A history of preterm birth (PTB) may be an important lifetime risk factor for cardiovascular disease (CVD) in women. We identified all peer-reviewed journal articles that met study criteria (English language, human studies, female, and adults ≥19 years old), that were found in the PubMed/MEDLINE databases, and that were published between Jan. 1, 1995, and Sept. 17, 2012. We summarized 10 studies that assessed the association between having a history of PTB and subsequent CVD morbidity or death. Compared with women who had term deliveries, women with any history of PTB had increased risk of CVD morbidity (variously defined; adjusted hazard ratio [aHR] ranged from 1.2–2.9; 2 studies), ischemic heart disease (aHR, 1.3–2.1; 3 studies), stroke (aHR, 1.7; 1 study), and atherosclerosis (aHR, 4.1; 1 study). Four of 5 studies that examined death showed that women with a history of PTB have twice the risk of CVD death compared with women who had term births. Two studies reported statistically significant higher risk of CVD–related morbidity and death outcomes (variously defined) among women with ≥2 pregnancies that ended in PTBs compared with women who had at least 2 births but which ended in only 1 PTB. Future research is needed to understand the potential impact of enhanced monitoring of CVD risk factors in women with a history of PTB on risk of future CVD risk.
Preterm birth (PTB), defined as delivery of an infant at <37 weeks’ gestation, is the leading cause of long-term neurologic disabilities in children and the most common cause of infant death. PTB not only poses risks for the child, but also it may identify women with elevated lifetime risks for cardiovascular disease (CVD).
In 2011, for the first time the American Heart Association identified 3 pregnancy complications (preeclampsia, gestational diabetes mellitus, and pregnancy-induced hypertension) as risk factors for CVD and 2 adverse birth outcomes (PTB and delivery of a small-for-gestational age infant) as possible risk factors for CVD. CVD typically refers to a host of diseases that affect the cardiovascular system and includes atherosclerosis, hypertension, coronary heart disease, stroke, heart failure and other conditions. CVD is the leading cause of death among women overall and the third leading cause of death among women 18-44 years old. Several systematic reviews have examined associations of pregnancy complications and future CVD, but none have provided an in-depth review of the studies that investigated the risk of CVD in mothers with a history of PTB. Some proportion of PTBs is caused by hypertension (with and without preeclampsia), infection, congenital anomalies, diabetes mellitus, prenatal smoking, and placental abnormalities, but the cause of PTB remains unknown in most cases. It is plausible that similar alterations in inflammatory mediators and immune function might be acting in the pathogenesis of both CVD and PTB. Assessment of the current evidence of the association between PTB and future CVD may identify a group of women who possibly could benefit from enhanced clinical screening and monitoring.
The aim of this systematic review was to summarize the evidence that is related to PTB and subsequent CVD in the mother.
Methods
We used a multistage search strategy to conduct a systematic review of the literature to address whether having a PTB is associated with increased risk of future CVD morbidity or death. Three investigators (C.L.R., Y.H., P.M.D.) developed the electronic search strategies using a combination of free text terms and controlled vocabulary concepts that were derived from PubMed’s “All Field” searches and “Medical Subject Headings” and “Title/Abstract” field ( Table 1 ). Additional filters that were applied to the searches included limiting the searches to English language, human studies, female, and adults who were ≥19 years old and to articles that were published from Jan. 1, 1995–Sept. 17, 2012. A 2000 Lancet article claimed that no previous studies had examined the association between PTB and cardiovascular death, and we found no relevant articles before 2000. For the systematic review search, the additional filters “Meta-analysis” and “Review” were applied. First, we searched the PubMed/MEDLINE and Cochrane Library databases to identify relevant systematic reviews or metaanalyses. Next, we searched PubMed/MEDLINE for relevant peer-reviewed individual studies.
