of Preterm Delivery and Long-Term All-Cause and Cause-Specific Underlying Mortality of the Collaborative Perinatal Project Mortality Linkage Study

Reason for preterm delivery
TermSpontaneousPROMInducedPrelabor cesarean deliveryUnknown
All-cause mortality
 Total, n (%)*14 814 (38.2)2353 (41.4)162 (54.4)75 (50.3)174 (71.9)261 (38.0)
 Risk difference per 100 (95% CI), unadjusted0 Reference2.9 (1.7–4.2)15.4 (10.2–20.7)12.3 (4.7–19.8)34.1 (28.3–39.9)−0.4 (−4.2 to 3.4)
 Risk difference per 100 (95% CI), adjusted0 Reference1.5 (−0.6 to 3.6)4.5 (0.3–8.7)6.0 (−0.1 to 12.1)19.1 (13.2–25.1)−1.7 (−5.1 to 1.7)
 HR (95% CI), unadjusted1 Reference1.11 (1.07–1.16)1.67 (1.43–1.94)1.51 (1.20–1.90)2.80 (2.39–3.27)0.98 (0.85–1.14)
 HR (95% CI), adjusted1 Reference1.07 (1.03–1.12)1.23 (1.05–1.44)1.31 (1.03–1.66)2.09 (1.75–2.48)0.92 (0.79–1.07)
Cause-specific mortality, adjusted HR (95% CI)
 Major causes
  Cancer1 Reference1.05 (0.97–1.14)1.07 (0.79–1.45)0.94 (0.57–1.54)1.34 (0.95–1.90)0.89 (0.68–1.16)
  Cardiovascular1 Reference1.18 (1.09–1.28)1.37 (1.04–1.80)1.74 (1.19–2.54)2.80 (2.19–3.58)1.01 (0.79–1.30)
  Diabetes1 Reference1.06 (0.86–1.31)1.83 (0.98–3.41)4.20 (2.25–7.83)5.39 (3.41–8.52)1.07 (0.58–2.00)
  Respiratory1 Reference1.05 (0.88–1.25)1.41 (0.83–2.39)0.24 (0.03–1.74)1.80 (1.02–3.18)0.98 (0.56–1.72)
  Dementia1 Reference0.89 (0.67–1.19)0.52 (0.17–1.63)1.02 (0.25–4.08)1.05 (0.39–2.83)0.61 (0.24–1.55)
  Infection1 Reference1.05 (0.83–1.33)1.27 (0.53–3.01)1.11 (0.28–4.45)1.90 (0.70–5.13)0.44 (0.13–1.52)
  Kidney1 Reference0.98 (0.71–1.35)1.32 (0.42–4.11)5.22 (2.14–12.75)3.53 (1.43–8.68)0.96 (0.38–2.43)
 Cardiovascular-specific causes
  Hypertensive diseases1 Reference1.34 (1.06–1.69)0.60 (0.15–2.38)1.63 (0.40–6.62)1.30 (0.32–5.23)0.87 (0.37–2.06)
  Ischemic heart disease1 Reference1.15 (1.02–1.31)1.30 (0.85–1.98)1.90 (1.12–3.24)3.86 (2.74–5.45)1.09 (0.77–1.54)
  Arrhythmia1 Reference0.99 (0.69–1.43)3.18 (1.49–6.76)4.44 (1.61–12.25)3.48 (1.39–8.72)0.87 (0.29–2.60)
  Heart failure1 Reference1.34 (0.94–1.89)1.29 (0.41–4.06)2.47 (0.91–6.76)1.13 (0.42–3.03)
  Cerebrovascular1 Reference1.06 (0.88–1.28)0.57 (0.21–1.52)1.41 (0.52–3.79)1.93 (0.95–3.91)0.59 (0.25–1.37)

Data reflect pregnancies from 1959 to 1965; vital status ascertainment through 2016. Elective and spontaneous abortions, <20 weeks gestation; preterm deliveries, 20 to <37 weeks gestation; term deliveries, ≥37 weeks gestation. HR indicates hazard ratio; and PROM, premature rupture of membranes.

* Cases and percentage based on imputed data.

† Models were weighted to control for potential selection bias introduced by restricting to pregnancies lasting ≥20 weeks.

