Skip to main content
NCBI home page
PLOS Medicine logoLink to PLOS Medicine
. 2021 Sep 28;18(9):e1003805. doi: 10.1371/journal.pmed.1003805

Maternal hypertensive disorder of pregnancy and offspring early-onset cardiovascular disease in childhood, adolescence, and young adulthood: A national population-based cohort study

Chen Huang 1,‡, Jiong Li 2,3,‡, Guoyou Qin 1,‡, Zeyan Liew 4,5, Jing Hu 1, Krisztina D László 6, Fangbiao Tao 7,8, Carsten Obel 9, Jørn Olsen 3, Yongfu Yu 1,3,*
Editor: Quique Bassat10
PMCID: PMC8478255  PMID: 34582464

Abstract

Background

The prevalence of cardiovascular disease (CVD) has been increasing in children, adolescents, and young adults in recent decades. Exposure to adverse intrauterine environment in fetal life may contribute to the elevated risk of early-onset CVD. Many studies have shown that maternal hypertensive disorders of pregnancy (HDP) are associated with increased risks of congenital heart disease, high blood pressure, increased BMI, and systemic vascular dysfunction in offspring. However, empirical evidence on the association between prenatal exposure to maternal HDP and early-onset CVD in childhood and adolescence remains limited.

Methods and findings

We conducted a population-based cohort study using Danish national health registers, including 2,491,340 individuals born in Denmark from 1977 to 2018. Follow-up started at birth and ended at the first diagnosis of CVD, emigration, death, or 31 December 2018, whichever came first. Exposure of maternal HDP was categorized as preeclampsia or eclampsia (n = 68,387), gestational hypertension (n = 18,603), and pregestational hypertension (n = 15,062). Outcome was the diagnosis of early-onset CVD from birth to young adulthood (up to 40 years old). We performed Cox proportional hazards regression to evaluate the associations and whether the association differed by maternal history of CVD or diabetes before childbirth. We further assessed the association by timing of onset and severity of preeclampsia. The median follow-up time was 18.37 years, and 51.3% of the participants were males. A total of 4,532 offspring in the exposed group (2.47 per 1,000 person-years) and 94,457 in the unexposed group (2.03 per 1,000 person-years) were diagnosed with CVD. We found that exposure to maternal HDP was associated with an increased risk of early-onset CVD (hazard ratio [HR]: 1.23; 95% CI = 1.19 to 1.26; P < 0.001). The HRs for preeclampsia or eclampsia, gestational hypertension, and pregestational hypertension were 1.22 (95% CI, 1.18 to 1.26; P < 0.001), 1.25 (95% CI, 1.17 to 1.34; P < 0.001), and 1.28 (95% CI, 1.15 to 1.42; P < 0.001), respectively. We also observed increased risks for type-specific CVDs, in particular for hypertensive disease (HR, 2.11; 95% CI, 1.96 to 2.27; P < 0.001) and myocardial infarction (HR, 1.49; 95% CI, 1.12 to 1.98; P = 0.007). Strong associations were found among offspring of mothers with CVD history (HR, 1.67; 95% CI, 1.41 to 1.98; P < 0.001) or comorbid diabetes (HR, 1.56; 95% CI, 1.34 to 1.83; P < 0.001). When considering timing of onset and severity of preeclampsia on offspring CVD, the strongest association was observed for early-onset and severe preeclampsia (HR, 1.48, 95% CI, 1.30 to 1.67; P < 0.001). Study limitations include the lack of information on certain potential confounders (including smoking, physical activity, and alcohol consumption) and limited generalizability in other countries with varying disparities in healthcare.

Conclusions

Offspring born to mothers with HDP, especially mothers with CVD or diabetes history, were at increased risks of overall and certain type-specific early-onset CVDs in their first decades of life. Further research is warranted to better understand the mechanisms underlying the relationship between maternal HDP and early-onset CVD in offspring.

Chen Huang and co-workers study associations between maternal hypertensive disorders and cardiovascular disease in offspring.

Author summary

Why was this study done?

  • The prevalence of cardiovascular disease (CVD) has been increasing in children, adolescents, and young adults in recent decades in developed countries.

  • Maternal hypertensive disorders of pregnancy (HDP) is associated with an increased risk of congenital heart disease and a number of risk factors of CVD in offspring.

  • Little is known about whether and to what extent prenatal exposure to HDP affects the development of early-onset CVD in offspring from birth to adolescence and beyond.

What did the researchers do and find?

  • We conducted a population-based cohort study that included all 2,491,340 live births in Denmark from 1977 to 2018 and followed them from birth to early adulthood (up to 40 years).

  • We found that individuals born to mothers with HDP had a 23% increased risk of early-onset CVD in offspring, especially of those mothers with a history of CVD (67% increased risk) or diabetes (56% increased risk).

What do these findings mean?

  • Offspring born to mothers with HDP, especially mothers with CVD or diabetes, are at an increased risk of early-onset CVD from birth to early adulthood.

  • These findings suggest that better management of maternal HDP, particularly in early phase of pregnancy, may improve cardiovascular health of children and adolescents and beyond, in terms of reducing the risk of early-onset CVD.

  • Further research is warranted to better understand the mechanisms underlying the relationship between maternal HDP and early-onset CVD in offspring in early decades of life.

Introduction

Cardiovascular disease (CVD) remains one of the leading causes of death worldwide [1,2], with a rising prevalence of CVD in children, adolescents, and young adults over the past few decades in developed countries and many undeveloped countries [3,4]. In addition to conventional risk factors of CVD, such as obesity, physical inactivity, dyslipidemia [3,5,6], Barker’s fetal origin theory proposed that CVD may have a prenatal origin [7–9]. An increasing body of evidence has suggested intergenerational associations between maternal illness during pregnancy and the risk of CVD in offspring [4,10–12].

Hypertensive disorders of pregnancy (HDP), including preeclampsia, eclampsia, gestational hypertension, and pregestational hypertension, complicates about 3% to 10% of pregnancies and has also been increasing in recent decades [13–15]. Empirical evidence has shown that children born to mothers with HDP had increased risks of congenital heart disease, high blood pressure, increased BMI, and systemic vascular dysfunction [16–20]. Previous studies have suggested that pregnancies complicated by HDP may lead to long-term changes in cardiac and vascular functions in offspring through fetal programming, which could, in turn, increase the risk of CVD in offspring later in life [7–9,17]. Although there has been some evidence suggesting a higher risk of stroke and hypertension in offspring with maternal HDP [21–25], little is known about whether or to what extent prenatal exposure to maternal HDP would increase the risk of overall and type-specific CVDs in the first decades of life.

Using the Danish national health registries, we aimed to examine the association between maternal HDP and early-onset CVD in offspring from birth to young adulthood (up to 40 years) and whether coexisting maternal history of CVD and diabetes further increased the risk of CVD among offspring [4]. We also assessed whether those associations differed by timing of onset and severity of preeclampsia [21,26].

Methods

Ethics statement

The study was approved by the Data Protection Agency (Record No. 2013-41-2569). By Danish law, no informed consent is required for a register-based study based on anonymized data.

Study design and participants

A unique civil personal identification number is assigned to all residents in Denmark, which allows individual-level linkage across various national registries (detailed descriptions of registers are provided in S2 Text) [27,28]. We conducted a population-based cohort study including all live births in Denmark between 1977 and 2018 (N = 2,537,421). The final cohort comprised 2,491,340 individuals after excluding 46,081 children with diagnosed congenital heart disease (Fig 1). The follow-up started at birth and ended at the first diagnosis of CVD, emigration, death, or 31 December 2018, whichever came first. The detailed prespecified study protocol is available in S1 Text. We have followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (STROBE Checklist is provided in S1 Checklist).

Fig 1. Flow chart of study population.

Fig 1

Open in a new tab

Maternal hypertensive disorders of pregnancy

Information on maternal HDP was retrieved from the Danish National Patient Register (DNPR) [27,28], using the International Classification of Diseases (ICD; ICD-8, 1978 to 1993; ICD-10, 1994 and forward) (S1 Table). HDP was classified as (1) preeclampsia or eclampsia; (2) gestational hypertension; and (3) pregestational hypertension. Preeclampsia was further categorized into unspecified preeclampsia, moderate preeclampsia, severe preeclampsia, and hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome according to the severity. For women who had more than one diagnosis of HDP, we categorized them according to the hierarchy: eclampsia, preeclampsia, pregestational hypertension, and gestational hypertension.

Preeclampsia was further categorized into early-onset preeclampsia (diagnosed before 34 weeks of gestation) and late-onset preeclampsia (diagnosed at or after 34 weeks of gestation) [26]. According to the severity of preeclampsia, preeclampsia was also categorized into moderate preeclampsia and severe preeclampsia (including severe preeclampsia and the HELLP syndrome).

Outcome of interest

The outcome of interest was early-onset CVD (excluding congenital heart disease), defined as the first occurrence of CVD in the DNPR and the Danish Cause of Death Register (Diagnostic codes and surgical codes for CVD were provided in S2 Table) [27,28]. We further investigated type-specific CVDs, such as myocardial infarction, cerebrovascular disease, stroke, heart failure, atrial fibrillation, hypertensive disease, deep vein thrombosis, pulmonary embolism, rheumatic heart disease, and peripheral arterial disease.

