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Duration of pregnancy, even at term, predicts long-term risk of coronary heart disease and stroke mortality in women: a population-based study

      Objective

      Preterm delivery may predict an increased risk of cardiovascular disease in mothers, providing opportunities for prevention. No study had examined whether gestation length within the term period predicts future CVD, and there are few data segregating spontaneous from medically indicated deliveries.

      Study Design

      We used proportional hazards models to predict CVD death by gestation length, adjusted for age, education, and delivery year among 688,662 women with births from 1967 through 1998 in the Medical Birth Registry of Norway. Mothers were traced in the National Cause of Death Registry through 2009; there were 2324 CVD deaths.

      Results

      Compared with women who delivered spontaneously at 39–41 weeks’ gestation, women who spontaneously delivered earlier had higher risks of CVD death. Hazard ratios were 1.9 at 22–31 weeks, 2.2 at 32–34 weeks, 1.6 at 35–36 weeks, and 1.4 at 37–38 weeks. Risks were higher among women with medically indicated deliveries (hazard ratio, 4.8 at 22–31 weeks, 2.7 at 32–34 weeks, 4.3 at 35–36 weeks, and 1.6 at 37–38 weeks compared with spontaneous deliveries at 39–41 weeks). Neither spontaneous nor indicated delivery after 41 weeks was associated with CVD mortality. Risks were highest with recurrent preterm pregnancies, and for women who delivered only one child, especially if that delivery was preterm.

      Conclusion

      Women who deliver spontaneously before 37 weeks had a 2-fold increased risk of CVD mortality compared with women who had delivered after 38 weeks. Even women with spontaneous deliveries at early term (37–38 weeks) had a 41% elevated risk of CVD death compared with women delivering at 39–41 weeks.

      Key words

      Common pregnancy complications, including preeclampsia, preterm delivery, gestational diabetes, and fetal growth restriction, are associated with elevated risks of future cardiovascular disease (CVD) in mothers.
      • Rich-Edwards J.W.
      • Fraser A.
      • Lawlor D.A.
      • Catov J.M.
      Pregnancy characteristics and women's future cardiovascular health: an underused opportunity to improve women’s health?.
      These associations may provide new insights into the development of cardiovascular disease and improve our understanding of the determinants of pregnancy complications.
      Women who have delivered preterm have approximately twice the risk of CVD mortality.
      • Bonamy A.-K.E.
      • Parikh N.I.
      • Cnattingius S.
      • Ludvigsson J.F.
      • Ingelsson E.
      Birth characteristics and subsequent risks of maternal cardiovascular disease: effects of gestational age and fetal growth.
      • Catov J.M.
      • Wu C.S.
      • Olsen J.
      • Sutton-Tyrrell K.
      • Li J.
      • Nohr E.A.
      Early or recurrent preterm birth and maternal cardiovascular disease risk.
      • Davey Smith G.
      • Hyppönen E.
      • Power C.
      • Lawlor D.A.
      Offspring birth weight and parental mortality: prospective observational study and meta-analysis.
      • Hastie C.E.
      • Smith G.C.
      • Mackay D.F.
      • Pell J.P.
      Maternal risk of ischaemic heart disease following elective and spontaneous pre-term delivery: retrospective cohort study of 750 350 singleton pregnancies.
      • Irgens H.U.
      • Reisæter L.
      • Irgens L.M.
      • Lie R.T.
      Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study.
      • Smith G.
      • Pell J.P.
      • Walsh D.
      Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129 290 births.
      • Davey Smith G.
      • Hart C.
      • Ferrell C.
      • et al.
      Birth weight of offspring and subsequent cardiovascular mortality of the parents.
      However, no study has examined the extent to which the association of gestation length with CVD varies within the term period, during which the vast majority of deliveries occur. Furthermore, with 2 exceptions,
      • Hastie C.E.
      • Smith G.C.
      • Mackay D.F.
      • Pell J.P.
      Maternal risk of ischaemic heart disease following elective and spontaneous pre-term delivery: retrospective cohort study of 750 350 singleton pregnancies.
      • Kessous R.
      • Shoham-Vardi I.
      • Pariente G.
      • Holcberg G.
      • Sheiner E.
      An association between preterm delivery and long-term maternal cardiovascular morbidity.
      studies have not distinguished spontaneous from medically indicated deliveries. Finally, no study has reported the association of spontaneous preterm delivery with risk of stroke.
      We utilized linked Norwegian birth and mortality registries to quantify the extent to which the gestation length of spontaneous and indicated deliveries is associated with maternal risk of CVD mortality up to 4 decades after birth. We hypothesized that length of gestation would be inversely associated with CVD risk, especially for medically indicated deliveries. We examined recurrent preterm delivery, hypothesizing that women with recurrent preterm deliveries would be at higher CVD risk than women with both preterm and term deliveries.
      • Catov J.M.
      • Wu C.S.
      • Olsen J.
      • Sutton-Tyrrell K.
      • Li J.
      • Nohr E.A.
      Early or recurrent preterm birth and maternal cardiovascular disease risk.
      Finally, having observed previously that the CVD risk associated with preeclampsia was especially strong when a preeclamptic first birth was not followed by a later birth, we examined whether mortality patterns varied by whether the preterm birth was the last birth.
      • Skjaerven R.
      • Wilcox A.J.
      • Klungsøyr K.
      • et al.
      Cardiovascular mortality after pre-eclampsia in one child mothers: prospective, population based cohort study.