‡ Analyses adjusted for the following index pregnancy variables: age, smoking, race and ethnicity, previous pregnancies, marital status, income, education, previous medical conditions (diabetes, cardiovascular, respiratory, renal, and neurological diseases, and cancer and tumors), site, year, and prepregnancy body mass index.

‖ HR could not be estimated because there were too few cases.

Overall, 4% of pregnancies were affected by chronic hypertension, 2% by gestational hypertension, 1% by preeclampsia or eclampsia, and 2% by superimposed preeclampsia or eclampsia. Black participants were more likely to have chronic hypertension (6% versus 3%) or superimposed preeclampsia or eclampsia (3% versus 1%) than White participants. Gestational hypertension, preeclampsia or eclampsia, and superimposed preeclampsia or eclampsia were associated with higher all-cause mortality adjusted HRs of 1.09 (0.97–1.22), 1.14 (0.99–1.32), and 1.32 (1.20–1.46), respectively, and corresponding excess risks of 1.7 (−1.2 to 4.7), 2.8 (−0.8 to 6.5), and 6.2 (3.1–9.3) deaths per 100 participants, respectively, compared with normotensive participants (Table 4). Gestational hypertension was associated with higher risks for cardiovascular and diabetes mortality. Preeclampsia was associated with higher risks for cardiovascular, diabetes, infection, and kidney disease mortality, albeit some of the estimates were imprecise because of the small sample for some of the specific causes of mortality. Finally, superimposed preeclampsia was associated with higher risks for cardiovascular and kidney disease mortality. The P value for an interaction between Black and White participants was P=0.05 (Table S7); the mortality risk associated with preeclampsia appeared stronger for Black (HR, 1.33 [1.08, 1.63]) compared with White (HR, 1.00 [0.81, 1.23]) participants, whereas the risk associated with superimposed preeclampsia or eclampsia appeared stronger for White (HR, 1.50 [1.26, 1.79]) compared with Black (HR, 1.27 [1.13, 1.43]) participants. Sensitivity analyses were performed to classify hypertensive disorders of pregnancy according to preterm delivery status. The estimates were imprecise because of small numbers, but there was not a consistent pattern of increasing risk with preterm delivery and hypertensive disorders in pregnancy (Table S8). Notably, even among normotensive deliveries, preterm delivery was associated with an increase in all-cause mortality risk (HR, 1.12 [1.07–1.17]).

Table 4. Associations for Hypertensive Disorders of Pregnancy and Long-Term All-Cause and Cause-Specific Underlying Mortality of the Collaborative Perinatal Project Mortality Linkage Study

NormotensiveGestational hypertensionPreeclampsia/eclampsiaSuperimposed
preeclampsia/eclampsia*
All-cause mortality
 Total, n (%)15 978 (37.5)338 (42.6)218 (47.2)596 (63.8)
 Risk difference per 100 (95% CI)
  Unadjusted0 Reference5.4 (2.2–8.6)10.0 (5.8–14.2)27.0 (23.8–30.1)
  Adjusted0 Reference1.7 (−1.2 to 4.7)2.8 (−0.8 to 6.5)6.2 (3.1–9.3)
 Hazard ratio (95% CI)
  Unadjusted1 Reference1.22 (1.09–1.36)1.42 (1.24–1.62)2.33 (2.13–2.54)
  Adjusted1 Reference1.09 (0.97–1.22)1.14 (0.99–1.32)1.32 (1.20–1.46)
Cause-specific mortality, adjusted HR (95% CI)
Major causes
  Cancer1 Reference0.87 (0.69–1.09)0.79 (0.57–1.08)0.99 (0.81–1.20)
  Cardiovascular1 Reference1.34 (1.11–1.61)1.37 (1.09–1.72)1.61 (1.40–1.86)
  Diabetes1 Reference1.72 (1.16–2.56)2.44 (1.58–3.75)1.28 (0.90–1.82)
  Respiratory1 Reference0.69 (0.41–1.18)0.99 (0.56–1.74)0.90 (0.59–1.35)
  Dementia1 Reference1.14 (0.67–1.96)0.62 (0.23–1.66)0.83 (0.49–1.42)
  Infection1 Reference1.26 (0.71–2.22)1.81 (0.97–3.37)1.33 (0.81–2.19)
  Kidney1 Reference1.05 (0.49–2.26)1.99 (0.98–4.04)2.40 (1.53–3.77)
 Cardiovascular-specific causes
  Hypertensive diseases1 Reference1.34 (1.11–1.61)1.37 (1.09–1.72)1.61 (1.40–1.86)
  Ischemic heart disease1 Reference1.14 (0.54–2.42)1.68 (0.79–3.57)1.91 (1.26–2.91)
  Arrhythmia1 Reference1.48 (1.11–1.97)1.36 (0.94–1.96)1.76 (0.94–3.31)
  Heart failure1 Reference0.58 (0.19–1.81)1.01 (0.33–3.12)1.25 (0.61–2.56)
  Cerebrovascular1 Reference1.55 (0.78–3.07)0.71 (0.18–2.86)2.32 (1.39–3.88)