| All fields and title abstract | Topic a |
|---|---|
| Predictors | Fetal growth restriction |
| Fetal growth retardation | |
| Low birthweight | |
| Low birthweight infant | |
| Small for gestational age | |
| Very low birthweight infant | |
| Extremely low birthweight infant | |
| Intrauterine growth restriction | |
| Intrauterine growth retardation | |
| Premature infant | |
| Prematurity | |
| Premature birth | |
| Birthweight | |
| Newborn | |
| Preterm delivery | |
| Pre-term delivery | |
| Newborn infant | |
| Complicated pregnancies | |
| Pregnancy complications | |
| Preterm birth | |
| Adverse pregnancy events | |
| Cardiovascular-related outcomes | Cardiovascular disease |
| Cardiovascular pregnancy complications | |
| Hypertension | |
| Dyslipidemia | |
| Hypercholesterolemia | |
| LDL cholesterol | |
| HDL cholesterol | |
| High blood pressure | |
| Hyperlipemia | |
| Hyperlipidemia | |
| Lipemia | |
| Lipidemia | |
| Lipid disorders | |
| Cholesterol | |
| Low density lipoprotein cholesterol | |
| High density lipoprotein cholesterol | |
| Triglycerides | |
| Cerebrovascular accident | |
| Cerebrovascular disease | |
| Ischemic heart disease | |
| Ischaemic heart disease | |
| Myocardial ischemia | |
| Myocardial ischaemia | |
| Thromboembolism | |
| Coronary heart disease | |
| Arteriosclerosis | |
| Cardiovascular death | |
| Cardiovascular morbidity | |
| Cardiovascular risk factors | |
| Cardiovascular risk | |
| Vascular risk | |
| Morbidity and death-related outcomes | Mortality |
| Death | |
| Cause of death | |
| Fatal outcome | |
| Survival rate | |
| Premature death | |
| Hospital death | |
| Maternal death | |
| Maternal risk | |
| Mothers’ risk | |
| Death risk | |
| Death of mothers |
Data collection entailed study selection and data extraction. Two researchers (C.L.R., Y.H.) examined the abstracts with titles that appeared to be relevant and selected all articles that examined the association between PTB and future CVD morbidity and/or death in the mother. We used researcher agreement to reconcile questions about eligibility. Finally, we reviewed reference lists of selected articles to identify any missed articles. We did not search unpublished or gray literatures. We considered all study designs. Data abstraction was performed by 1 investigator (Y.H.) with Table 2 and was verified by another (C.L.R.).
| Study | Study design/country | Eligible population and description of sample | Assessment of gestational age | Assessment of outcome |
|---|---|---|---|---|
| Smith et al, 2000 | Cohort study/Finland | Women with live, singleton births from 1954-1963 in Helsinki; analytic sample, 3706 women | Preterm: <37 weeks’ gestation; source: Helsinki maternity care records | Cardiovascular disease death; source: Finnish central population and cause-of-death registers |
| Smith et al, 2001 | Cohort study/Scotland | Women with singleton first births in Scotland from 1981-1985 (n = 137,094); exclusions: stillbirths, infants born alive at <24 weeks’ gestation and those with birthweight <500 g, women with previous pregnancies; analytic sample, 129,920 women (94.8%) | Based on estimated date of delivery; preterm: 24-36 weeks’ gestation; source: Scottish Morbidity Record System | Death because of ischemic heart disease or any ischemic heart disease hospitalization or death per ICD-9 or 10 codes; source: Scottish Morbidity Record System |
| Pell et al, 2004 | Cohort/Scotland | Women with singleton first births in Scotland from 1981-1985 (n = 137,094 women); exclusions: stillbirths, infants born alive at <24 weeks’ gestation and those with birthweight <500 g, women with previous pregnancies; analytic sample = 119,668 (87.3%) | Based on estimated date of delivery; preterm: 24-and 36 weeks’ gestation; source: Scottish Morbidity Record System | Death or hospital admission because of a principal diagnosis of stroke (ischemic stroke, intracranial hemorrhage, or transient ischemic attack) per ICD-9 codes; source: Scottish Morbidity Record System |
| Nardi et al, 2006 | Retrospective nested case control study from the E3N study cohort/France | Cases were women born 1925-1950 who self-reported having had a first myocardial infarction from 1990-2000 and had a singleton live birth (n = 144); exclusions: previous cardiovascular problems, psychiatric disorders, and other noncardiac diseases; analytic sample = 504 women: 109 cases (75.7%), and 395 randomly selected control subjects matched on birth year, month/year of E3N enrollment, education, and residence area | Preterm: self-reported length of pregnancy at ≤8 months; source: survey | Self-reported ischemic heart disease; source: survey responses validated by review of hospital discharge records or death because of ischemic heart disease per ICD-9 code |
| Catov et al, 2007 | Cross-sectional study (the study of health, aging and body composition -health ABC)/Pittsburgh, PA | Women 70-79 years old in 1997-1998 who reported having had ≥1 live birth, were well-functioning, had ongoing plans for community-dwelling (n = 507 women); exclusion: women who did not provide pregnancy history details at the interview; analytic sample = 446 (88.0%) | Preterm: self-reported length of pregnancy at <37 weeks; source: survey | Self-reported cardiovascular disease: ischemic heart disease, stroke; or peripheral vascular disease; ischemic heart disease included myocardial infarction, angina, coronary artery bypass surgery, or percutaneous transluminal angioplasty; source: survey responses validated by medications and electrocardiogram results |