      Materials and Methods

      This study was based on the Medical Birth Registry of Norway (MBRN), a registry of mandatory birth notifications completed by the attending clinician for all live births and stillbirths lasting at least 16 weeks in Norway since 1967. Gestational length was recorded as completed weeks from the last menstrual period because ultrasound dating was not recorded before 1999.
      We considered women with a first singleton live birth or stillbirth between 1967 and 1998. Births were linked to mothers by the national identification number. For most analyses, a woman’s first pregnancy was the exposure; to examine recurrent preterm birth, we considered first and second births. Of the 751,651 women with first singleton pregnancies, we excluded 46,261 (6.2%) whose records lacked gestational age and 978 (0.1%) missing birthweight. We excluded 1241 women whose first pregnancies lasted less than 22 weeks and 5604 women whose first pregnancies lasted longer than 44 weeks.
      To exclude obviously misclassified gestational ages, we used sex-specific birthweight-for-gestational-age Z-scores based on Norwegian standards to exclude 2671 women in which the birthweights were more than 4 SD higher or lower than the appropriate means.
      • Skjærven R.
      • Gjessing H.K.
      • Bakketeig L.S.
      New standards for birth weight by gestational age using family data.
      Finally, we excluded 6226 women missing maternal education and 8 women whose deaths lacked dates.
      Sensitivity analyses including women missing data on education, using missing indicator terms or assigning high or low education, yielded nearly identical results. For the analysis of second births, we applied the previously cited exclusion criteria for missing and implausible gestational lengths to second births. The study population was 688,662 women for first births and 641,362 women for the analysis of first and second births.
      Clinicians reported the start of delivery as spontaneous labor, induced labor, or planned cesarean delivery. In this analysis, induced labor and planned cesarean delivery were considered medically indicated delivery. Labor induced after spontaneous rupture of membranes was considered spontaneous. Augmentation of labor was recorded separately from induction of labor and was not used to define delivery type. If amniotomy was listed as a means of labor induction, the delivery was classified as medically indicated; amniotomy in the context of spontaneous start of delivery was classified as spontaneous delivery. If spontaneous labor or rupture of membranes preceded a planned cesarean delivery by less than 8 hours, the delivery was considered spontaneous; if 8 or more hours passed between spontaneous labor and the time of a planned cesarean delivery, the delivery was classified as a planned cesarean delivery and therefore medically indicated.
      Preeclampsia was identified by the eighth revision of the International Classification of Disease (ICD), code 637, for births in 1967–1998 and by ICD-10 codes O14–15 for births after 1998. A test of the accuracy of MBRN preeclampsia reports showed good predictive value: 86% of MBRN registry reports were validated by medical record review.
      • Thomsen L.C.
      • Klungsøyr K.
      • Roten L.T.
      • et al.
      Validity of the diagnosis of pre-eclampsia in the medical birth registry of Norway.
      Small for gestational age was defined as below the 10th percentile and large for gestational age as above the 90th percentile of birthweight for gestational age by Norwegian standards.
      • Skjaerven R.
      • Gjessing H.K.
      • Bakketeig L.S.
      Birthweight by gestational age in norway.
      Women were linked to the National Cause of Death Registry through 2009 via the national identification number. We identified CVD deaths by ICD codes (ICD-8 from 1967 to 1985; ICD-9 for 1986–1995; and ICD-10 for 1996–2009). Deaths caused by coronary heart disease (CHD; 410–414 for ICD-8 and ICD-9; I20–I25 for ICD10) and cerebrovascular disease (430–438 ICD-8 and ICD-9; I60–I69 ICD10) were considered as CVD deaths. We examined cardiovascular mortality as a whole as well as CHD and stroke separately. Forty records had both CHD and stroke listed as the cause of death so that the total number of CVD deaths is less than the sum of the CHD and stroke deaths.
      Each participant was followed up from her first delivery between Jan. 1, 1967, and Dec. 31, 1998, until CVD death, other fatality, emigration, or Dec. 31, 2009. We used Kaplan Meier curves to estimate the survival time free of CVD death up to 40 years after first birth; the median follow-up was 24.8 years. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), using years since first birth as the time axis.
      Spontaneous delivery at 39–41 completed weeks was the reference group for the detailed analyses of gestational length and delivery type; however, to allow comparisons to less detailed estimates in the literature, where stated, we also provided statistics that use deliveries from 37 to 44 weeks (term deliveries) as the reference group.
      We adjusted for year of delivery (continuous), maternal age (continuous), and maternal education (less than high school, completed high school, attended university) at first birth. Multiplicative interaction was tested by modeling a cross-product interaction term between indication (yes/no) and gestational length categories. As a sensitivity analysis, we restricted to women whose births were uncomplicated by preeclampsia, fetal growth restriction, or macrosomia (less than the 10th or greater than the 90th percentile of birthweight for gestational length, respectively).
      We also performed sensitivity analyses to account for unmeasured confounding by smoking and obesity, using the bias correction method described by Lash et al.
      • Lash T.L.
      • Fox M.P.
      • Fink A.K.
      Unmeasured and unknown cofounders.
      Statistical analyses were performed with SPSS for Windows (version 19.0; SAS Institute, Cary, NC) and bias correction with the web site developed by Lash et al
      • Lash T.L.
      • Fox M.P.
      • Fink A.K.
      Unmeasured and unknown cofounders.
      for that purpose.
      This study complies with the Declaration of Helsinki and was approved by the review board of the Medical Birth Registry of Norway, the regional ethics committee, and REK Vest (Norway).