Data reflect pregnancies from 1959 to 1965; follow-up through 2016.

* Estimates for chronic hypertension not shown. Superimposed preeclampsia or eclampsia is preeclampsia or eclampsia with pre-existing chronic hypertension.

† Patients, expressed as n (%), based on imputed data.

‡ Analyses adjusted for the following index pregnancy variables: age, smoking, race and ethnicity, previous pregnancies, marital status, income, education, previous medical conditions (diabetes, cardiovascular, respiratory, renal, and neurological diseases, and cancer and tumors), site, year, and prepregnancy body mass index.

Overall, 1% of pregnancies were affected by gestational diabetes/impaired glucose tolerance (GD/IGT) with no difference between Black (1%) and White (1%) participants. GD/IGT was associated with an adjusted higher hazard of 1.14 (1.00–1.30) for all-cause mortality and a corresponding excess risk of 2.8 (−0.6 to 6.1) deaths per 100 compared with normoglycemic participants (Table 5). GD/IGT was associated with higher risks for diabetes, infection, and kidney disease mortality. There were no differences in the estimates for all-cause mortality between Black and White participants (P=0.92; Table S9).

Table 5. Associations for Gestational Diabetes/Impaired Glucose Tolerance in Pregnancy and Long-Term All-Cause and Cause Specific Underlying Mortality, Collaborative Perinatal Project Mortality Linkage Study

Normoglycemic*Gestational diabetes/impaired glucose tolerance
All-cause mortality
 Cases, n (%)17 359 (38.4)267 (49.0)
 Risk difference per 100 (95% CI)
  Unadjusted0 Reference11.3 (7.3–15.2)
  Adjusted0 Reference2.8 (−0.6 to 6.1)
 HR (95% CI)
  Unadjusted1 Reference1.47 (1.30–1.66)
  Adjusted1 Reference1.14 (1.00–1.30)
Cause-specific mortality, adjusted HR (95% CI)
 Major causes
  Cancer1 Reference0.93 (0.72–1.21)
  Cardiovascular1 Reference0.94 (0.74–1.20)
  Diabetes1 Reference3.12 (2.22–4.37)
  Respiratory1 Reference0.83 (0.47–1.47)
  Dementia1 Reference1.27 (0.70–2.32)
  Infection1 Reference1.79 (1.02–3.12)
  Kidney1 Reference2.13 (1.16–3.92)
 Cardiovascular-specific causes
  Hypertensive diseases1 Reference0.94 (0.74–1.20)
  Ischemic heart disease1 Reference0.27 (0.07–1.09)
  Arrhythmia1 Reference1.17 (0.83–1.66)
  Heart failure1 Reference0.91 (0.30–2.75)
  Cerebrovascular1 Reference1.13 (0.46–2.76)

Data reflect pregnancies from 1959 to 1965; follow-up through 2016.

* Estimates for preexisting diabetes not shown.

† Cases and percentage based on imputed data.

‡ Analyses adjusted for the following index pregnancy variables: age, smoking, race and ethnicity, previous pregnancies, marital status, income, education, previous medical conditions (diabetes, cardiovascular, respiratory, renal, and neurological diseases, and cancer and tumors), site, year, prepregnancy body mass index.

DISCUSSION

In this large cohort, consisting of almost half Black and half White pregnant participants from the 1950s through 1960s, those experiencing common pregnancy complications of preterm delivery, hypertensive disorders of pregnancy, or GD/IGT had an increased risk for mortality in the ≈50 years after pregnancy. Because much of the previous literature has been limited to primarily White populations, this article fills a critical data gap in the field of long-term implications of adverse pregnancy outcomes by using a diverse cohort and examining for potential heterogeneity in associations by race. Black individuals have a higher risk for pregnancy complications and earlier mortality, and in some instances, the mortality risks conferred from pregnancy complications were higher in Black compared with White individuals.