| Catov et al, 2010 | Cohort study/Denmark | Women with no previous cardiovascular disease or diabetes mellitus diagnoses who delivered a singleton live or still birth in Denmark from 1973-1983 (n = 453,337); exclusions: children who were adopted or could not be matched to mothers, women with missing information related to gestational age, previous hospitalization for cardiovascular disease or diabetes mellitus, death during delivery, missing information on education; analytic sample = 427,765 (94.4%); analytic subsample of women with ≥2 births = 182,146 | Based on last menstrual period; preterm: <37 weeks’ gestation; categorized as: ≤32, 33-34, or 35-36 weeks’ gestation; source: the Danish Medical Birth Registry | Composite endpoint per ICD-8 or ICD-10 code was first cardiovascular disease outpatient visit, hospitalization, or death (because of atherosclerosis; hypertensive disease; ischemic heart disease; stroke; and thrombosis); ischemic heart disease, stroke, hypertension, atherosclerosis, or thrombosis examined separately; source: the National Hospital Discharge Register |
| Lykke et al, 2010 | National registry-based cohort study/Denmark | Women 15-50 years old with no previous cardiovascular or diabetes mellitus diagnoses who delivered a first singleton in Denmark from January 1978 to October 2007 (n = 796,915); exclusions: women with previous cardiovascular or diabetes mellitus diagnoses and those who died or emigrated within 3 months of delivery; analytic sample for cohort 1 = 782,287 (98.2%); cohort 2 = subpopulation of cohort 1, defined as women who had a first delivery at >15 years old and second singleton delivery at <50 years old (n = 550,809); exclusions: women with cardiovascular or diabetes mellitus diagnoses before the second delivery and those who died or emigrated within 3 months of the second delivery Analytic sample for cohort 2 = 536,419 (97.4%) | Preterm: <37 weeks’ gestation; categorized as: 20-27, 28-31, or 32-36 weeks’ gestation; source: the National Patient Registry | First diagnosis of ischemic heart disease per ICD-8 and 10 codes; source: linked data from the National Patient Registry, the Danish Central Person Registry, and the Cause of Death Registry |
| Lykke et al, 2010 | National cohort study/Denmark | See description for cohort 1 | Preterm: <37 weeks’ gestation; source: National Patient Registry | Death from any cardiovascular disease per ICD-8 or 10 codes or a first cardiovascular disease diagnosis reported at ≤1 week before death (caused by any cardiovascular disease, hypertensive disease; ischemic heart disease; myocardial diseases, stroke; and thromboembolic diseases, or type 2 diabetes mellitus); sources: linked data from the National Patient Registry, the Danish Central Person Registry, and the Cause of Death Registry |
| Bonamy et al, 2011 | National cohort study/Sweden | Resident women with a first singleton birth in Sweden from 1983-2005 and no previous cardiovascular event (n = 957,412); exclusions: missing information on birthweight or gestational age or missing record in the medical birth register; analytic sample = 923,686 (96.5%) | Term: ≥37 weeks’ gestation; moderately preterm: 32-36 weeks’ gestation; very preterm: 28-31 weeks’ gestation; extremely preterm: ≤27 weeks’ gestation; source: ultrasound scan or last menstrual period | Cardiovascular disease incidence or death (defined as primary diagnosis for first hospitalization or underlying cause of death caused by coronary heart disease, unstable angina or acute myocardial infarction), stroke (cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, transient ischemic attack, or other acute stroke), or heart failure per ICD-8 and 9 codes; sources: the Hospital Discharge Register, the Cause of Death Registry |
| Hastie et al, 2011 | Cohort study/Scotland | Women with first singleton live-births from January 1969 to July 2007 and 35-65 years old at the time of their first ischemic heart disease event or at the end of follow-up (n = 750,350); exclusions: women with maternal age at delivery of <12 years, birthweight <500 g, and gestational age <24 weeks or >43 weeks; analytic sample = 551,488 (73.5%) | Preterm: <37 weeks’ gestation; term: ≥37 weeks’ gestation; mild-moderate preterm:33-36 weeks’ gestation; extreme preterm: 24-32 weeks’ gestation; source: Scottish Morbidity Record System | Ischemic heart disease death or event per ICD-8, ICD-9, or ICD-10 code; source: linked data from the Scottish Morbidity Records and Scotland’s Registrar General |
We used the Community Guide’s methods and a structured tool to assess the quality of bias in individual studies because this tool offered flexibility in the evaluation of articles with different study designs (available at: http://www.thecommunityguide.org/library/ajpm355_d.pdf ). This method evaluates validity threats by assessing points for each of 6 categories: study description (1), sampling (1), measurement (2), data analysis (1), interpretation of results (3), and other (ie, limitations not identified in the other 5 categories; 1). Pairs of investigators (Y.H/C.L.R., Y.H/P.M.D., C.L.R/P.M.D.) independently assessed the quality of studies by summing the number of possible flaws and categorizing the study accordingly: good (0-1 flaws), fair (2-4), or poor (>4). Differences between independent assessments were discussed by 3 investigators (Y.H., C.L.R., P.M.D.) and were resolved by consensus. This study was exempt from institutional review board approval because it did not involve human subjects.
