History of Pregnancy Loss and Risk for Higher Midlife Blood Pressure in Parous Females

Abstract

Introduction:

Pregnancy loss has been associated with later cardiometabolic conditions, potentially due to shared underlying etiology, but associations with midlife blood pressure (BP) remain unclear.

Methods:

We examined participants enrolled 1999–2002 in prospective Project Viva. At midlife ∼18 years after enrollment, we collected lifetime pregnancy history and measured BP. Exposures included any pregnancy loss or number of pregnancy losses. Outcomes were systolic and diastolic BP (SBP, DBP), and American Heart Association (AHA) BP categories. We performed multivariable regression adjusted for race and ethnicity, education, income, perceived body size at age 10 years, and age at outcome.

Results:

Of 623 participants, 33.7% reported pregnancy loss, 9.6% had elevated BP, and 34.8% had hypertension. Mean(±standard deviation) age was 50.7 ± 5.0 years, SBP 118.1 ± 15.6 mmHg, and DBP 74.8 ± 11.5 mmHg. In adjusted models, any pregnancy loss was associated with higher SBP (β = 2.25 mmHg, 95% confidence interval [CI]: −0.23, 4.78). Strongest associations with SBP were among those with first pregnancy loss ≥35 years (β = 5.58 mmHg, 95% CI: 1.76, 9.40 versus 0 pregnancy losses and first pregnancy <35 years). All associations with DBP were nonsignificant but similar in direction. For AHA outcomes, pregnancy loss was associated with higher risk for elevated BP (relative-risk ratio [RRR] = 2.93, 95% CI: 1.58, 5.43) but not with hypertension (RRR = 1.45, 95% CI: 0.95, 2.22) versus normotension. In models examining race and ethnicity, SBP was higher among non-Hispanic White and Hispanic individuals with pregnancy loss; non-Hispanic Black individuals had higher BP regardless of pregnancy loss status.

Conclusions:

History of pregnancy loss was associated with higher SBP and elevated BP category at midlife. These findings highlight reproductive history as an important consideration for cardiopreventive strategies and interventions.

Introduction

Hypertension is widespread, affecting 43% of females ≥20 years of age in the United States,¹ contributing to renal disease, coronary heart disease, and stroke.² Throughout the reproductive years, female adults tend to have lower rates of hypertension than males of the same age.³ However, these differences shift across the menopausal transition. Through the menopausal transition and after menopause, females experience a steeper increase in blood pressure (BP) than age-matched male counterparts⁴ and poorer hypertension control after age 65 years,^5,6 a divergence in management that may worsen with advancing age and lead to higher rates of cardiovascular disease in women.⁶

Newer evidence suggests sex-specific risk factors for hypertension exist, pointing to reproductive factors across the female lifecourse as important contributors to risk.⁷ Independent of traditional cardiovascular risk factors, history of pregnancy loss as miscarriage (<20 weeks) or stillbirth (≥20 weeks) has previously been associated with coronary heart disease and stroke.^7

–10 Estimates suggest that 20–30% of all pregnancies result in miscarriage,¹¹ and ∼80% of pregnancy loss occurs <13 weeks gestation—often before the pregnancy is identified.¹² Results from recent studies link both types of pregnancy loss with risk for elevated BP¹³ or hypertension,^9,13,14 and the risk for hypertension may be greater with late-term or recurrent (≥2) pregnancy loss.^13
–15 Further, risk for stillbirth may be higher for certain racial and ethnic groups: for people in the United States identifying as non-Hispanic Black, risk for stillbirth is more than twice the risk of non-Hispanic White counterparts.¹⁶ However, there is a lack of evidence describing associations of pregnancy loss with subsequent hypertension among different racial and ethnic groups.

Although pregnancy loss has previously been associated with diagnosed hypertension, to our knowledge no studies have predicted systolic and diastolic BP or risk for different categories of elevated BP according to the 2017 American Heart Association (AHA) guidelines. In addition, so far as we are aware, no studies have specifically examined these relationships in the context of race and ethnicity. Using longitudinal data from the Project Viva pregnancy cohort, we sought to examine associations of pregnancy loss history with midlife BP in parous females. We hypothesized that (1) a lifetime history of pregnancy loss would be associated with higher midlife systolic and diastolic BP, as well as risk for elevated BP and hypertension as defined by the AHA, and that (2) risk would be higher in non-Hispanic Black participants.

Methods

Study design and cohort

Project Viva, a prospective cohort, enrolled pregnant individuals <22 weeks gestation seeking prenatal care from Atrius Harvard Vanguard Medical Associates between 1999 and 2002 in the greater Boston area¹⁷ and continued following participants after pregnancies with a singleton live birth. The Midlife Visit occurred at ∼18 years postdelivery (mean age 50.7 years) (Table 1). Of the 2,100 original participants, 752 reported pregnancy history via questionnaire at midlife and 653 individuals also had BP measured (Fig. 1). We excluded participants missing either exposure (pregnancy loss) or outcome variables (BP). In addition, we excluded 30 participants with only one lifetime pregnancy since they would not have the potential for exposure, as livebirth of the index pregnancy was an inclusion criterion. A comparison of individuals included (n = 623) and excluded from analyses is provided in Supplementary Table S1. Participants included were less likely to have identified as non-Hispanic Black (14.1% versus 17.7%) or have ever smoked (27.0% versus 33.4%), but were more highly educated (74.6% versus 60.3% college graduates) and reported higher household income at enrollment (65.5% versus 58.7% with >$70,000). The Harvard Pilgrim Health Care Institutional Review Board approved study protocols and participants provided written informed consent at each study visit. This study followed STROBE reporting guidelines.