      Results

      The demographic characteristics of the cohort are classified by length of first pregnancy in Table 1. Six percent of first births were preterm (<37 weeks). Eighty-five percent of first deliveries were spontaneous (85% of term and 81% of preterm births). As expected from trends in clinical practice, medically indicated deliveries were more prevalent in recent time periods and were more likely in the presence of preeclampsia. Women with medically indicated deliveries were slightly older and more educated (especially if the delivery was preterm).
      Table 1Characteristics of first births by gestation length and indication status, Norwegian Medical Birth Registry
      CharacteristicSpontaneous deliveriesMedically indicated deliveries
      Weeks of gestation22–3132–3435–3637–4422–3132–3435–3637–44
      n (%)5488 (0.9)8534 (1.5)19208 (3.3)550604 (94.3)1648 (1.6)2283 (2.2)3820 (3.6)97077 (92.6)
      Maternal age, mean (SD)23.6 (5.2)23.6 (4.9)23.9 (4.7)23.9 (4.3)25.7 (5.4)25.7 (5.3)25.6 (5.1)25.0 (4.9)
      Year of mother’s birth, mean (SD)1956 (9)1957 (9)1957 (9)1957 (9)1961 (9)1961 (9)1960 (9)1958 (9)
      Year of delivery, mean (SD)1980 (9)1981 (10)1982 (10)1982 (9)1987 (8)1987 (9)1986 (9)1983 (9)
      Offspring birthweight (g), mean (SD)1218 (534)2342 (597)2847 (535)3485 (467)1037 (496)1967 (632)2636 (637)3548 (541)
      Maternal education, %
       Less than high school56.453.351.246.443.642.842.244.0
       High school completed21.222.923.223.625.125.426.123.4
       Attended college22.423.825.630.031.431.831.732.5
      Married, %73.476.078.982.381.783.485.184.2
      Preeclamptic, %5.57.05.32.232.035.932.510.7
      Rich-Edwards. Gestation length and maternal CVD. Am J Obstet Gynecol 2015.
      Over a median 25 years of follow-up, there were 2324 CVD deaths, including 1182 deaths from CHD and 1181 deaths from stroke. Figure 1 shows CVD mortality by gestational length through 4 decades after first birth. The cumulative risk of CVD was less than 3% in any group, consistent with the age of the cohort at the end of follow-up (median, 52; interquartile range, 45–59 years). The lowest CVD mortality was among women with spontaneous term deliveries, followed by indicated term, spontaneous preterm, and medically indicated preterm deliveries. The absolute risks of CVD mortality began to diverge within the first decade after birth and grew wider over 4 decades.
      Figure thumbnail gr1
      Figure 1Cumulative CVD-free survival in 40 years after delivery
      Cumulative survival free from cardiovascular disease mortality in the 40 years after first delivery, by gestational length and spontaneous vs medically indicated delivery (Norwegian Medical Birth Registry).
      CVD, cardiovascular disease.
      Rich-Edwards. Gestation length and maternal CVD. Am J Obstet Gynecol 2015.
      Women whose first delivery was preterm had nearly double the risk of cardiovascular mortality compared with women who delivered at term (37–44 weeks) (HR, 1.9; 95% CI, 1.7–2.2). Spontaneous preterm delivery was associated with an HR of 1.7 (95% CI, 1.5–2.0) and medically indicated preterm delivery with an HR of 3.7 (95% CI, 2.9–4.8), both compared with a spontaneous term delivery.