Results
We identified 185 possible titles of systematic reviews or metaanalyses in PubMed/MEDLINE, but none of the articles focused on the association between PTB and future CVD in the mother. Additionally, we found no relevant reviews in the Cochrane library. The initial search for individual studies generated 4828 articles. Many reports were deemed not relevant based on title (n = 4432). We identified 10 of the remaining 396 abstracts (2.5%) that addressed PTB as a primary exposure for CVD-related outcomes ( Figure 1 ).
Study designs and samples
Table 2 describes exposures, outcomes, and other individual study details in ascending chronologic order of publication date. Study designs included case-control (n = 1), cohort (n = 8), and cross sectional (n = 1). Study populations were from Denmark (3), Finland (1), France (1), Scotland (3), Sweden (1), and the United States (1). Follow-up time from delivery to onset of morbidity or death ranged from 12-35 years ( Table 3 ). All but 1 study omitted details about the racial composition of their study samples, but most were conducted in countries with predominantly white populations.
| Study | Sample, n | Outcome | Follow up, y | Statistically significant association a | Adjustment b | Quality | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Yes | No | 95% CI | Age | Race | Socioeconomic status | Hypertension or preeclampsia | Diabetes mellitus | Birthweight | Tobacco | Other | |||||
| Smith et al, 2000 | 3706 | CVD death | 35 | 2.1 | 1.2–3.5 | x | x | x | x | Poor | |||||
| Smith et al, 2001 | 129,920 | IHD death | 15-19 | 1.9 | 0.7–4.9 | x | x | x | x | x | Fair | ||||
| IHD hospitalization or death | 15-19 | 1.8 | 1.3–2.5 | x | x | x | x | x | Fair | ||||||
| Pell et al, 2004 | 119,668 | Stroke hospitalization or death | 14-19 | 1.9 | 1.4–2.7 | x | x | x | x | x | Fair | ||||
| Nardi et al, 2006 | 504 | IHD hospitalization or death | N/A c | 2.1 | 1.1–4.1 | x | x | x | x | x | x | Fair | |||
| Catov et al, 2007 | 446 | CVD morbidity | N/A d | 2.9 e | 1.2–6.9 | x | x | x | x | x | Fair | ||||
| Catov et al, 2010 | 427,765 | CVD hospitalization | 28 | 1.2 | 1.1–1.3 | x | x | x | x | x | x | Fair | |||
| IHD | 28 | 1.4 | 1.3–1.5 | x | x | x | x | x | |||||||
| Stroke | 28 | 1.7 | 1.5–1.9 | x | x | x | x | x | |||||||
| Atherosclerosis | 28 | 4.1 | 3.3–5.1 | x | x | x | x | x | |||||||
| CVD death | 28 | 2.0 | 1.7–2.3 | x | x | x | x | x | x | ||||||
| Lykke et al, 2010 | 782,287 | IHD hospitalizations | 15 | 1.6 f | 1.1–2.4 | x | x | x | x | Good | |||||
| 15 | 1.0 g | 0.8–1.3 | x | x | x | x | |||||||||
| 15 | 1.3 h | 1.2–1.5 | x | x | x | x | |||||||||
| Lykke et al, 2010 | 782,287 | CVD death | 15 | 1.9 | 1.5–2.4 | x | x | x | x | Good | |||||
| Bonamy et al, 2011 | 923,686 | CVD hospitalization or death | 12 | 2.2 f , i | 1.3–3.6 | x | x | x | x | x | x | Good | |||
| 12 | 2.6 g , i | 2.0–3.3 | x | x | x | x | x | x | |||||||
| 12 | 1.4 h , i | 1.2–1.6 | x | x | x | x | x | x | |||||||
| Hastie et al, 2011 | 750,350 | IHD death | 22 | 2.3 j | 1.9–2.7 | x | x | x | x | x | Fair | ||||
| 22 | 2.2 k | 1.7–2.7 | x | x | x | x | x | ||||||||
| 22 | 2.5 l | 1.9–3.3 | x | x | x | x | x | ||||||||
| IHD hospitalization or death | 22 | 1.6 j | 1.5–1.7 | x | x | x | x | x | Fair | ||||||
| 22 | 1.5 k | 1.3–1.6 | x | x | x | x | x | ||||||||
| 22 | 1.8 l | 1.6–2.0 | x | x | x | x | x | ||||||||
a Adjusted hazard ratios, unless otherwise noted
b Adjustments noted if variable was included in model, if stratified analyses were conducted, or if exclusions were made based on the variable
c Not reported; women recruited at 55 years old on average; mean time from recruitment to event was 5.2 years
d Not reported; women interviewed at 80 years old on average
f Preterm, ≤27 weeks’ gestation
g Preterm, 28-31 weeks’ gestation
h Preterm, 32-36 weeks’ gestation
i Excludes small for gestational age
k Spontaneous preterm (defined as vaginal delivery without induction or caesarean delivery after onset of labor)
l Elective preterm (induced delivery without onset of labor).