Covariates

Potential confounders were selected by directed acyclic graphs (S1 Fig), including sex (male, female), singleton (yes, no), birth year of the child (1977 to 1980, 5-year intervals during 1981 to 2015, and 2016 to 2018), maternal age (<20, 20 to 24, 25 to 29, 30 to 34, or ≥35 years), maternal education (0 to 9, 10 to 14, or ≥15 years), maternal income at birth (no income, 3 tertiles), maternal prepregnancy BMI (underweight <18.5, normal 18.5 to 24.9, overweight 25.0 to 29.9, obese ≥30.0), maternal smoking during pregnancy (yes or no), parity (1, 2, or ≥3 children), maternal cohabitation (single or cohabitating), maternal residence (Copenhagen, cities with ≥100,000 inhabitants, or other), maternal history of diabetes, and maternal and parental history of CVD before childbirth (yes or no). A missing indicator method was used to deal with missing values. A detailed description of the covariates is presented in S3 Text.

Statistical analysis

Considering non-CVD deaths as the competing events, competing risk analysis was performed to estimate cumulative incidence of CVD among offspring exposed and unexposed to maternal HDP. We used Cox regression to estimate hazard ratios (HRs) and 95% CIs to assess the association between maternal HDP and overall or type-specific CVD in offspring. The proportional hazards assumption was assessed graphically using the log-minus-log plot, suggesting that there was no obvious violation. We examined the interaction term between maternal HDP and maternal history of CVD or diabetes to assess whether the association was varied by maternal CVD or diabetes. Besides, we assessed the association by timing of onset and severity of preeclampsia (moderate, severe eclampsia, and HELLP syndrome).

We performed the following sensitivity analyses: (1) In order to assess the influence of family or genetic factors, we conducted sibship analysis by restricting offspring to sibling pairs born to same mother but different father (half-sibling) or same father and mother (full-sibling) to compare the difference in the outcomes of each sibling exposed to maternal HDP and the unexposed sibling. (2) We evaluated whether timing of delivery would affect the observed associations by dividing offspring to preterm birth and term birth. (3) We undertook stratified analysis by baseline characteristics including offspring sex, singleton, parity, maternal age, maternal education, maternal smoking during pregnancy, maternal cohabitation, maternal residence, maternal history of diabetes, and maternal and parental history of CVD before childbirth. (4) We used paternal hypertension before pregnancy as “control exposure” to examine the underlying genetic or family factors of the association. (5) We assessed the association between maternal HDP and CVD in offspring according to the timing of diagnosis of maternal HDP since childbirth (diagnosed before childbirth and diagnosed ≤3 years, 3 to 5 years, 5 to 10 years, and 10 to 15 years after childbirth). (6) We performed subanalyses: further adjusted for paternal hypertension; due to the change in ICD code and availability of data on confounders, the main analyses restricted to offspring born after 1991, 1994, and 2004; multiple imputation and complete cases analyses. All analyses were performed using SAS 9.4 (SAS Institute, Cary, North Carolina) and Stata 15.1 (StataCorp, College Station, Texas, United States).

Results

Among 2,491,340 live-born offspring in the final cohort, 102,052 (4.10%) individuals were exposed to maternal HDP (preeclampsia or eclampsia: 2.74%; gestational hypertension: 0.75%; pregestational hypertension: 0.60%). A total of 88,275 offspring (3.55%) were censored during the follow-up, of which 68,675 (2.76%) were due to emigration and 19,600 (0.79%) were due to noncardiovascular death. Mothers with HDP were more likely to be primiparous women with lower education, live alone, and to have a history of diabetes or CVD. Offspring exposed to maternal HDP also had a higher proportion with parental history of CVD (Table 1).

Table 1. Baseline characteristics according to offspring’s exposure to maternal HDP, Denmark, 1977–2018.

Characteristicsa No HDP (n = 2,389,288) Preeclampsia or eclampsiab (n = 68,387) Pregestational hypertension (n = 15,062) Gestational hypertension (n = 18,603) Total (n = 2,491,340)
Singleton
    No 73,123 (3.1) 6,142 (9.0) 633 (4.2) 791 (4.3) 80,689 (3.2)
    Yes 2,316,165 (96.9) 62,245 (91.0) 14,429 (95.8) 17,812 (95.7) 2,410,651 (96.8)
Sex
    Boy 1,224,718 (51.3) 35,566 (52.0) 7,766 (51.6) 9,656 (51.9) 1,277,706 (51.3)
    Girl 1,163,239 (48.7) 32,782 (47.9) 7,295 (48.4) 8,938 (48.0) 1,212,254 (48.7)
    Unknown 1,331 (0.1) 39 (0.1) 1 (0.0) 9 (0.0) 1,380 (0.1)
Maternal parity
    1 1,061,709 (44.4) 44,903 (65.7) 4,980 (33.1) 10,910 (58.6) 1,122,502 (45.1)
    2 895,651 (37.5) 15,903 (23.3) 6,380 (42.4) 5,012 (26.9) 922,946 (37.0)
≥3 431,928 (18.1) 7,581 (11.1) 3,702 (24.6) 2,681 (14.4) 445,892 (17.9)
Maternal age at childbirth (years)
    <20 54,569 (2.3) 2,051 (3.0) 46 (0.3) 270 (1.5) 56,936 (2.3)
    20–24 413,120 (17.3) 13,999 (20.5) 935 (6.2) 2,685 (14.4) 430,739 (17.3)
    25–29 868,600 (36.4) 24,488 (35.8) 3,684 (24.5) 6,136 (33.0) 902,908 (36.2)
    30–34 722,932 (30.3) 17,864 (26.1) 5,586 (37.1) 5,690 (30.6) 752,072 (30.2)
    35+ 330,067 (13.8) 9,985 (14.6) 4,811 (31.9) 3,822 (20.5) 348,685 (14.0)
Maternal smoking during pregnancy c
    No 1,306,384 (77.3) 38,415 (81.0) 11,744 (83.8) 11,536 (84.2) 1,368,079 (77.5)
    Yes 310,460 (18.4) 6,684 (14.1) 1,722 (12.3) 1,709 (12.5) 320,575 (18.2)
    Unknown 74,034 (4.4) 2,304 (4.9) 552 (3.9) 461 (3.4) 77,351 (4.4)
Maternal education at childbirth, years
    0–9 620,503 (26.0) 19,272 (28.2) 2,627 (17.4) 4,157 (22.3) 646,559 (26.0)
    10–14 1,016,818 (42.6) 30,354 (44.4) 6,629 (44.0) 8,315 (44.7) 1,062,116 (42.6)
    15+ 708,837 (29.7) 17,972 (26.3) 5,661 (37.6) 5,890 (31.7) 738,360 (29.6)
    Unknown 43,130 (1.8) 789 (1.2) 145 (1.0) 241 (1.3) 44,305 (1.8)
Maternal cohabitation at childbirth
    No 1,084,136 (45.4) 35,198 (51.5) 6,724 (44.6) 8,974 (48.2) 1,135,032 (45.6)
    Yes 1,301,473 (54.5) 33,167 (48.5) 8,336 (55.3) 9,622 (51.7) 1,352,598 (54.3)
    Unknown 3,679 (0.2) 22 (0.0) 2 (0.0) 7 (0.0) 3,710 (0.1)
Maternal residence at childbirth
    Copenhagen 277,438 (11.6) 7,690 (11.2) 1,572 (10.4) 2,106 (11.3) 288,806 (11.6)
    Big cities ≥100,000 inhabitants 306,552 (12.8) 9,181 (13.4) 1,959 (13) 3,025 (16.3) 320,717 (12.9)
    Others 1,805,298 (75.6) 51,516 (75.3) 11,531 (76.6) 13,472 (72.4) 1,881,817 (75.5)
Maternal CVD history before childbirth
    No 2,327,447 (97.4) 66,150 (96.7) 13,937 (92.5) 17,956 (96.5) 2,425,490 (97.4)
    Yes 61,841 (2.6) 2,237 (3.3) 1,125 (7.5) 647 (3.5) 65,850 (2.6)
Paternal CVD history before birth of the child
    No 2,286,742 (95.7) 65,082 (95.2) 14,136 (93.9) 17,672 (95) 2,383,632 (95.7)
    Yes 77,890 (3.3) 2,368 (3.5) 746 (5) 692 (3.7) 81,696 (3.3)
    Unknown 24,656 (1.0) 937 (1.4) 180 (1.2) 239 (1.3) 26,012 (1.0)
Maternal DM history before childbirth
    No 2,350,874 (98.4) 65,529 (95.8) 13,719 (91.1) 17,603 (94.6) 2,447,725 (98.2)
    Yes 38,414 (1.6) 2,858 (4.2) 1,343 (8.9) 1,000 (5.4) 43,615 (1.8)
Open in a new tab

aHR, adjusted hazard ratio; cHR, crude hazard ratio; CVD, cardiovascular disease; DM, diabetes mellitus; HDP, hypertensive disorders of pregnancy; HELLP, hemolysis, elevated liver enzymes, and low platelet.

aExpressed as frequency (percentage).

bIncludes all preeclampsia or eclampsia diagnoses (moderate preeclampsia, severe preeclampsia, HELLP syndrome, unspecified preeclampsia, and eclampsia).

cMaternal smoking during pregnancy was available from 1991 to 2018.