FIG. 1.

Participant flowchart.

Table 1.

Characteristics for Participants in Project Viva Included in Analyses, Overall and by Pregnancy Loss Status at Midlife

		Lifetime history of pregnancy loss
	Total	No	Yes^a
	Mean ± SD or n (%)
n (%)	623	413 (66.3)	210 (33.7)
Age at enrollment, years	32.4 ± 4.9	32.0 ± 5.0	33.3 ± 4.7
Age at midlife, years	50.7 ± 5.0	50.2 ± 5.0	51.6 ± 4.8
First pregnancy <35 years, n(%)	546 (88.1)	368 (89.1)	178 (86.0)
First pregnancy ≥35 years, n(%)	74 (11.9)	45 (10.9)	29 (14.0)
Age at first pregnancy loss, years	—	—	32.3 ± 5.7
Gravidity at midlife	3.4 ± 1.3	3.0 ± 1.1	4.2 ± 1.3
Prepregnancy BMI (kg/m²)	24.7 ± 5.1	24.7 ± 5.1	24.7 ± 5.1
Race and ethnicity^b
Non-Hispanic White	422 (67.9)	283 (68.7)	139 (66.2)
Non-Hispanic Black	88 (14.2)	57 (13.8)	31 (14.8)
Hispanic	58 (9.3)	37 (9.0)	21 (10.0)
Non-Hispanic Other	54 (8.7)	35 (8.5)	19 (9.1)
College graduate	463 (74.6)	297 (72.1)	166 (79.4)
Married or cohabitating	576 (92.8)	381 (92.5)	195 (93.3)
Household income, >$70,000/year	372 (65.5)	239 (63.9)	133 (68.6)
Smoking status, ever	168 (27.0)	113 (27.4)	55 (26.2)
Blood pressure medication at midlife	71 (11.4)	46 (11.1)	25 (11.9)
Baseline blood pressure, first trimester
Systolic blood pressure, mmHg	110.9 ± 8.8	110.8 ± 9.1	111.1 ± 8.2
Diastolic blood pressure, mmHg	69.4 ± 6.6	69.5 ± 6.8	69.2 ± 6.0
Midlife blood pressure
Systolic blood pressure,^c mmHg	117.0 ± 14.4	116.2 ± 14.4	118.5 ± 14.4
Adjusted systolic blood pressure,^d mmHg	118.1 ± 15.6	117.3 ± 15.6	119.7 ± 15.4
Diastolic blood pressure,^c mmHg	74.2 ± 11.0	73.9 ± 11.3	74.7 ± 10.3
Adjusted diastolic blood pressure,^d mmHg	74.8 ± 11.5	74.5 ± 11.9	75.3 ± 10.8
Midlife blood pressure category^e
Normotension	346 (55.5)	244 (59.1)	102 (48.6)
Elevated	60 (9.6)	29 (7.0)	31 (14.8)
Hypertension	217 (34.8)	140 (33.9)	77 (36.7)
Midlife blood pressure by race and ethnicity
Adjusted systolic blood pressure,^d mmHg
Non-Hispanic White	116.2 ± 14.0	114.8 ± 13.6	119.1 ± 14.5
Non-Hispanic Black	124.7 ± 18.8	126.1 ± 18.8	122.1 ± 18.7
Hispanic	120.0 ± 15.8	117.9 ± 14.7	123.6 ± 17.4
Non-Hispanic Other	119.3 ± 17.2	120.7 ± 18.7	116.8 ± 13.9
Adjusted diastolic blood pressure^d mmHg
Non-Hispanic White	73.3 ± 10.7	75.6 ± 10.7	74.9 ± 10.5
Non-Hispanic Black	79.8 ± 12.6	82.3 ± 12.8	75.2 ± 10.8
Hispanic	76.9 ± 12.4	75.4 ± 11.8	79.6 ± 13.2
Non-Hispanic Other	75.3 ± 12.5	75.8 ± 14.0	74.3 ± 9.4

BMI indicates body mass index.

Includes 195 miscarriages and 15 stillbirths.

Includes non-Hispanic Asian.

Measured blood pressure.

Includes adjusted BP if participant taking blood pressure-lowering medication: +10 mmHg for systolic and +5 mmHg for diastolic blood pressure.

Based on measured blood pressure; participants taking blood pressure-lowering medication included in hypertension category. Normotension: <120/80; elevated: systolic 120–129 and diastolic <80; Hypertension: systolic ≥130 and/or diastolic ≥80.

BP, blood pressure; SD, standard deviation.