Preterm delivery was related to increased mortality. Interestingly, the risk differed according to the reason for the preterm delivery, the risk was highest in individuals with preterm prelabor cesarean delivery. Whereas preterm deliveries attributable to spontaneous labor were associated with an increased risk for cardiovascular mortality, preterm deliveries attributable to other reasons were also associated with mortality resulting from additional causes, including diabetes and kidney and respiratory diseases. Preterm delivery may contribute to disparities in earlier mortality. Preterm deliveries attributable to induced labor were associated with greater mortality risk among Black compared with White participants. Additionally, even as the mortality risk associated with spontaneous labor was similar for Black and White participants, the incidence was substantially higher for Black compared with White pregnant participants (19% versus 8%), also contributing to disparities in premature mortality.12 Our findings advance previous work by extending the follow-up period to >50 years and by including a diverse population. Previous cohort studies on preterm and all-cause or cardiovascular mortality were based on primarily White populations and had follow-up times ranging from only 14 to 25 years.16,32–34 We have demonstrated that the etiology of the differing types of preterm delivery contributes to substantially different mortality risks, especially when considering causes of mortality outside of cardiovascular disease, which is consistent with the few previous studies that have also separated by indication.32,34 The observed association of an increased risk for diabetes and kidney disease mortality with preterm induced labor and prelabor cesarean deliveries is consistent with previous studies, although these studies examined morbidity and not mortality.5,6,35 More research is needed to expand the understanding of preterm delivery on outcomes beyond cardiovascular disease, particularly in cohorts that are not primarily comprised of White participants only. Finally, while indications for preterm delivery have changed since the participants in this study were pregnant, we observed adverse associations with spontaneous preterm delivery as well. Our findings highlight the importance of understanding the etiology of the preterm delivery when considering future risk of complications.

In general, hypertensive disorders of pregnancy were associated with an increased risk of all-cause mortality, with the associations strongest for superimposed preeclampsia or eclampsia. Our findings are consistent with reports of hypertensive disorders of pregnancy and increased mortality risks—specifically cardiovascular disease mortality—among cohorts of predominantly White participants.4 Importantly, we extend these studies with the inclusion of a cohort that was composed of >50% non-White participants. Another previous study also evaluated for an interaction between hypertensive disorders of pregnancy and prepregnancy hypertension status and race and ethnicity for all-cause mortality, but they were limited to a follow-up of only ≤5 years after pregnancy.36 They found a stronger association for hypertensive disorders of pregnancy (combined) among non-Hispanic Black compared with non-Hispanic White and similar associations for prepregnancy hypertension in the presence of hypertensive disorders of pregnancy. We observed that preeclampsia or eclampsia may be associated with a greater mortality risk in Black compared with White pregnant participants. Moreover, the 3-fold higher incidence of superimposed preeclampsia or eclampsia during pregnancy in Black compared with White pregnant participants also signals that disparities in pregnancy health may have lifelong implications for earlier mortality.

GD/IGT in pregnancy was associated with an increased all-cause and cause-specific mortality attributable to diabetes, infection, and kidney disease. There was no difference in the incidence or size of the associations between Black and White individuals. Although the relationship between gestational diabetes and future development of cardiovascular disease, type 2 diabetes, and kidney disease is well reported, few studies have examined long-term mortality risks.4,37,38 Interestingly, while gestational diabetes has been associated with future cardiovascular morbidity, we did not observe an association with cardiovascular end points as the underlying cause of mortality. The lack of research on mortality associated with gestational diabetes corresponds with the shorter follow-up time observed in many of the previous studies. During the CPP study period (1959–1966), gestational diabetes was lower than currently observed, which may be largely attributable to a lack of major risk factors (eg, obesity) and inconsistent screening practices.39 In addition, the criteria for diagnosis differed from current guidelines. Nevertheless, these findings further demonstrate the long-term implications of glucose intolerance in pregnancy, reinforcing the importance of current measures screening for type 2 diabetes in the postpartum period after gestational diabetes, enabling earlier diagnosis and disease management.40