During a follow-up of up to 40 years (median: 18.37 years, IQR: 9.13 to 27.28 years), 4,532 offspring (2.47 per 1,000 person-years) were diagnosed with CVD in the exposed cohort and 94,457 (2.03 per 1,000 person-years) in the unexposed cohort. Offspring exposed to maternal HDP had a higher risk of developing CVD in their first 40 years of life, compared with offspring without maternal HDP (Fig 2). Maternal HDP was associated with 23% increased risk of early-onset CVD in offspring (HR: 1.23; 95% CI: 1.19 to 1.26; P < 0.001) in the fully adjusted model. The risk of early-onset CVD was higher among offspring exposed to preeclampsia and eclampsia (1.22, 95% CI: 1.18 to 1.26; P < 0.001), gestational hypertension (HR, 1.25; 95% CI, 1.17 to 1.34; P < 0.001), and pregestational hypertension (HR, 1.28; 95% CI, 1.15 to 1.42; P < 0.001), respectively, compared to offspring of mothers without HDP. We also observed increased risks for most type-specific CVDs, in particular hypertensive disease (HR, 2.11; 95% CI, 1.96 to 2.27; P < 0.001), myocardial infarction (HR, 1.49; 95% CI, 1.12 to 1.98; P = 0.007), pulmonary embolism (HR, 1.33; 95% CI, 1.11 to 1.58; P = 0.002), and heart failure (HR, 1.30; 95% CI, 1.02 to 1.66; P = 0.037) (Table 2).

Fig 2. Cumulative incidence of early-onset CVD among offspring exposed and unexposed to HDP.

Fig 2

Open in a new tab

CVD, cardiovascular disease; HDP, hypertensive disorders of pregnancy.

Table 2. HRs for associations between maternal HDP and overall early-onset CVD and type-specific CVDs in offspring.

Outcomea Exposure No. of CVD cases Rate (1/103) cHR (95% CI) P value aHRb (95% CI) P value
Overall CVD No maternal HDP 94,457 2.03 1.0(Reference) 1.0(Reference)
Maternal HDP 4,532 2.47 1.24 (1.21–1.28) <0.001 1.23 (1.19–1.26) <0.001
Preeclampsia or eclampsia 3,372 2.52 1.23 (1.19–1.27) <0.001 1.22 (1.18–1.26) <0.001
Preeclampsia 3,345 2.53 1.23 (1.19–1.27) <0.001 1.22 (1.18–1.26) <0.001
Moderate 2,607 2.55 1.21 (1.16–1.26) <0.001 1.21 (1.16–1.25) <0.001
Severe 502 2.50 1.35 (1.24–1.48) <0.001 1.31 (1.20–1.43) <0.001
HELLP syndrome 30 1.73 1.73 (1.21–2.47) 0.003 1.38 (0.97–1.98) 0.077
Unspecified 206 2.44 1.16 (1.01–1.33) 0.031 1.16 (1.01–1.32) 0.039
Eclampsia 27 2.13 1.09 (0.75–1.59) 0.653 1.07 (0.73–1.56) 0.728
Hypertension 1,160 2.32 1.29 (1.22–1.37) <0.001 1.26 (1.19–1.33) <0.001
Pregestational 351 1.97 1.44 (1.30–1.60) <0.001 1.28 (1.15–1.42) <0.001
Gestational 809 2.51 1.24 (1.16–1.33) <0.001 1.25 (1.17–1.34) <0.001
Specific CVD
Myocardial infarction No maternal HDP 867 0.02 1.0(Reference) 1.0(Reference)
Maternal HDP 50 0.03 1.50 (1.13–2.00) 0.005 1.49 (1.12–1.98) 0.007
Preeclampsia or eclampsia 41 0.03 1.61 (1.17–2.20) 0.003 1.56 (1.14–2.14) 0.006
Hypertension 9 0.02 1.17 (0.61–2.25) 0.643 1.23 (0.64–2.37) 0.538
Cerebrovascular disease No maternal HDP 6,618 0.14 1.0(Reference) 1.0(Reference)
Maternal HDP 317 0.17 1.22 (1.09–1.37) <0.001 1.20 (1.07–1.35) 0.002
Preeclampsia or eclampsia 246 0.18 1.27 (1.12–1.44) <0.001 1.24 (1.09–1.41) <0.001
Hypertension 71 0.14 1.09 (0.86–1.37) 0.488 1.09 (0.86–1.37) 0.491
Stroke No maternal HDP 4,107 0.09 1.0(Reference) 1.0(Reference)
Maternal HDP 209 0.11 1.29 (1.13–1.49) <0.001 1.26 (1.10–1.45) 0.001
Preeclampsia or eclampsia 164 0.12 1.37 (1.17–1.60) <0.001 1.32 (1.13–1.55) <0.001
Hypertension 45 0.09 1.08 (0.81–1.45) 0.593 1.08 (0.80–1.45) 0.623
Heart failure No maternal HDP 1,321 0.03 1.0(Reference) 1.0(Reference)
Maternal HDP 68 0.04 1.32 (1.03–1.68) 0.027 1.30 (1.02–1.66) 0.037
Preeclampsia or eclampsia 53 0.04 1.37 (1.04–1.80) 0.024 1.34 (1.01–1.76) 0.040
Hypertension 15 0.03 1.15 (0.69–1.92) 0.582 1.18 (0.71–1.97) 0.517
Atrial fibrillation No maternal HDP 2,461 0.05 1.0(Reference) 1.0(Reference)
Maternal HDP 110 0.06 1.16 (0.96–1.41) 0.122 1.16 (0.95–1.40) 0.140
Preeclampsia or eclampsia 93 0.07 1.28 (1.04–1.57) 0.020 1.26 (1.03–1.56) 0.027
Hypertension 17 0.03 0.78 (0.48–1.25) 0.305 0.79 (0.49–1.27) 0.325
Hypertensive disease No maternal HDP 9,892 0.21 1.0(Reference) 1.0(Reference)
Maternal HDP 822 0.44 2.17 (2.02–2.33) <0.001 2.11 (1.96–2.27) <0.001
Preeclampsia or eclampsia 577 0.42 1.99 (1.83–2.16) <0.001 1.94 (1.78–2.11) <0.001
Hypertension 245 0.48 2.76 (2.43–3.13) <0.001 2.67 (2.35–3.03) <0.001
Deep vein thrombosis No maternal HDP 5,084 0.11 1.0(Reference) 1.0(Reference)
Maternal HDP 223 0.12 1.14 (1.00–1.31) 0.050 1.14 (1.00–1.30) 0.056
Preeclampsia or eclampsia 178 0.13 1.18 (1.02–1.37) 0.028 1.16 (1.00–1.35) 0.047
Hypertension 45 0.09 1.01 (0.76–1.36) 0.934 1.06 (0.79–1.42) 0.720
Pulmonary embolism No maternal HDP 2,577 0.05 1.0(Reference) 1.0(Reference)
Maternal HDP 132 0.07 1.33 (1.12–1.59) 0.001 1.33 (1.11–1.58) 0.002
Preeclampsia or eclampsia 99 0.07 1.30 (1.06–1.59) 0.011 1.27 (1.04–1.56) 0.019
Hypertension 33 0.06 1.45 (1.03–2.04) 0.035 1.51 (1.07–2.13) 0.018
Rheumatic heart disease No maternal HDP 302 0.01 1.0(Reference) 1.0(Reference)
Maternal HDP 13 0.01 1.09 (0.63–1.90) 0.763 1.13 (0.65–1.98) 0.659
Preeclampsia or eclampsiac - - - - - -
Hypertensionc - - - - - -
Peripheral arterial disease No maternal HDP 511 0.01 1.0(Reference) 1.0(Reference)
Maternal HDP 26 0.01 1.32 (0.89–1.96) 0.168 1.31 (0.88–1.94) 0.183
Preeclampsia or eclampsia 19 0.01 1.27 (0.80–2.00) 0.314 1.24 (0.78–1.97) 0.355
Hypertension 7 0.01 1.49 (0.71–3.14) 0.295 1.53 (0.72–3.23) 0.266
Open in a new tab

aHR, adjusted hazard ratio; cHR, crude hazard ratio; CVD, cardiovascular disease; HDP, hypertensive disorders of pregnancy; HELLP, hemolysis, elevated liver enzymes, and low platelet; HR, hazard ratio; ICD, International Classification of Diseases.

aOverall CVD (ICD-8: 390 to 444.1, 444.3 to 458, 782.4; ICD-10: I00 to I99). Myocardial infarction (ICD-8: 410; ICD-10: I21), cerebrovascular disease (ICD-8: 430 to 438; ICD-10: I60 to I69), stroke (ICD-8: 430 to 436; ICD-10: I61 to I64), heart failure (ICD-8: 427.0, 427.1, 782.4; ICD-10: I110, I130, I132, I50), atrial fibrillation (ICD-8: 427.93, 427.94; ICD-10: I48), hypertensive disease (ICD-8: 400 to 404; ICD-10: I10 to I15), deep vein thrombosis (ICD-8: 451.00; ICD-10: I80.1 to I80.3), pulmonary embolism (ICD-8: 450.99; ICD-10: I26), rheumatic heart disease (ICD-8: 393 to 398; ICD-10: I05 to I09), and peripheral arterial disease (ICD-8: 443.89 to 443.99; ICD-10: I73.9).

bAdjusted for calendar year, sex, singleton status, parity, maternal age, maternal smoking, maternal education, maternal cohabitation, maternal country of origin, maternal income at birth, maternal BMI, maternal residence at birth, maternal history of CVD and diabetes before childbirth, and paternal history of CVD before childbirth.

c<6 cases are not allowed to report due to data protection in Denmark.