History of pregnancy loss

At midlife, participants completed questionnaires about all past pregnancies (between 2 and 9 total). For each pregnancy, participants reported age, pregnancy outcome (singleton/twin live birth, miscarriage/stillbirth, induced abortion for any reason, or tubal/ectopic pregnancy), and gestational age at pregnancy outcome. Of 1,570 reported lifetime pregnancies, 948 (60.4%) occurred before Project Viva enrollment. We identified pregnancy loss as miscarriage <20 wk gestation and stillbirth if ≥20 weeks gestation. We categorized pregnancy loss as (1) any versus none or (2) one or recurrent (≥2) versus none. Supplementary Table S1 also provides a comparison of participants who experienced any pregnancy loss included in analyses (n = 210) versus excluded from analyses (n = 34). Minimal differences existed between those included versus excluded with a history of pregnancy loss, although those included were slightly younger at midlife (50.7 years versus 53.3 years), less likely to be non-Hispanic White (67.5% versus 76.5%) or to have ever smoked (26.8% versus 39.4%), and more likely to be a college graduate (75.3% versus 73.5%) or have a household income >$70,000 at enrollment (65.7% versus 63.3%).

Blood pressure and hypertension categories

At midlife, research assistants followed optimal research protocols to precisely measure BP in all participants. Individuals were fitted for the appropriate cuff and instructed not to speak or move during measurements. Five readings were recorded, each 1-minute apart, using the Omron HEM-907XL (Omron Healthcare, Inc., Lake Forest, IL) automated BP machine. We averaged measurements for data analysis. For participants who reported currently taking BP-lowering medication, we added a constant to averaged systolic (+10 mmHg) and diastolic (+5 mmHg) BP measures to account for the pharmacologic impact on participants’ BP (medication-adjusted BP).^18,19 BP readings were categorized according to the AHA BP guidelines as (1) normotension versus any elevated BP (≥120 mmHg systolic and ≥80 mmHg diastolic) and for a more granular examination (2) normotension, elevated BP (120–129 mmHg systolic/<80 mmHg diastolic), or any stage of hypertension (≥130 mmHg systolic and/or ≥80 mmHg diastolic). We included participants who reported taking BP-lowering medications in any elevated BP category for the binary outcome and the hypertension category for the ternary outcome.

Statistical analyses

We investigated associations between history of pregnancy loss with midlife BP in unadjusted models to examine overall associations, as well as adjusted models to put estimates in the context of other risk factors that may contribute to elevated BP. In fully adjusted models, we included covariates that have known relationships with BP: advancing age,^20
–22 income (>$70,000 at enrollment, yes/no), and educational attainment (college graduate at enrollment, yes/no) as markers of socioeconomic status,^23,24 smoking status (ever at enrollment, yes/no),^25,26 weight,^27,28 and race and ethnicity.^10,16 We did not adjust models for gravidity due to collinearity with history of pregnancy loss. Race and ethnicity were included in models as a marker of social and structural experiences, not biological differences. Since the Project Viva enrollment pregnancy may not have been the first pregnancy, and hence potentially downstream of our exposure, we did not adjust for prepregnancy body mass index (BMI) as an indicator of weight. Further, we did not adjust for midlife BMI in primary models because it may act as a mediator of the relationship between pregnancy loss and BP. Rather, since several systematic reviews provide evidence for the persistence of body size from childhood to adulthood,^29,30 we used perceived body size at age 10 years (underweight, healthy weight, overweight) that was collected via questionnaire at the Midlife Visit. In sensitivity analysis, we compared the use of prepregnancy or midlife BMI instead of this variable (described below).

In the primary models, we used multivariable linear regression to estimate associations between a prior history of pregnancy loss with measured midlife systolic or diastolic BP or medication-adjusted BP (Table 2). We examined unadjusted models followed by models adjusted for the covariate set previously described. For a more detailed examination of associations of pregnancy loss with systolic and diastolic BP, we examined pregnancy loss using (1) any pregnancy loss versus none, (2) one or recurrent pregnancy loss (≥2 pregnancy loss) versus none, and (3) any pregnancy loss versus none, stratified by age (<35 years versus ≥35 years) at first pregnancy with no pregnancy loss or first pregnancy loss (because risk for pregnancy loss increases starting at age 35 years).¹² The categories for the latter analysis included (1) <35 years at first pregnancy and no pregnancy loss (reference), (2) <35 years at first pregnancy loss, (3) ≥35 years at first pregnancy and no pregnancy loss, and (4) ≥35 years at first pregnancy loss.

Table 2.