Exposure
Definitions and sources of PTB varied among the studies ( Tables 2 and 4 ). Most came from registries that relied on International Classification of Diseases codes (n = 7) or medical records systems (n = 1) ; 2 studies relied on validated self-report histories among women 55 or 80 years old (on average). Some studies restricted their study population to women who gave birth to babies at 24 weeks’ gestation at least ; some studies used 20 weeks’ gestation, and other studies had no minimum number of weeks’ gestation. All but one study used 36 weeks’ gestation to define the upper gestation limit of preterm; Nardi et al defined PTB as ≤8 months’ gestation. In the 8 studies that used vital records or birth registries, gestational age was based on last menstrual period, estimated date of delivery, or a combination of last menstrual period and ultrasound dating ; 1 study did not specify how gestational age was determined.
| Reference | Definition details | Source code | ||||
|---|---|---|---|---|---|---|
| ICD-7 | ICD-8 | ICD-9 | ICD-10 | Other | ||
| Atherosclerosis | ||||||
| Catov et al, 2010 | Atherosclerosis hospitalization or death | 440 | I70-I70.9 | |||
| Cerebrovascular disease | ||||||
| Pell et al, 2004 | Stroke hospitalization or death | 430-438 | I60-I69, G45 | |||
| Catov et al, 2010 | Stroke hospitalization or death | 430-438 | I60-I69.8 | |||
| Cardiovascular disease | ||||||
| Smith et al, 2000 | Cardiovascular disease deaths | Not specified | ||||
| Catov et al, 2007 | Cardiovascular disease morbidity: myocardial infarction, stroke, peripheral vascular disease, angina, coronary artery bypass surgery, or percutaneous transluminal angioplasty | Self-reported and validated with algorithms that included selected medications and electrocardiogram | ||||
| Catov et al, 2010 | Cardiovascular disease outpatient visit, hospitalization, or cardiovascular disease deaths from atherosclerosis; hypertensive disease; ischemic heart disease; stroke; and thrombosis; NOTE: ischemic heart disease, stroke, hypertension, atherosclerosis, or thrombosis also examined separately | 390-459 | I00-I99 | |||
| Bonamy et al, 2011 | Cardiovascular disease deaths or hospitalizations: coronary heart disease, stroke, or heart failure | 410, 411, 430-436, 427, 427.10 | 410, 411B, 430-436, 428 | I20.0, I21-I22, G45, I160-I164, I50 | ||
| Lykke et al, 2010 | Cardiovascular disease deaths: any cardiovascular disease or ischemic heart disease, stroke, myocardial infarction, hypertension, thromboembolic disease, or type 2 diabetes mellitus | |||||
| Ischemic heart disease | ||||||
| Smith et al, 2001 | Ischemic heart disease hospitalization or death | 410-414 | I20-I25 | |||
| Nardi et al, 2006 | Myocardial infarction | Self-reported and validated with information on diagnosis, ECC, and enzymatic dosages via interviews with general practitioners and review of hospital and ischemic heart disease death records | ||||
| Catov et al, 2010 | Ischemic heart disease hospitalization or death | 410-414 | I20-I25.5 | |||
| Lykke et al, 2010 | Ischemic heart disease hospitalization | 410-414 | I20-I25 | |||
| Hastie et al, 2011 | Ischemic heart disease hospitalization or death | 410-414 | 410-414 | I20-I25 | ||
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