We found offspring of mothers with both HDP and history of CVD had a higher risk of early-onset CVD (HR, 1.67; 95% CI, 1.41 to 1.98; P < 0.001), compared to offspring born to mothers with HDP alone (HR, 1.23; 95% CI, 1.19 to 1.26; P < 0.001). Offspring born to mothers with HDP and history of diabetes also tended to have a higher risk of early-onset CVD (HR, 1.56; 95% CI, 1.34 to 1.83; P < 0.001), compared to offspring of mothers with HDP alone (HR, 1.23; 95% CI, 1.19 to 1.27; P < 0.001) (Table 3).

Table 3. The joint effect of maternal HDP and maternal CVD/maternal diabetes history before childbirth on early-onset CVD in offspring.

Attributing effects No. of CVD cases Rate (1/103) cHR P value aHRa P value
(95% CI) (95% CI)
Interaction for HDP and maternal CVD history
Main effects
Maternal HDP only 4,397 2.46 1.24 (1.20–1.28) <0.001 1.23 (1.19–1.26) <0.001
    Maternal CVD only 1,906 2.24 1.37 (1.31–1.43) <0.001 1.29 (1.24–1.35) <0.001
Joint effects
    Maternal HDP and CVD 135 2.83 1.83 (1.54–2.16) <0.001 1.67 (1.41–1.98) <0.001
Interaction for HDP and maternal diabetes history
Main effects
Maternal HDP only 4,376 2.46 1.23 (1.20–1.27) <0.001 1.23 (1.19–1.27) <0.001
    Maternal diabetes only 929 2.10 1.37 (1.28–1.46) <0.001 1.26 (1.18–1.34) <0.001
Joint effects
    Maternal HDP and diabetes 156 2.62 1.70 (1.45–1.99) <0.001 1.56 (1.34–1.83) <0.001
Open in a new tab

aHR, adjusted hazard ratio; cHR, crude hazard ratio; CVD, cardiovascular disease; HDP, hypertensive disorders of pregnancy.

aAdjusted for calendar year, sex, singleton status, parity, maternal age, maternal smoking, maternal education, maternal cohabitation, maternal country of origin, maternal income at birth, maternal BMI, maternal residence at birth, maternal history of CVD and diabetes before childbirth, and paternal history of CVD before childbirth.

Offspring born to mothers with early-onset preeclampsia had a higher risk of early-onset CVD (HR, 1.30; 95% CI, 1.22 to 1.39; P < 0.001), compared with late-onset preeclampsia (HR, 1.19; 95% CI, 1.14 to 1.24; P < 0.001). The risk of early-onset CVD tended to increase with the severity of preeclampsia, the estimated risk for severe preeclampsia and HELLP syndrome (HR, 1.32, 95% CI, 1.21 to 1.43; P < 0.001) was higher than moderate preeclampsia (HR, 1.21; 95% CI, 1.16 to 1.25; P < 0.001). Considering both timing of onset and severity of preeclampsia on offspring CVD, the strongest association was found for early-onset and severe preeclampsia (HR, 1.48; 95% CI, 1.30 to 1.67; P < 0.001) (Table 4).

Table 4. The risk of early-onset CVD in offspring according to the timing and severity of maternal preeclampsia.

No. of CVD cases Rate (1/103) cHR (95% CI) P value aHRa (95% CI) P value
By timing of preeclampsia b
Early-onset 904 2.52 1.37 (1.28–1.46) <0.001 1.30 (1.22–1.39) <0.001
Late-onset 2,235 2.54 1.19 (1.14–1.24) <0.001 1.19 (1.14–1.24) <0.001
By severity of preeclampsia
Moderate 2,607 2.55 1.21 (1.16–1.26) <0.001 1.21 (1.16–1.25) <0.001
Severe and HELLP 532 2.44 1.37 (1.26–1.49) <0.001 1.32 (1.21–1.43) <0.001
Timing and severity of preeclampsia
Late-onset* Moderate 1,953 2.58 1.18 (1.13–1.23) <0.001 1.19 (1.14–1.25) <0.001
Late-onset* Severe/HELLP 282 2.31 1.23 (1.09–1.38) <0.001 1.20 (1.07–1.35) 0.002
Early-onset* Moderate 654 2.49 1.30 (1.21–1.41) <0.001 1.25 (1.16–1.35) <0.001
Early-onset* Severe/HELLP 250 2.61 1.57 (1.39–1.78) <0.001 1.48 (1.30–1.67) <0.001
Open in a new tab

aHR, adjusted hazard ratio; cHR, crude hazard ratio; CVD, cardiovascular disease; HELLP, hemolysis, elevated liver enzymes, and low platelet.

aAdjusted for calendar year, sex, singleton status, parity, maternal age, maternal smoking, maternal education, maternal cohabitation, maternal country of origin, maternal income at birth, maternal BMI, maternal residence at birth, maternal history of CVD and diabetes before childbirth, and paternal history of CVD before childbirth.

bIncludes moderate preeclampsia, severe preeclampsia, and HELLP syndrome.

Sibship analyses restricting offspring to sibling pairs with same mother but different father (half-sibling) or sibling pairs with same mother and father (full-sibling) showed the increased risks of most type-specific CVDs (S2 Fig), such as hypertensive disease (half-sibling [HR, 2.05; 95% CI, 1.88 to 2.24; P < 0.001]; full-sibling [HR, 2.08; 95% CI, 1.89 to 2.28; P < 0.001]), pulmonary embolism (half-sibling [HR, 1.47; 95% CI, 1.20 to 1.79; P < 0.001]; full-sibling [HR, 1.41; 95% CI, 1.13 to 1.75]; P = 0.002), and deep vein thrombosis (half-sibling [HR, 1.28; 95% CI, 1.10 to 1.49; P = 0.001]; full-sibling [HR, 1.31; 95% CI, 1.11 to 1.54; P = 0.001]). Analyses using paternal hypertension before pregnancy as “control exposure” indicated a weak association (HR, 1.07; 95% CI, 0.95 to 1.22; P = 0.267) between paternal hypertension and offspring CVD (S3 Table). Moreover, for the timing of the diagnosis of maternal HDP, the association was the strongest when maternal HDP was diagnosed before childbirth (HR, 1.20; 95% CI, 1.16 to 1.23; P < 0.001). The associations attenuated with elapsed time after birth when maternal HDP diagnosis was made (S3 Fig). The analyses stratified by preterm births or baseline characteristics, additionally adjusted for paternal hypertension, restricted to offspring born after 1991, 1994, 2001, used multiple imputation and complete cases analyses, yielded similar results to those obtained in the primary analyses (S4–S6 Tables).

Discussion

In this large population-based cohort study with a follow-up of up to 40 years, we found that offspring born to mothers with preeclampsia or eclampsia, gestational hypertension, and pregestational hypertension had 22%, 25%, and 28% increased risks of early-onset CVD in offspring from birth to early adulthood, respectively, compared to offspring born to mothers without HDP. Similar associations were observed in certain specific types of CVD, for example, hypertensive disease and myocardial infarction. Stronger associations were found among offspring of mothers with a history of diabetes (56% increased risk) or CVD (67% increased risk). Timing of onset and severity of preeclampsia would also influence the association, and the strongest association was observed for early-onset and severe preeclampsia.

Multiple case–control and cohort studies have provided evidence of the association between HDP and a range of CVD risk factors and CVD-related diseases in offspring during neonatal period, childhood, adolescence, and young adulthood, including biochemical markers of CVD in newborns (lower birth weight and smaller abdominal circumference) [29], higher systolic and diastolic blood pressure [19,23,30–33], BMI [19,31,34], and waist circumference [18], unfavorable lipid profile [18,35], and obesity [36]. There has been limited empirical evidence on the associations of HDP (mainly preeclampsia) with CVD morbidity and few subtypes of CVD, including stroke and hypertension [21–25]. A population-based study of offspring up to 18 years of age in Israel found that severe preeclampsia was associated with more than 2-fold increased risk of cardiovascular morbidity (including hypertension, arrhythmia, and heart failure) in offspring born at term, but not in offspring born preterm [21]. Studies from New England Birth Cohort and Western Australian Pregnancy Cohort found that young adults exposed to maternal HDP was at an increased risk of self-reported hypertension [22,23]. The Helsinki Birth Cohort Study demonstrated that the risks of thrombotic stroke and hypertension were higher among offspring exposed to mothers with gestational hypertension and severe preeclampsia [24]. The empirical evidence on the association remains preliminary, due to the relatively small sample size or short follow-up that did not permit detailed analyses for subtypes of exposure and outcomes. The validity of self-reported diseases might also be prone to bias [21–24]. Our large cohort study found an increased risk of overall and certain type-specific CVDs from birth to young adulthood (up to 40 years old) in individuals of mothers with preeclampsia or eclampsia, which was in line with previous studies. And we also observed similar increased risks in relation to prenatal exposure to maternal gestational hypertension and pregestational hypertension. In addition to increased risks of hypertensive disease, heart failure, and stroke that were observed in previous studies, we provided evidence on the association of maternal HDP with several other types of CVD like myocardial infarction for the first time. The differences in the association between maternal HDP and type-specific CVDs in offspring may be due to complex pathophysiology and the effects of various future risk factors for the development of type-specific CVDs [37]. Further investigation on the underlying mechanisms and to explore the effects of other different risk factors during life for specific CVDs are warranted. We further observed an increasing trend of CVD risk in offspring with increased severity of preeclampsia, consistent with the observation in a previous study [24]. Interestingly, we observed an increased risk early-onset CVD in offspring born to mothers with preeclampsia, irrespective of being preterm or not, suggesting that the association between preeclampsia and early-onset CVD in offspring may be independent of preterm birth or gestational age [21].