Associations of History of Pregnancy Loss with Systolic or Diastolic Blood Pressure at Midlife (N = 623)

History of pregnancy loss	n	Systolic blood pressure,^a mmHg		Diastolic blood pressure,^a mmHg
		Unadjusted β (95% CI)	Adjusted β (95% CI)	Unadjusted β (95% CI)	Adjusted β (95% CI)
		Any history of pregnancy loss
0 Pregnancy losses	413	Referent (0)		Referent (0)
≥1 Pregnancy losses	210	2.46 (−0.12, 5.04)	2.25 (−0.29, 4.79)	0.86 (−1.05, 2.78)	0.73 (−1.15, 2.60)
Number of pregnancy losses
0 Pregnancy losses	413	Referent (0)		Referent (0)
1 Pregnancy loss	150	3.15 (0.24, 6.01)	2.77 (−0.08, 5.62)	1.44 (−0.71, 3.59)	1.11 (−0.99, 3.22)
≥2 Pregnancy losses	60	0.75 (−3.46, 4.96)	0.92 (−3.23, 5.06)	−0.57 (−3.69, 2.55)	−0.26 (−3.32, 2.80)

Values are β-coefficients (95% CI) for multivariable linear regression adjusted for race and ethnicity (Hispanic, non-Hispanic White, non-Hispanic Black, non-Hispanic other), education at enrollment (college graduate versus not), annual household income at enrollment (<or ≥$70,000), smoking status (ever), and perceived body size at 10 years of age (underweight, healthy weight, overweight).

Bold values indicate p < 0.05.

Includes corrected blood pressure for participants taking blood pressure-lowering medication: 10 mmHg was added to systolic blood pressure and 5 mmHg was added to diastolic blood pressure.

CI, confidence interval.

In addition, to examine categorical AHA BP outcomes, we used modified Poisson regression with a robust variance estimator³¹ for binary outcomes and multinomial logistic regression models for ternary outcomes to assess risk for elevated BP or hypertension (Table 3). Compared with individuals with no pregnancy loss history, we assessed unadjusted and adjusted models examining associations of one (n = 150) lifetime pregnancy loss or recurrent (n = 60) lifetime pregnancy losses with (1) any elevated BP versus normotension or (2) elevated BP or any stage of hypertension versus normotension.

Table 3.

Associations of Pregnancy Loss History with AHA BP Categories at Midlife Among 623 Women in Project Viva with Two or More Lifetime Pregnancies

History of pregnancy loss	n	Any elevated blood pressure^a n = 277		Elevated blood pressure n = 60	Hypertension^b n = 217	Elevated blood pressure n = 60	Hypertension^b n = 217
History of pregnancy loss	n	Unadjusted RR (95% CI)	Adjusted RR (95% CI)	Unadjusted RRR (95% CI)		Adjusted RRR (95% CI)
Any history of pregnancy loss
0 Pregnancy losses	413	Referent (1)	Referent (1)	Referent (1)		Referent (1)
≥1 Pregnancy losses	210	1.26 (1.05, 1.50)	1.27 (1.08, 1.50)	2.56 (1.47, 4.46)	1.32 (0.92, 1.89)	2.64 (1.51, 4.59)	1.42 (0.99, 2.05)
Number of pregnancy Losses
0 Pregnancy losses	413	Referent (1)	Referent (1)	Referent (1)		Referent (1)
1 Pregnancy loss	150	1.34 (1.11, 1.61)	1.30 (1.08, 1.56)	2.85 (1.55, 5.24)	1.51 (1.01, 2.27)	2.92 (1.58, 5.41)	1.45 (0.95, 2.22)
≥2 Pregnancy losses	60	1.06 (0.78, 1.45)	1.08 (0.80, 1.45)	1.98 (0.84, 4.68)	0.92 (0.50, 1.69)	2.00 (0.83, 4.80)	0.96 (0.51, 1.82)

Normotension is the reference group. Values are risk ratios (95% CI) from modified Poisson regression with robust variance and relative-risk ratios from multinomial logistic regression, adjusted for race and ethnicity (Hispanic, non-Hispanic White, non-Hispanic Black, non-Hispanic other), education at enrollment (college graduate versus not), annual household income at enrollment (≤or >$70,000), smoking status (ever), and perceived body size at 10 years of age (underweight, healthy weight, and overweight).

Bold values indicate p < 0.05.

AHA BP categories, normotension: <120/80; any elevated BP: systolic ≥120 mmHg and/or diastolic ≥80 mmHg.

AHA BP categories, normotension: <120/80; elevated BP: systolic 120–129 mmHg and diastolic <80 mmHg, hypertension: systolic ≥130 mmHg, and/or diastolic ≥80 mmHg.

AHA, American Heart Association; CI, confidence interval.

Severity and prevalence of adverse pregnancy outcomes are higher among individuals who identify as Black, Asian, and Hispanic compared with White individuals.¹⁰ Furthermore, non-Hispanic Black females are at greater risk for hypertension compared with non-Hispanic White individuals.³² Thus, in secondary analyses, we examined adjusted models of any pregnancy loss versus no pregnancy loss with systolic BP, diastolic BP, or any elevated BP by race and ethnicity group (non-Hispanic White, non-Hispanic Black, Hispanic, and non-Hispanic Other) (Table 4). Due to small cell sizes for some subgroups with a history of pregnancy loss, we were unable to examine elevated BP or hypertension versus normotension according to the AHA guidelines in these secondary analyses.

To account for missing covariates, we used multiple imputation by chained equations.³³ All models included 50 imputations conducted among all 2100 participants with a livebirth, using all model covariates and potential predictors of missingness. For all analyses, we report pooled estimates of the 50 imputations among the 623 participants with complete exposure and outcome data. All analyses were conducted in Stata v17.0 (StataCorp LLC, College Station, TX).