The major strength of this study was its racial and socioeconomic diversity: the cohort was nearly equally split among Black and White participants. There is a dearth of diversity in the existing studies on pregnancy complications and long-term morbidity and mortality. The size of the cohort was also a strength, as it allowed us to not only report the associations overall, but also to examine for interactions between race and pregnancy complications. An additional strength of this study was the long-term follow-up (median, 52 years). When interpreting the findings, it is important to remember that they represent the underlying cause of death and not a contributing cause of death, an important distinction, as these are mutually exclusive mortality categories that do not represent the overall prevalence of disease in participants. More research into the contributing causes of death and coexisting morbidities is warranted. Additionally, because this study stemmed from a well-characterized prospective pregnancy cohort, we were able to adjust for important confounders, such as prepregnancy body mass index and previous medical conditions, that have been missing from many previous studies. We cannot distinguish whether the pregnancy complications cause harm that put individuals at a greater risk for disease later in life or whether these individuals were more prone to pregnancy complications attributable to unmeasured causes. Thus, these pregnancy complications should be regarded as predictive factors and not necessarily causal factors for morbidity and mortality.

There are also limitations to this work. First, the participants were pregnant in the 1950s to 1960s. As expected, the prevalence of pregnancy complications, as well as risk factors such as obesity and smoking, differ from the current obstetric setting.41 Nonetheless, long-term mortality is a critical outcome that is, by definition, impossible to study in a current obstetric cohort. To address this limitation, and importantly, to make our findings more relevant to current clinical practice, we utilized the well-documented data on blood pressure in pregnancy and proteinuria to apply the current definitions of preeclampsia/gestational hypertension. Additionally, there was less obstetrical intervention in the 1950s and 1960s, with fewer inductions and planned cesareans deliveries, highlighting an advantage of using the CPP. In modern obstetrics, the iatrogenic earlier deliveries lead to less time in which pregnancy complications such as preeclampsia can develop; the CPP enabled us to more fully explore those relationships. Because of the different clinical definitions for gestational diabetes, we conservatively labeled this variable as “gestational diabetes or impaired glucose tolerance” to avoid overgeneralizing that these were directly comparable to the current obstetric setting. Also, because of the likely low-true incidence of gestational diabetes (attributable to lower prevalence of obesity) and low, potentially underreported rates of gestational diabetes (attributable to limited surveillance), we did not have a large enough sample size to evaluate risk for GD/IGT separately. This analysis was based on only a single pregnancy. Future studies including complete pregnancy histories may examine the “dose–response” of experiencing pregnancy complications in more than one pregnancy. Finally, there may be misclassification of deaths because of linkages with the NDI and SSDMF. Of those classified as deceased, 89% were sourced from the NDI. We previously found that there was good agreement between the NDI and vital status determined by review from an expert genealogist (κ=0.66 [95% CI, 0.61–0.70]).20,42 With bias estimates informed by expert genealogist review,20 we used the quantitative bias analysis tools for outcome misclassification from Fox et al,43 and estimate that this misclassification may have biased our findings slightly toward null.

Pregnancy has been regarded as a stress test that can unveil those who are at increased risk for chronic diseases in the future.44 Alternatively, pregnancy complications themselves may cause vascular dysfunction that may lead to lifelong health impacts.45 Irrespective of the mechanisms, current efforts are focused on educating pregnant and postpartum individuals and their health care professionals, particularly in primary care, to recognize the risks associated with pregnancy complications.1 An important piece of this research is extending this concept of lifelong health implications from pregnancy complications to a cohort that was nearly half comprised of Black individuals—those often at greater risk for major pregnancy complications. Significant efforts are needed, particularly toward alleviating racial disparities in cardiovascular and diabetes screenings, among patients with a history of pregnancy complications.46

Article Information

Supplemental Material

Tables S1–S9

Figure S1

Nonstandard Abbreviations and Acronyms

aHR

adjusted hazard ratio

CPP

Collaborative Perinatal Project

GD/IGT

gestational diabetes/impaired glucose tolerance

NDI

National Death Index

PROM

premature rupture of membranes

SSDMF

Social Security Death Master File

Disclosures None.

Footnotes

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.122.062177.

For Sources of Funding and Disclosures, see page 1024.

Circulation is available at www.ahajournals.org/journal/circ

Correspondence to: Cuilin Zhang, MD, PhD, Yong Loo Lin School of Medicine, National University of Singapore, 12 Science Drive 2, Tahir Foundation Building 16-03E, Singapore 117549. Email

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