Several underlying mechanisms may be used to interpret our findings. It has been proposed that in utero exposure to adverse intrauterine environment was associated with a series of cardiovascular outcomes later in life [7–9]. HDP may exert an adverse effect on abnormal placental development in early pregnancy, which would lead to an ischemic and hypoxic environment for fetal development from the first trimester and activate an overexpress of antiangiogenic factors from the second trimester, thereby inhibiting vascular endothelial and placental growth [15,17]. Placental ischemia and intrauterine hypoxia environment would result in impaired metabolism, ventricular and myocardial hypoplasia, and epicardial detachment in rat fetuses [38,39]. These abnormal intrauterine environmental factors would affect cardiac development later in life by inducing adverse structural and functional changes to the cardiovascular system both in fetal and postfetal life [7–9,17,40–42]. Several studies have found that adverse structural and functional changes in the heart and blood vessels in offspring born to mothers with preeclampsia, including systemic vascular dysfunction, decreased measures of microvascular function, and smaller hearts from childhood [16,42,43]. In addition to the abovementioned mechanisms, damaged DNA and epigenetic changes, an overactive sympathetic nervous system, shared genetic and environmental characteristics, and lifestyle factors may contribute to the association between HDP and CVD in offspring [17].

We found higher risks of CVD in offspring born to mothers with both HDP and a history of diabetes or CVD, compared to offspring born to mothers with no HDP and no history of diabetes or CVD. Although the pathophysiology and interplay of maternal HDP and maternal history of CVD with diabetes on the development of CVD in offspring remains less understood, the added influence of maternal history of diabetes or CVD on CVD risk in offspring needs further research to evaluate the burden of multimorbidity during pregnancy.

A previous study has reported that severe preeclampsia was reported to be an independent risk factor for cardiovascular morbidity in offspring [21]. It was suggested that placental gene expression between severe early-onset and late-onset preeclampsia was different and that placentas in the early preeclampsia groups had a higher risk of infarction [26,44]. In line with these evidences, we observed that offspring born to mothers with early-onset and severe preeclampsia had a higher risk of developing CVD.

Strengths and limitations

This study has some strengths. First, the prospectively collected register data and the inclusion of all Danish live-born children minimized the probability of recall bias and selection bias. Second, the long-term follow-up and the large sample size allowed us to investigate the association between HDP and the CVD subtypes from birth to childhood, adolescence, and beyond. Third, we were able to use sibship design to assess the influences of uncontrolled confounding due to shared inheritance or common characteristics within the family.

Some limitations are also worth mentioning. First, we could not exclude the possibility of residual confounding due to lack of information on certain important confounders, such as smoking status, physical activity, alcohol use, diet, and other lifestyle factors [2,45]. However, we have adjusted for a large number of potential confounding factors, which have been considered as the most important ones. Moreover, sibling-matched analysis yielded similar results. In addition, the considerably great impact of maternal hypertension, compared with paternal hypertension, on the CVD risk in offspring, further suggested that observed associations are unlikely to be attributable completely to uncontrolled confounding. Second, there might be misclassification in the diagnosis of HDP and CVD. However, in a validity study of preeclampsia-related diagnosis in Denmark, a moderate sensitivity of 69% and a high specificity of 99% were shown for all-type preeclampsia [15,46]. Besides, the diagnoses of the most common CVD were recorded accurately, and the positive predictive values exceeded 90% in DNPR [47]. Third, our study was conducted in Denmark where a secure social welfare system has well been established [27], thus our findings may not be generalized to other countries. Further studies are warranted to replicate our findings in developing countries in particular, where prevalence of maternal HDP and early-onset CVD might be different from the countries in the Nordic setting.

Conclusions

Our findings suggest that offspring born to mothers with HDP, especially mothers with CVD history or diabetes history, are at increased risks of overall and certain type-specific early-onset CVDs in their first decades of life. Further research is warranted to better understand the mechanisms underlying the relationship between maternal HDP and early-onset CVD in offspring.

Supporting information

S1 Checklist. STROBE checklist for reporting cohort studies.

(DOCX)

Click here for additional data file. (21.7KB, docx)
S1 Text. Study protocol.

(DOCX)

Click here for additional data file. (72.3KB, docx)
S2 Text. Detailed description of registers used in this study.

(DOCX)

Click here for additional data file. (16.7KB, docx)
S3 Text. Detailed description of covariates.

(DOCX)

Click here for additional data file. (15.6KB, docx)
S1 Table. Exposure classification of hypertensive disorders from the International Classification of Diseases, the eighth and 10th version (ICD-8 and ICD-10).

(DOCX)

Click here for additional data file. (16KB, docx)
S2 Table. Outcome classification of overall CVD and specific CVD from the International Classification of Diseases, the eighth and 10th version (ICD-8 and ICD-10).

(DOCX)

Click here for additional data file. (16.1KB, docx)
S3 Table. Associations between paternal hypertension before pregnancy and early-onset CVD in offspring.

(DOCX)

Click here for additional data file. (15.7KB, docx)
S4 Table. Associations between maternal preeclampsia or eclampsia and early-onset CVD in offspring according to the timing of the delivery.

(DOCX)

Click here for additional data file. (16.7KB, docx)
S5 Table. Associations between maternal hypertensive disorder of pregnancy and early-onset CVD in offspring, by characteristics.

(DOCX)

Click here for additional data file. (22.8KB, docx)
S6 Table. Subanalyses of the association between maternal hypertensive disorder of pregnancy and early-onset CVD in offspring.

(DOCX)

Click here for additional data file. (29KB, docx)
S1 Fig. Causal diagram showing selection of covariates for confounding control.

(DOCX)

Click here for additional data file. (129.1KB, docx)
S2 Fig. Associations between maternal hypertensive disorders of pregnancy and early-onset CVD in offspring of sibling pairs.

(DOCX)

Click here for additional data file. (127.6KB, docx)
S3 Fig. Associations between maternal hypertensive disorder of pregnancy and early-onset CVD in offspring, according to the timing of the maternal HDP diagnosis.

(DOCX)

Click here for additional data file. (98.7KB, docx)
S4 Fig. The log-minus-log survival curve.

(DOCX)

Click here for additional data file. (100.8KB, docx)

Abbreviations

CVD

cardiovascular disease

DNPR

Danish National Patient Register

HDP

hypertensive disorders of pregnancy

HELLP

hemolysis, elevated liver enzymes, and low platelet

HR

hazard ratio

ICD

International Classification of Diseases

Data Availability

All data is stored at the secure platform of Denmark Statistics, which is the central authority on Danish statistics with the mission to collect, compile and publish statistics on the Danish society. Due to restrictions related to Danish law and protecting patient privacy, the combined set of data as used in this study can only be made available through a trusted third party, Statistics Denmark (https://www.dst.dk/en/kontakt). This state organisation holds the data used for this study. University-based Danish scientific organisations can be authorized to work with data within Statistics Denmark and such organisation can provide access to individual scientists inside and outside of Denmark. Researchers can apply for access to these data when the request is approved by the Danish Data Protection Agency: https://www.datatilsynet.dk, the email address for the Danish Data Protection Agency is: dt@datatilsynet.dk. Requests for data may be sent to Statistics Denmark: http://www.dst.dk/en/OmDS/organisation/TelefonbogOrg.aspx?kontor=13&tlfbogsort=sektion or the Danish Data Protection Agency: https://www.datatilsynet.dk.