Table 4.

Adjusted Associations of No Pregnancy Loss Versus ≥1 Pregnancy Loss with Blood Pressure or Blood Pressure Category at Midlife by Race and Ethnicity (N = 623)

Outcome at midlife	n	Systolic pressure	Diastolic pressure	n	Any elevated Blood pressure^a
Outcome at midlife	n	β (95% CI)	β (95% CI)	n	RR (95% CI)
No pregnancy loss		β (95% CI)	β (95% CI)
Non-Hispanic White	283	Referent (0)		95	Referent (1)
Non-Hispanic Black	57	13.21 (8.61, 17.81)	10.13 (6.73, 13.53)	38	2.14 (1.63, 2.82)
Hispanic	37	4.74 (−0.60, 10.09)	3.53 (−0.42, 7.48)	16	1.40 (0.93, 2.11)
Non-Hispanic Other^b	35	6.87 (1.57, 12.18)	4.01 (0.09, 7.93)	19	1.74 (1.23, 2.47)
≥1 Pregnancy loss
Non-Hispanic White	139	4.45 (1.39, 7.52)	2.54 (0.27, 4.80)	67	1.47 (1.16, 1.87)
Non-Hispanic Black	31	8.52 (2.85, 14.19)	3.15 (−1.04, 7.34)	19	1.97 (1.42, 2.75)
Hispanic	21	9.01 (2.09, 15.92)	6.05 (0.94, 11.16)	14	1.87 (1.30, 2.71)
Non-Hispanic Other	19	2.61 (−4.39, 9.61)	1.98 (−3.19, 7.15)	8	1.30 (0.77, 2.17)

Normotensive is the reference group for AHA blood pressure category. Values are β-coefficients (95% CI) for multivariable linear regression or risk ratios for multivariable logistic regression adjusted for education at enrollment (college graduate versus not), annual household income at enrollment (≤or >$70,000), smoking status (ever), and perceived body size at 10 years of age (underweight, healthy weight, and overweight).

Bold values indicate p < 0.05.

AHA blood pressure categories, normotensive: <120/80; any elevated BP: systolic ≥120 mmHg and/or diastolic ≥80 mmHg.

Includes non-Hispanic Asian and multiracial.

AHA, American Heart Association; CI, confidence interval.

Sensitivity analyses

We conducted four subgroup analyses (Supplementary Tables S2 and S3). First, since a history of stillbirth may be associated with higher rates of hypertension,^10,14 we investigated whether a history of stillbirth versus miscarriage was driving pregnancy loss results by limiting our analyses to individuals with no history of stillbirth (n = 608; excluded 15 individuals with stillbirth history from the original sample of 623). Second, since BMI at enrollment may be upstream of the primary exposure (pregnancy loss) for some individuals, in primary analyses we used perceived body size at 10 years of age. To ensure the robustness of our findings, we compared sensitivity analyses substituting prepregnancy BMI at enrollment for perceived body size at 10 years. Third, since midlife BMI may mediate the association between pregnancy loss and BP, we compared results substituting midlife BMI for perceived body size at 10 years. Fourth, since hypertensive disorders of pregnancy are known to increase risk for hypertension,⁷ we stratified results by history of prenatal hypertensive disorders (n = 97).

Results

Of the 623 participants included in analyses, 210 (33.7%) had a history of pregnancy loss—15 (2.4%) of whom had experienced a stillbirth in their lifetimes. Those who had experienced any pregnancy loss were slightly older at midlife (51.6 years versus 50.2 years) and more likely to have experienced their first pregnancy ≥35 years (13.8% versus 10.4%), attained higher education (79.4% versus 72.1% college graduate), and reported higher annual household income (68.6% versus 63.9% with >$70,000) at enrollment (Table 1). BP in the first trimester of the index pregnancy was similar between participants with or without a history of pregnancy loss. However, for those with a history of pregnancy loss (any versus no loss), midlife systolic BP was modestly higher for both medication-adjusted (119.7 versus 117.3 mmHg) and measured values (118.5 versus 116.2 mmHg), as was the prevalence of elevated BP (14.8% versus 7.0%) or hypertension (36.7% versus 33.9%). At midlife, individuals who identified as non-Hispanic Black had the highest BP (124.7 mmHg/79.8 mmHg).

History of pregnancy loss (any versus none) was associated with higher systolic BP in both unadjusted and adjusted models, but confidence intervals (CIs) included the null (adjusted β = 2.25 mmHg, 95% CI: −0.29, 4.79) (Table 2). We did not observe evidence of a dose–response relationship between the number of pregnancy losses and systolic BP. However, a strong association with higher systolic BP was evident for individuals who experienced their first pregnancy loss ≥35 years (β = 5.58 mmHg, 95% CI: 1.76, 9.40) compared with individuals with no pregnancy loss whose first pregnancy was <35 years. Indeed, we observed a positive trend by age (<35 years or ≥35 years) with ≥1 pregnancy loss versus no loss for both systolic and diastolic BP (Fig. 2). No exposure categories were associated with diastolic BP.

FIG. 2.