Funding Statement

This study was supported by a grant from Shanghai Rising-Star Program (21QA1401300) to YY; grants from the Independent Research Fund Denmark (DFF-6110-00019B, DFF-9039-00010B, and DFF-1030-00012B) to JL; a grant from the Nordic Cancer Union (R275-A15770) to JL; a grant from the Karen Elise Jensens Fond (2016) to JL; a grant from Novo Nordisk Foundation (NNF18OC0052029) to JL; grants from the National Natural Science Foundation of China (82073570 and 11871164 to GQ); and a grant from Swedish Heart and Lung Foundation (20180306) to KL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.Timmis A, Townsend N, Gale CP, Torbica A, Lettino M, Petersen SE, et al. European Society of Cardiology: Cardiovascular Disease Statistics 2019. Eur Heart J. 2020;41(1):12–85. Epub 2019/12/11. doi: 10.1093/eurheartj/ehz859 . [DOI] [PubMed] [Google Scholar]
  • 2.Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, et al. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation. 2021;143(8):e254–e743. Epub 2021/01/28. doi: 10.1161/CIR.0000000000000950 . [DOI] [PubMed] [Google Scholar]
  • 3.Andersson C, Vasan RS. Epidemiology of cardiovascular disease in young individuals. Nat Rev Cardiol. 2018;15(4):230–40. Epub 2017/10/13. doi: 10.1038/nrcardio.2017.154 . [DOI] [PubMed] [Google Scholar]
  • 4.Yu Y, Arah OA, Liew Z, Cnattingius S, Olsen J, Sorensen HT, et al. Maternal diabetes during pregnancy and early onset of cardiovascular disease in offspring: population based cohort study with 40 years of follow-up. BMJ. 2019;367:l6398. Epub 2019/12/06. doi: 10.1136/bmj.l6398; PubMed Central PMCID: PMC6891797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Jousilahti P, Tuomilehto J, Vartiainen E, Pekkanen J, Puska P. Body weight, cardiovascular risk factors, and coronary mortality. 15-year follow-up of middle-aged men and women in eastern Finland. Circulation. 1996;93(7):1372–9. Epub 1996/04/01. doi: 10.1161/01.cir.93.7.1372 [DOI] [PubMed] [Google Scholar]
  • 6.Riaz H, Khan MS, Siddiqi TJ, Usman MS, Shah N, Goyal A, et al. Association Between Obesity and Cardiovascular Outcomes: A Systematic Review and Meta-analysis of Mendelian Randomization Studies. JAMA Netw Open. 2018;1(7):e183788. Epub 2019/01/16. doi: 10.1001/jamanetworkopen.2018.3788; PubMed Central PMCID: PMC6324374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Barker DJ. Fetal origins of coronary heart disease. BMJ. 1995;311(6998):171–4. Epub 1995/07/15. doi: 10.1136/bmj.311.6998.171 ; PubMed Central PMCID: PMC2550226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Barker DJ. In utero programming of cardiovascular disease. Theriogenology. 2000;53(2):555–74. Epub 2000/03/29. doi: 10.1016/s0093-691x(99)00258-7 . [DOI] [PubMed] [Google Scholar]
  • 9.Barker DJ, Bagby SP, Hanson MA. Mechanisms of disease: in utero programming in the pathogenesis of hypertension. Nat Clin Pract Nephrol. 2006;2(12):700–7. Epub 2006/11/25. doi: 10.1038/ncpneph0344 . [DOI] [PubMed] [Google Scholar]
  • 10.Persson M, Razaz N, Edstedt Bonamy AK, Villamor E, Cnattingius S. Maternal Overweight and Obesity and Risk of Congenital Heart Defects. J Am Coll Cardiol. 2019;73(1):44–53. Epub 2019/01/10. doi: 10.1016/j.jacc.2018.10.050 . [DOI] [PubMed] [Google Scholar]
  • 11.Tyrrell J, Richmond RC, Palmer TM, Feenstra B, Rangarajan J, Metrustry S, et al. Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight. JAMA. 2016;315(11):1129–40. Epub 2016/03/16. doi: 10.1001/jama.2016.1975 ; PubMed Central PMCID: PMC4811305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Gaillard R. Maternal obesity during pregnancy and cardiovascular development and disease in the offspring. Eur J Epidemiol. 2015;30(11):1141–52. Epub 2015/09/18. doi: 10.1007/s10654-015-0085-7 ; PubMed Central PMCID: PMC4684830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Webster K, Fishburn S, Maresh M, Findlay SC, Chappell LC, Guideline C. Diagnosis and management of hypertension in pregnancy: summary of updated NICE guidance. BMJ. 2019;366:l5119. Epub 2019/09/11. doi: 10.1136/bmj.l5119. [DOI] [PubMed] [Google Scholar]
  • 14.Roberts JM, Pearson G, Cutler J, Lindheimer M, Pregnancy NWGoRoHD. Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy. Hypertension. 2003;41(3):437–45. Epub 2003/03/08. doi: 10.1161/01.HYP.0000054981.03589.E9 . [DOI] [PubMed] [Google Scholar]
  • 15.Arendt LH, Henriksen TB, Lindhard MS, Parner ET, Olsen J, Ramlau-Hansen CH. Hypertensive Disorders of Pregnancy and Genital Anomalies in Boys: A Danish Nationwide Cohort Study. Epidemiology. 2018;29(5):739–48. Epub 2018/06/19. doi: 10.1097/EDE.0000000000000878 . [DOI] [PubMed] [Google Scholar]
  • 16.Jayet PY, Rimoldi SF, Stuber T, Salmon CS, Hutter D, Rexhaj E, et al. Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia. Circulation. 2010;122(5):488–94. Epub 2010/07/21. doi: 10.1161/CIRCULATIONAHA.110.941203 . [DOI] [PubMed] [Google Scholar]
  • 17.Davis EF, Newton L, Lewandowski AJ, Lazdam M, Kelly BA, Kyriakou T, et al. Pre-eclampsia and offspring cardiovascular health: mechanistic insights from experimental studies. Clin Sci (Lond). 2012;123(2):53–72. Epub 2012/03/30. doi: 10.1042/CS20110627 ; PubMed Central PMCID: PMC3315178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Alsnes IV, Vatten LJ, Fraser A, Bjorngaard JH, Rich-Edwards J, Romundstad PR, et al. Hypertension in Pregnancy and Offspring Cardiovascular Risk in Young Adulthood: Prospective and Sibling Studies in the HUNT Study (Nord-Trondelag Health Study) in Norway. Hypertension. 2017;69(4):591–8. Epub 2017/02/23. doi: 10.1161/HYPERTENSIONAHA.116.08414 . [DOI] [PubMed] [Google Scholar]
  • 19.Davis EF, Lazdam M, Lewandowski AJ, Worton SA, Kelly B, Kenworthy Y, et al. Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review. Pediatrics. 2012;129(6):e1552–61. Epub 2012/05/23. doi: 10.1542/peds.2011-3093 . [DOI] [PubMed] [Google Scholar]
  • 20.Auger N, Fraser WD, Healy-Profitos J, Arbour L. Association Between Preeclampsia and Congenital Heart Defects. JAMA. 2015;314(15):1588–98. Epub 2015/10/27. doi: 10.1001/jama.2015.12505 . [DOI] [PubMed] [Google Scholar]
  • 21.Nahum Sacks K, Friger M, Shoham-Vardi I, Spiegel E, Sergienko R, Landau D, et al. Prenatal exposure to preeclampsia as an independent risk factor for long-term cardiovascular morbidity of the offspring. Pregnancy Hypertens. 2018;13:181–6. Epub 2018/09/05. doi: 10.1016/j.preghy.2018.06.013 . [DOI] [PubMed] [Google Scholar]
  • 22.Palmsten K, Buka SL, Michels KB. Maternal pregnancy-related hypertension and risk for hypertension in offspring later in life. Obstet Gynecol. 2010;116(4):858–64. Epub 2010/09/23. doi: 10.1097/AOG.0b013e3181f3a1f9 ; PubMed Central PMCID: PMC3514878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Davis EF, Lewandowski AJ, Aye C, Williamson W, Boardman H, Huang RC, et al. Clinical cardiovascular risk during young adulthood in offspring of hypertensive pregnancies: insights from a 20-year prospective follow-up birth cohort. BMJ Open. 2015;5(6):e008136. Epub 2015/06/25. doi: 10.1136/bmjopen-2015-008136; PubMed Central PMCID: PMC4480003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DJ. Pre-eclampsia is associated with increased risk of stroke in the adult offspring: the Helsinki birth cohort study. Stroke. 2009;40(4):1176–80. Epub 2009/03/07. doi: 10.1161/STROKEAHA.108.538025 . [DOI] [PubMed] [Google Scholar]
  • 25.Herrera-Garcia G, Contag S. Maternal preeclampsia and risk for cardiovascular disease in offspring. Curr Hypertens Rep. 2014;16(9):475. Epub 2014/08/07. doi: 10.1007/s11906-014-0475-3. [DOI] [PubMed] [Google Scholar]
  • 26.van der Merwe JL, Hall DR, Wright C, Schubert P, Grove D. Are early and late preeclampsia distinct subclasses of the disease—what does the placenta reveal? Hypertens Pregnancy. 2010;29(4):457–67. Epub 2010/08/13. doi: 10.3109/10641950903572282 . [DOI] [PubMed] [Google Scholar]
  • 27.Schmidt M, Schmidt SAJ, Adelborg K, Sundboll J, Laugesen K, Ehrenstein V, et al. The Danish health care system and epidemiological research: from health care contacts to database records. Clin Epidemiol. 2019;11:563–91. Epub 2019/08/03. doi: 10.2147/CLEP.S179083 ; PubMed Central PMCID: PMC6634267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Sorensen HT, Christensen T, Schlosser HK, et al. Use of medical databases in clinical epidemiology. 2nd ed. Aarhus, Denmark: SUN-TRYK, Aarhus Universitet; 2009. [Google Scholar]
  • 29.Ophir E, Dourleshter G, Hirsh Y, Fait V, German L, Bornstein J. Newborns of pre-eclamptic women: a biochemical difference present in utero. Acta Obstet Gynecol Scand. 2006;85(10):1172–8. Epub 2006/10/28. doi: 10.1080/00016340600697272 . [DOI] [PubMed] [Google Scholar]
  • 30.Mamun AA, Kinarivala MK, O’Callaghan M, Williams G, Najman J, Callaway L. Does hypertensive disorder of pregnancy predict offspring blood pressure at 21 years? Evidence from a birth cohort study. J Hum Hypertens. 2012;26(5):288–94. Epub 2011/04/22. doi: 10.1038/jhh.2011.35 . [DOI] [PubMed] [Google Scholar]
  • 31.Kurbasic A, Fraser A, Mogren I, Hallmans G, Franks PW, Rich-Edwards JW, et al. Maternal Hypertensive Disorders of Pregnancy and Offspring Risk of Hypertension: A Population-Based Cohort and Sibling Study. Am J Hypertens. 2019;32(4):331–4. Epub 2018/11/27. doi: 10.1093/ajh/hpy176 ; PubMed Central PMCID: PMC6420682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Tripathi RR, Rifas-Shiman SL, Hawley N, Hivert MF, Oken E. Hypertensive Disorders of Pregnancy and Offspring Cardiometabolic Health at Midchildhood: Project Viva Findings. J Am Heart Assoc. 2018;7(3). Epub 2018/02/01. doi: 10.1161/JAHA.117.007426; PubMed Central PMCID: PMC5850245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Lawlor DA, Macdonald-Wallis C, Fraser A, Nelson SM, Hingorani A, Davey Smith G, et al. Cardiovascular biomarkers and vascular function during childhood in the offspring of mothers with hypertensive disorders of pregnancy: findings from the Avon Longitudinal Study of Parents and Children. Eur Heart J. 2012;33(3):335–45. Epub 2011/08/25. doi: 10.1093/eurheartj/ehr300 ; PubMed Central PMCID: PMC3270043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Wang LB, Qu B, Xu P, Wu LL, Gu JS, Shah NK, et al. Preeclampsia exposed offspring have greater body mass index than non-exposed offspring during peripubertal life: A meta-analysis. Pregnancy Hypertens. 2020;19:247–52. Epub 2019/12/07. doi: 10.1016/j.preghy.2019.09.010 . [DOI] [PubMed] [Google Scholar]
  • 35.Miettola S, Hartikainen AL, Vaarasmaki M, Bloigu A, Ruokonen A, Jarvelin MR, et al. Offspring’s blood pressure and metabolic phenotype after exposure to gestational hypertension in utero. Eur J Epidemiol. 2013;28(1):87–98. Epub 2013/01/29. doi: 10.1007/s10654-013-9763-5 . [DOI] [PubMed] [Google Scholar]
  • 36.Zhang S, Wang L, Leng J, Liu H, Li W, Zhang T, et al. Hypertensive disorders of pregnancy in women with gestational diabetes mellitus on overweight status of their children. J Hum Hypertens. 2017;31(11):731–6. Epub 2017/03/17. doi: 10.1038/jhh.2017.17 ; PubMed Central PMCID: PMC5600626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Schiano C, Benincasa G, Franzese M, Della Mura N, Pane K, Salvatore M, et al. Epigenetic-sensitive pathways in personalized therapy of major cardiovascular diseases. Pharmacol Ther. 2020;210:107514. Epub 2020/02/28. doi: 10.1016/j.pharmthera.2020.107514. [DOI] [PubMed] [Google Scholar]
  • 38.Ream M, Ray AM, Chandra R, Chikaraishi DM. Early fetal hypoxia leads to growth restriction and myocardial thinning. Am J Physiol Regul Integr Comp Physiol. 2008;295(2):R583–95. Epub 2008/05/30. doi: 10.1152/ajpregu.00771.2007 ; PubMed Central PMCID: PMC2519936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Heltemes A, Gingery A, Soldner EL, Bozadjieva N, Jahr KN, Johnson BK, et al. Chronic placental ischemia alters amniotic fluid milieu and results in impaired glucose tolerance, insulin resistance and hyperleptinemia in young rats. Exp Biol Med (Maywood). 2010;235(7):892–9. Epub 2010/06/19. doi: 10.1258/ebm.2010.009357 . [DOI] [PubMed] [Google Scholar]
  • 40.Lewandowski AJ, Lazdam M, Davis E, Kylintireas I, Diesch J, Francis J, et al. Short-term exposure to exogenous lipids in premature infants and long-term changes in aortic and cardiac function. Arterioscler Thromb Vasc Biol. 2011;31(9):2125–35. Epub 2011/08/06. doi: 10.1161/ATVBAHA.111.227298 . [DOI] [PubMed] [Google Scholar]
  • 41.Akcakus M, Altunay L, Yikilmaz A, Yazici C, Koklu E. The relationship between abdominal aortic intima-media thickness and lipid profile in neonates born to mothers with preeclampsia. J Pediatr Endocrinol Metab. 2010;23(11):1143–9. Epub 2011/02/03. doi: 10.1515/jpem.2010.179 . [DOI] [PubMed] [Google Scholar]
  • 42.Fugelseth D, Ramstad HB, Kvehaugen AS, Nestaas E, Stoylen A, Staff AC. Myocardial function in offspring 5-8years after pregnancy complicated by preeclampsia. Early Hum Dev. 2011;87(8):531–5. Epub 2011/05/10. doi: 10.1016/j.earlhumdev.2011.04.006 . [DOI] [PubMed] [Google Scholar]
  • 43.Plummer MD, Andraweera PH, Garrett A, Leemaqz S, Wittwer M, Aldridge E, et al. Hypertensive disorders of pregnancy and later cardiovascular disease risk in mothers and children. J Dev Orig Health Dis. 2020:1–6. Epub 2020/10/16. doi: 10.1017/S2040174420000896 . [DOI] [PubMed] [Google Scholar]
  • 44.Nevalainen J, Skarp S, Savolainen ER, Ryynanen M, Jarvenpaa J. Intrauterine growth restriction and placental gene expression in severe preeclampsia, comparing early-onset and late-onset forms. J Perinat Med. 2017;45(7):869–77. Epub 2017/06/09. doi: 10.1515/jpm-2016-0406 . [DOI] [PubMed] [Google Scholar]
  • 45.Bliddal M, Broe A, Pottegard A, Olsen J, Langhoff-Roos J. The Danish Medical Birth Register. Eur J Epidemiol. 2018;33(1):27–36. Epub 2018/01/20. doi: 10.1007/s10654-018-0356-1 . [DOI] [PubMed] [Google Scholar]
  • 46.Klemmensen AK, Olsen SF, Osterdal ML, Tabor A. Validity of preeclampsia-related diagnoses recorded in a national hospital registry and in a postpartum interview of the women. Am J Epidemiol. 2007;166(2):117–24. Epub 2007/06/09. doi: 10.1093/aje/kwm139 . [DOI] [PubMed] [Google Scholar]
  • 47.Sundboll J, Adelborg K, Munch T, Froslev T, Sorensen HT, Botker HE, et al. Positive predictive value of cardiovascular diagnoses in the Danish National Patient Registry: a validation study. BMJ Open. 2016;6(11):e012832. Epub 2016/11/20. doi: 10.1136/bmjopen-2016-012832; PubMed Central PMCID: PMC5129042. [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Richard Turner