Adjusted difference in blood pressure by age at first pregnancy with no pregnancy loss or age at first pregnancy loss (n = 623, 413 with no pregnancy loss and 210 with pregnancy loss).

When examining relationships of pregnancy loss with AHA BP categories (Table 3), we detected a consistent increased risk for any elevated BP for those with a history of pregnancy loss, without evidence for a dose–response relationship between number of pregnancy losses and elevated BP. In models with the three-category BP outcome, a history of one pregnancy loss was associated with being in the elevated BP category (relative-risk ratio [RRR] = 2.93, 95% CI: 1.58, 5.43) and with hypertension (RRR = 1.45, 95% CI: 0.95, 2.22), although the 95% CI included the null for the latter. A strong association with increased risk for any elevated BP was evident for individuals who experienced their first pregnancy loss ≥35 years (Fig. 3). We were not able to examine associations of categories of pregnancy timing and loss with further categorical outcomes because of small cell sizes.

FIG. 3.

Adjusted difference in blood pressure category by age at first pregnancy with no pregnancy loss or age at first pregnancy loss (n = 623, 413 with no pregnancy loss and 210 with pregnancy loss).

When we further categorized our exposure according to race and ethnicity, we observed a risk for elevated systolic and diastolic BP in most groups when compared with non-Hispanic White participants with no history of pregnancy loss (Table 4). Risk was elevated among those with any pregnancy loss and who identified as other than non-Hispanic White. For non-Hispanic White and Hispanic individuals, associations were highest for those with a history of pregnancy loss. But, for non-Hispanic Black individuals, estimates were higher among those with no history of pregnancy loss (systolic β = 13.21 mmHg, 95% CI: 8.61, 17.81; diastolic β = 10.13 mmHg, 95% CI: 6.73, 13.53) compared with those who did experience pregnancy loss (systolic β = 8.52 mmHg, 95% CI: 2.85, 14.19; diastolic β = 3.15 mmHg, 95% CI: -1.04, 7.34). Results for diastolic BP were less consistent. Results for non-Hispanic White, non-Hispanic Black, and Hispanic individuals with a history of pregnancy loss were elevated, although results for non-Hispanic Black individuals contained the null. In analyses examining associations with BP categories of any elevated BP versus normotension, a history of pregnancy loss was associated with a relative risk of 1.47 (95% CI: 1.16, 1.87) for non-Hispanic White, 1.97 (95% CI: 1.42, 2.75) for non-Hispanic Black, and 1.87 (95% CI: 1.30, 2.71) for Hispanic individuals compared with non-Hispanic White individuals with no pregnancy loss history.

We conducted four sensitivity analyses presented in Supplementary Tables S2 and S3. We examined the use of adjustment by (1) prepregnancy BMI or (2) midlife BMI instead of perceived weight at age 10 years. The sensitivity results reflect similar risk as primary analyses; however, in the model adjusted for prepregnancy BMI, history of one pregnancy loss was associated with significantly higher systolic BP (β = 2.85 mmHg, 95% CI: 0.04, 5.66) compared with no history of pregnancy loss and the 95% CI now excluded the null. Likewise, when using prepregnancy BMI, estimates for both systolic and diastolic BP were modestly stronger for participants who experienced pregnancy loss after the age of 35 years (systolic β = 5.88 mmHg, 95% CI: 2.11, 9.65; diastolic β = 2.90 mmHg, 95% CI: 0.18, 5.63) compared to individuals with the first pregnancy before age 35 and no pregnancy losses. When adjusted for midlife BMI, results were similar to primary models (model III β = 5.54 mmHg, 95% CI: 1.81, 9.26). Next, in sensitivity analyses excluding participants with (3) a history of stillbirth (n = 15), findings were consistent with primary models. Finally, stratified analysis by (4) history of hypertensive disorders (Supplementary Table S3) demonstrated similar risk as primary analyses, including risk for increased systolic BP with first pregnancy loss ≥35 years.

Discussion

In this novel investigation of parous females with 24 years of follow-up, one-third of participants experienced at least one pregnancy loss in their lifetimes and approximately 10% experienced recurrent pregnancy loss. This prior lifetime history was associated with a modest increase in systolic BP (2.3 mmHg) in the overall sample, and ∼5.6 mmHg for those experiencing a first pregnancy loss ≥35 years. We also observed a trend in diastolic BP for any pregnancy loss and a weak association for those who experienced a first pregnancy loss after age 35 years, although effect estimates were nonsignificant. In addition, we detected a nearly 30% higher risk for having any elevated BP, a systolic BP ≥120 mmHg and/or diastolic ≥80 mmHg, with a history of pregnancy loss. When stratified by age, individuals with pregnancy loss over the age of 35 years had a 43% increased risk for being categorized as any elevated BP compared with individuals with no pregnancy loss. We observed similar trends in analyses of multiple clinical categories of elevated BP and hypertension according to AHA guidelines. Those with one pregnancy loss had nearly three times the risk for the category of any elevated BP specifically compared with individuals who never experienced pregnancy loss. The association for risk of hypertension was more modest and included the null, and in adjusted models, we did not observe associations with recurrent pregnancy loss—both likely due to inadequate sample size.

Sensitivity analyses supported our primary findings. In models stratified by racial and ethnic groups, we saw consistently elevated risk for higher BP in non-White participants, particularly those with a history of pregnancy loss. In particular, non-Hispanic Black and Hispanic participants had dramatically elevated BP compared with non-Hispanic White participants. Overall, estimates for non-Hispanic Black participants were higher than for White participants. However, the inverse results for non-Hispanic Black individuals with pregnancy loss versus no pregnancy loss were unexpected. We believe this result may be due to low power (n = 31) when examining the sample of Black individuals with pregnancy loss, likely incurring a ceiling effect.

Our findings align with prior studies that found a positive relationship between pregnancy loss and subsequent cardiovascular risk factors or hypertension. The rate of pregnancy loss in our study (34%) was similar to the rate (35%) reported in 79,121 individuals in the US Women’s Health Initiative, in which pregnancy loss was associated with an 11% (6% to 16%) higher adjusted risk of incident cardiovascular disease over 16 years of study follow-up after pregnancy loss.¹³ In a Danish study of more than one million female subjects, the 18.3% who experienced pregnancy loss had higher risk for myocardial infarction, cerebral infarction, and renovascular hypertension compared with individuals with no history of pregnancy loss.⁹ Further, individuals with a history of stillbirth had a nearly 2.5-fold increased rate and individuals with miscarriage history had a 1.2-fold increased rate of renovascular hypertension. Interestingly, recurrent miscarriages were associated with increased risk for all cardiovascular outcomes compared with nonrecurrent miscarriages. In a Nurses’ Health Study II analysis that examined pregnancy loss for the first-lifetime pregnancy, varying associations with hypertension were observed with early pregnancy loss (<12 weeks; hazard ratio [HR] = 1.05, 95% CI: 1.00, 1.11), late pregnancy loss (12–19 weeks; HR = 1.15, 95% CI: 1.05–1.25), and stillbirth (≥20 weeks; HR = 1.15, 95% CI: 1.01, 1.30).¹⁴ In an additional analysis evaluating lifetime pregnancy history in this cohort, recurrent pregnancy loss increased risk for hypertension by 19% with early pregnancy loss (<12 weeks), 12% with late pregnancy loss (12–19 weeks), and a nonsignificant 34% with stillbirth (≥20 weeks).¹⁴ We identified only one prior study that examined associations of pregnancy loss with continuous systolic and diastolic BP. In a Swedish cohort of 1535 females aged 40 years, a borderline significant increase in systolic BP (2.41 mmHg, p = 0.05) was observed with a history of stillbirth ≥28 weeks versus no history of pregnancy loss. Previous findings align with our hypothesis that a lifetime history of pregnancy loss would be associated with higher systolic and diastolic BP and AHA BP categories. However, rather than assessing measured BP as an indicator of risk, these studies relied on medical diagnosis and/or self-reported hypertension and only one study estimated systolic and diastolic BP. Further, these investigations did not specifically examine newer BP staging according to the 2017 AHA guidelines that include elevated BP, potentially missing an important indicator of cardiovascular risk.

The etiology of the association between pregnancy loss and increasing BP is unclear. It has been postulated that endothelial dysfunction precedes both pregnancy loss, potentially through placentation defects,³⁴ and cardiovascular risk factors, including hypertension.³⁵ Previously, associations with later ischemic heart disease were observed with early pregnancy loss before the first livebirth,³⁶ potentially due to underlying endothelial dysfunction linked to adverse pregnancy outcomes.³⁷ Further, recurrent pregnancy loss has been independently associated with hypertension plausibly related to vascular abnormalities, namely endothelial dysfunction characterized by lower endothelium-mediated vasodilation and blood nitrates, that may lead to pregnancy placentation defects.³⁷ Endothelial dysfunction second to systemic inflammation is a plausible mechanism that could explain the link between pregnancy loss and cardiovascular outcomes^9,35 and deserves deeper investigation.

To our knowledge, this is the first examination of the associations between pregnancy loss with midlife BP according to the AHA’s 2017 guidelines. These findings highlight the importance of identifying individuals early and targeting treatment with lifestyle interventions, particularly for individuals with BP in the elevated category. Since females are high risk for cardiovascular disease and may be underdiagnosed,³⁸ fewer individuals may be identified with elevated BP (compared with hypertension). In addition, at the population level, BP rises ∼7 mmHg for every decade of life after age 40,³⁹ and systolic BP increases with age at a greater rate than diastolic BP.⁴⁰ Our sample characteristics support these population values, but our results provide clinically valuable BP differences to argue for ongoing observation, closer monitoring, and maybe preventive approaches for individuals with pregnancy loss. Further, considering that ours was a relatively healthy sample with a young average age at analysis (∼51 years), it stands to reason that the BP disparity between those who did and did not experience a pregnancy loss may be even greater at the population level.