15 Feb 2021

Dear Dr Yu,

Thank you for submitting your manuscript entitled "Maternal hypertensive disorder of pregnancy and offspring early-onset cardiovascular disease in childhood, adolescence, and young adulthood: A national population-based cohort study" for consideration by PLOS Medicine for our upcoming Special Issue.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff as well as by the Guest Editors, and I am writing to let you know that we would like to send your submission out for external assessment.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by .

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for external assessment.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Richard Turner, PhD

Senior Editor, PLOS Medicine

rturner@plos.org

Decision Letter 1

Richard Turner

23 Apr 2021

Dear Dr. Yu,

Thank you very much for submitting your manuscript "Maternal hypertensive disorder of pregnancy and offspring early-onset cardiovascular disease in childhood, adolescence, and young adulthood: A national population-based cohort study" (PMEDICINE-D-21-00753R1) for consideration at PLOS Medicine for our upcoming Special Issue.

Your paper was evaluated by the Guest Editors for the issue, discussed among the editorial team and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to invite you to submit a revised version that addresses the reviewers' and editors' comments fully. You will appreciate that we cannot make a decision about publication until we have seen the revised manuscript and your response. We expect to seek re-review by one or more of the reviewers, and may enlist an additional reviewer.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We hope to receive your revised manuscript by May 14 2021 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

Please let me know if you have any questions, and we look forward to receiving your revised manuscript.

Sincerely,

Richard Turner, PhD

Senior Editor, PLOS Medicine

rturner@plos.org

-----------------------------------------------------------

Requests from the editors:

In the abstract, please quote summary demographic details for study participants.

Please add a new final sentence to the "Methods and findings" subsection of your abstract, which should begin "Study limitations include ..." or similar and quote 2-3 of the study's main limitations.

Please add bullets to the individual points in your author summary.

Early in the Methods section, please state whether the study had a protocol or prespecified analysis plan, and if so attach the relevant document(s) as supplementary files, referred to in the text. Please highlight non-prespecified analyses.

At line 186, would " ... preplanned sensitivity analyses:" be appropriate?

At line 330 and any other relevant points, please make that "... also worth mentioning.".

Throughout the text, please remove spaces from within your reference call-outs (e.g., "... undeveloped countries [3,4].").

At the end of the main text, please remove information on funding, competing interests and data availability. In the event of publication, this information will appear in the article metadata, via entries in the submission form.

In the reference list, please remove the information on competing interests and so on from reference 4, and any other relevant references.

Noting reference 26, please ensure that all references have full access information.

Noting table 1, please substitute "sex" for "gender" where appropriate.

Please move figure S1 to the main body of the paper.

Please add a completed checklist for the most appropriate reporting guideline, e.g., STROBE, labelled "S1_STROBE_Checklist" or similar and referred to as such in your Methods section. In the checklist, please refer to individual items by section (e.g., "Methods") and paragraph number rather than by line or page numbers, as the latter generally change in the event of publication,

Comments from the reviewers:

*** Reviewer #1:

Using Danish national health registries, this population-based cohort study aims to examine the association between maternal HDP and early-onset CVD in offspring from birth to young adulthood (up to 40 years), and whether co-existing maternal history of CVD and diabetes further increases the risk of CVD among offspring.

Comments:

This is a thorough and comprehensive analysis, applying an appropriate and rigorous statistical methodology.

An extensive array of sensitivity and subgroup analyses have been completed demonstrating robustness and providing confidence in the results.

The authors have also adequately acknowledged the main study limitations within the discussion section.

*** Reviewer #2:

This is a very interesting study involving a very large number of subjects exposed to a variety of hypertensive disorders of pregnancy including preeclampsia and eclampsia. The authors also divide preeclampsia in early onset and late onset. The authors conclude that exposure to preeclampsia is associated with a variety of adverse cardiovascular events over a broad range of ages;up to the age of 40 years. The authors also report that maternal history of diabetes and cardiovascular disease are risk factors for cardiovascular disease in the offspring. The data are robust, the analysis very detail and I suggest that the manuscript gets published in its current form

*** Reviewer #3:

Maternal hypertensive disorder of pregnancy and offspring early-onset cardiovascular disease in childhood, and young adulthood:A national population-based cohort study. by Huang, Li, Qin, Liew, Hu et al.

This is a good study and gives unique information from a large population registry in Denmark. There were only a few issue that concerned me and may require the authors to remove of explain.

the conclusion that treatment of the ?maternal hypertensive disorder of pregnancy may reduce the burden of CVD in offspring is unfounded and cannot be stated and should be removed.

I have a few questions:

?how many in the cohort were lost to follow-up due to emigration and how would this confound the results due to lost data?

the CVD endpoints are very inclusive and include both arterial and venous disease. Although these may all be linked to disorders of coagulation, they have many other different risk factors during life and this may act as a confounder. How can this be managed differentially?

rheumatic heart disease was included as a CVD. This disorder is an infective disease (streptococcus) with a genetic risk factor component very different to the other CVD studied. I note there were only a few patients in this group, but I wonder why this group was included?

In the discussion, inclusion of smoking as a potentially lifestyle risk factor in the cohort should be mentioned alongside physical activity and alcohol use as smoking is one of the "big five" CVD risk factors.

I would keen for this study to be published as it adds useful information to the study of maternal placental syndromes.

***

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 2

Richard Turner

6 Sep 2021

Dear Dr. Yu,

Thank you very much for re-submitting your manuscript "Maternal hypertensive disorder of pregnancy and offspring early-onset cardiovascular disease in childhood, adolescence, and young adulthood: A national population-based cohort study" (PMEDICINE-D-21-00753R2) for consideration at PLOS Medicine for our upcoming Special Issue. We apologize for the delay in sending you a decision.

I have discussed the paper with the guest editors and it was also seen by one reviewer. I am pleased to tell you that, provided the remaining editorial and production issues are fully dealt with, we expect to be able to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We hope to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

Please let me know if you have any questions, and we look forward to receiving the revised manuscript.   

Sincerely,

Richard Turner, PhD

Senior Editor, PLOS Medicine

rturner@plos.org

------------------------------------------------------------

Requests from Editors:

In the abstract and throughout the results section, please quote p values alongside 95% CI, where available.

At line 62, please make that "... an increased risk of early onset CVD ..." (the "23%" is implicit in the quoted HR).

At line 73, please make that "... including smoking ..." and remove "etc.".

At line 88, please make that "extent".

At line 95, we suggest making that "(67% increased risk)" for clarity.

Thank you for including the study protocol. Were there any non-prespecified analyses?

At lines 230 and 232, the upper bound of the 95% CI is quoted as "1.26" and "1.27". Please check that both numbers are correct.

Please revisit the author list for reference 28 so that the format matches that of the other references.

We suggest breaking the study protocol and STROBE checklist out into separate attached files, labelled and referred to in the text as "S2_STROBE_Checklist" and similar.

Comments from Reviewers:

*** Reviewer #4:

Review of:

Maternal hypertensive disorder of pregnancy and offspring early-onset cardiovascular disease in childhood, adolescence, and young adulthood: A national population-based cohort study

This study set out to elucidate the association between maternal hypertensive diseases of pregnancy and early-onset CVD in childhood and youth (before 40 years of age). It was conducted as a population-based cohort study of 2.5 million individuals. The study found that maternal HDP (defined as preeclampsia, eclampsia, gestational hypertension or pre-existing hypertension) increased the risk of early CVD by 23%. Specific risk increases were found for MI and hypertension. The association was strongest for early-onset and severe preeclampsia with a 48% risk increase for CVD.

The study however lacked information on some potential confounders such smoking and physical activity, yet a range of other covariables were available.

Major Comments:

This study is unique and has beautiful statistical strength in having such a vast register-based material with follow up over several decades. I congratulate the authors on this feat. Further extensive subgroup analyses have been performed including sibship analyses, timing of delivery and stratified analyses by offspring sex, singleton/gemelli, maternal parity and a range of maternal covariables.

This is a rather extraordinary study which warrants immediate publication and follow-up studies.

Minor comments:

Perhaps I lack understanding of the nature of sibship analysis, but I believe maybe some wording is missing from lines 242-247, to fully understand the implications of the analyses?

***

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 3

Richard Turner

9 Sep 2021

Dear Dr Yu, 

On behalf of my colleagues and the Academic Editor, Dr Bassat, I am pleased to inform you that we have agreed to publish your manuscript "Maternal hypertensive disorder of pregnancy and offspring early-onset cardiovascular disease in childhood, adolescence, and young adulthood: A national population-based cohort study" (PMEDICINE-D-21-00753R3) in PLOS Medicine for our upcoming Special Issue.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process. 

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper. 

Sincerely, 

Richard Turner, PhD 

Senior Editor, PLOS Medicine

rturner@plos.org

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist. STROBE checklist for reporting cohort studies.

    (DOCX)

    Click here for additional data file. (21.7KB, docx)
    S1 Text. Study protocol.

    (DOCX)

    Click here for additional data file. (72.3KB, docx)
    S2 Text. Detailed description of registers used in this study.

    (DOCX)

    Click here for additional data file. (16.7KB, docx)
    S3 Text. Detailed description of covariates.

    (DOCX)

    Click here for additional data file. (15.6KB, docx)
    S1 Table. Exposure classification of hypertensive disorders from the International Classification of Diseases, the eighth and 10th version (ICD-8 and ICD-10).

    (DOCX)

    Click here for additional data file. (16KB, docx)
    S2 Table. Outcome classification of overall CVD and specific CVD from the International Classification of Diseases, the eighth and 10th version (ICD-8 and ICD-10).

    (DOCX)

    Click here for additional data file. (16.1KB, docx)
    S3 Table. Associations between paternal hypertension before pregnancy and early-onset CVD in offspring.

    (DOCX)

    Click here for additional data file. (15.7KB, docx)
    S4 Table. Associations between maternal preeclampsia or eclampsia and early-onset CVD in offspring according to the timing of the delivery.

    (DOCX)

    Click here for additional data file. (16.7KB, docx)
    S5 Table. Associations between maternal hypertensive disorder of pregnancy and early-onset CVD in offspring, by characteristics.

    (DOCX)

    Click here for additional data file. (22.8KB, docx)
    S6 Table. Subanalyses of the association between maternal hypertensive disorder of pregnancy and early-onset CVD in offspring.

    (DOCX)

    Click here for additional data file. (29KB, docx)
    S1 Fig. Causal diagram showing selection of covariates for confounding control.

    (DOCX)

    Click here for additional data file. (129.1KB, docx)
    S2 Fig. Associations between maternal hypertensive disorders of pregnancy and early-onset CVD in offspring of sibling pairs.

    (DOCX)

    Click here for additional data file. (127.6KB, docx)
    S3 Fig. Associations between maternal hypertensive disorder of pregnancy and early-onset CVD in offspring, according to the timing of the maternal HDP diagnosis.

    (DOCX)

    Click here for additional data file. (98.7KB, docx)
    S4 Fig. The log-minus-log survival curve.

    (DOCX)

    Click here for additional data file. (100.8KB, docx)
    Attachment

    Submitted filename: PMEDICINE-D-21-00753R1_rebuttal letter.docx

    Click here for additional data file. (37.5KB, docx)
    Attachment

    Submitted filename: PMEDICINE-D-21-00753R2_rebuttal letter.docx

    Click here for additional data file. (31.4KB, docx)

    Data Availability Statement

    All data is stored at the secure platform of Denmark Statistics, which is the central authority on Danish statistics with the mission to collect, compile and publish statistics on the Danish society. Due to restrictions related to Danish law and protecting patient privacy, the combined set of data as used in this study can only be made available through a trusted third party, Statistics Denmark (https://www.dst.dk/en/kontakt). This state organisation holds the data used for this study. University-based Danish scientific organisations can be authorized to work with data within Statistics Denmark and such organisation can provide access to individual scientists inside and outside of Denmark. Researchers can apply for access to these data when the request is approved by the Danish Data Protection Agency: https://www.datatilsynet.dk, the email address for the Danish Data Protection Agency is: dt@datatilsynet.dk. Requests for data may be sent to Statistics Denmark: http://www.dst.dk/en/OmDS/organisation/TelefonbogOrg.aspx?kontor=13&tlfbogsort=sektion or the Danish Data Protection Agency: https://www.datatilsynet.dk.

    Articles from PLoS Medicine are provided here courtesy of PLOS

    RESOURCES