Of particular relevance to cardiopreventive interventions, our results indicate individuals with a history of pregnancy loss who identified as non-Hispanic Black or Hispanic had higher systolic and diastolic BP, as well as higher risk for any elevated BP. Evidence demonstrates that adults who identify as Black, Asian, and Hispanic have significantly higher rates of hypertension than White counterparts.⁴¹ Generally, Black individuals in the United States have the highest prevalence of hypertension—with Black females 50% more likely to develop hypertension compared with White females.⁴² Further, Black females have the highest risk for sequelae associated with hypertension, including stroke, heart failure, and coronary artery disease compared with other females.⁴³ It is probable that pregnancy loss contributes to this higher risk. Prior evidence has shown that individuals who identify as Black have a twofold increased risk for miscarriage at 10–20 weeks gestation compared with White individuals.^16,44 An analysis of fetal deaths 2015–2017 in the United States revealed that Black females are more than twice as likely to experience stillbirth compared with White and Hispanic counterparts;⁴⁵ potential causes were more likely to be prepregnancy or pregnancy-related health conditions including diabetes, hypertension, placental abruption, and premature rupture of membranes.⁴⁶ These racial disparities in pregnancy losses persist even with early prenatal care.⁴⁷ The etiology of our findings that the risk for higher BP with history of pregnancy loss was greater in participants who identified as non-Hispanic Black and Hispanic versus non-Hispanic White is unclear and likely multifactorial. Evidence indicates that financial, emotional, traumatic, and partner-related stressful life events increase risk for stillbirth, and Black females are at higher risk for multiple stressful events,⁴⁸ including structural and interpersonal racism by health care providers.^49,50 Further, chronic psychological stress, such as discrimination,⁵¹ likely contributes to the development of hypertension.^50,52 However, the specific physiological mechanisms linking pregnancy loss and hypertension are not known, nor how these mechanisms may differ across ethnic groups. As a group and particularly with a history of pregnancy loss, females who identify as Black deserve early screening and targeted care.

This study has many strengths. Few studies have specifically examined midlife BP outcomes in relation to lifetime history of pregnancy loss. Moreover, to our knowledge, this investigation was the first to utilize the AHA’s 2017 BP guidelines or examine the racial and ethnic inequities in the relationship between pregnancy loss and midlife BP—a research area that deserves further attention. Other strengths include the long-term follow-up with participants that allowed us to ascertain reproductive history and systematically measure and categorize BP. In addition, this study investigated individuals with pregnancy loss and at least one livebirth. These results are important for understanding risk factors and cardiopreventive interventions among individuals with successful pregnancies since their physiological changes and psychosocial experiences differ from nulliparous individuals. Our study is not without limitations. The participants in this cohort are predominantly well-educated, non-Hispanic White individuals with access to health care. Therefore, generalizability may be limited, although the racial and ethnic distribution of our cohort was similar to the composition of Boston at enrollment. Nevertheless, we had small samples in some groups that we were not able to examine separately (such as non-Hispanic Asians) and also limited power to examine multiple strata, for example, by age at pregnancy loss and race and ethnicity. In addition, because only ∼10% of our sample experienced recurrent pregnancy loss, we were likely underpowered to assess the true relationship between recurrent pregnancy loss and midlife BP. Due to the nature of questionnaire data collected at midlife, there is also the possibility for residual confounding from unmeasured covariates and recall bias with misclassification of pregnancy loss, especially due to under-reporting of early spontaneous miscarriage or reporting therapeutic abortion as a miscarriage. However, this suggests that our results may have underestimated the true relationship between pregnancy loss and BP.

Conclusions

The results of this study expand upon the limited evidence that pregnancy loss increases risk for elevated midlife BP, an important contributor to cardiovascular disease burden. Further, among those who identify as non-Hispanic Black or Hispanic, BP appears to be higher, which may be of particular concern with pregnancy loss. The underlying etiology of pregnancy loss and relationship with other cardiometabolic sequelae deserve further investigation. If the true relationship between pregnancy loss and hypertension is linked through endothelial dysfunction present throughout the female reproductive lifetime and beyond, this is a condition not readily diagnosed clinically. Hence, quality preventive care must rely on screening for reproductive risk factors across the lifecourse, including pregnancy loss. In addition to reproductive conditions associated with increased risk of cardiovascular disease, for example, preterm birth, preeclampsia, gestational diabetes, and polycystic ovary syndrome, primary prevention tools that include screening for pregnancy loss and early hypertension at the clinic level may aid amelioration of cardiovascular disease risk.

Footnotes

Authors’ Contributions

A.R.N.: conception, design, data management, analysis, interpretation, and composition of the manuscript. I.A.: design, interpretation, feedback on the manuscript. S.L.R.: data acquisition and interpretation, critical feedback on the manuscript. M.H.: conception, design, interpretation, feedback on the manuscript. J.E.C.: conception, design, interpretation, oversaw composition and provided critical manuscript review, obtained funding. E.O.: conception, design, interpretation, oversaw composition and provided critical manuscript review, obtained funding.

Author Disclosure Statement

The authors have no conflicts of interest to disclose.

Funding Information

This study received funding from grants T32DK007703: National Institute of Diabetes and Digestive and Kidney Diseases; R01HD0960342: Eunice Kennedy Shriver National Institute of Child Health & Human Development; R24ES030894: National Institute of Environmental Health Sciences; and U54AG062322 NIH: National Institutes of Aging and Office of Research on Women’s Health.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

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