      Figure 2 depicts the hazard ratios for CVD mortality for medically indicated and spontaneous first deliveries of varying gestational lengths, adjusted for maternal age, education, and year of delivery. All gestational lengths shorter than 39–41 weeks, including spontaneous term births at 37–38 weeks, were associated with elevated CVD mortality compared with spontaneous delivery at 39–41 weeks. Women with a history of medically indicated preterm delivery had 2.7- to 4.8-fold higher risks of CVD death, whereas women with a history of spontaneous preterm delivery had 1.6- to 2.2-fold higher risks of CVD death compared with women who had delivered spontaneously at 39-41 weeks (P = .01 for interaction between gestational length categories and indicated delivery status). Deliveries after 41 completed weeks, whether spontaneous or indicated, predicted the same risk of CVD death as spontaneous deliveries at 39-41 weeks. There was no interaction between type of preterm delivery and maternal age at birth (<30 vs ≥30 years) in predicting CVD mortality (P = .22).
      Figure thumbnail gr2
      Figure 2Cardiovascular disease mortality
      Hazard ratios (95% CIs) for cardiovascular disease mortality by gestational length and indication status of first pregnancy (Norwegian Medical Birth Registry).
      CI, confidence interval.
      Rich-Edwards. Gestation length and maternal CVD. Am J Obstet Gynecol 2015.
      Women who delivered preterm spontaneously had twice the risk of CHD death (HR, 2.1; 95% CI, 1.7–2.5) compared with women who delivered spontaneously at term (37–44 weeks). Table 2 shows the hazard ratios of CHD death by gestational length. Even early term spontaneous deliveries (37–38 weeks) predicted 49% (25–78%) higher CHD mortality compared with later term spontaneous delivery (39–41 weeks) (Table 2). Although the HRs for medically indicated delivery were higher than those for spontaneous delivery, the statistical test of interaction was not significant (P = .30).
      Table 2HRs (95% CIs) for cardiovascular death by gestation length and indication
      VariableWomenCoronary heart diseaseStroke
      Weeks of gestationDeaths, n (%)Age-adjusted HRMultivariate HR
      Adjusted for maternal age at delivery, year of delivery, and maternal education (less than high school, completed high school, attended university).
      95% CIDeaths, n (%)Age-adjusted HRMultivariate HR
      Adjusted for maternal age at delivery, year of delivery, and maternal education (less than high school, completed high school, attended university).
      95% CI
      Spontaneous deliveries
       22-31548823 (0.42)2.52.31.5–3.419 (0.35)1.91.81.1–2.8
       32-34853433 (0.39)2.52.41.7–3.429 (0.34)2.01.91.3–2.8
       35-3619,20862 (0.32)2.32.11.6–2.741 (0.21)1.31.30.9–1.7
       37-3871,111155 (0.22)1.61.51.3–1.8161 (0.23)1.51.41.2–1.7
       39-41403,028573 (0.14)1.01.0Reference640 (0.16)1.01.0Reference
       42-4476,465104 (0.14)1.01.00.8–1.2116 (0.15)1.01.00.8–1.2
      Medically indicated deliveries
       22-3116487 (0.42)5.94.72.2–9.89 (0.55)5.95.42.8–10.4
       32-3422838 (0.35)4.43.41.7–6.95 (0.22)2.21.90.8–4.7
       35-36382025 (0.65)7.76.24.2–9.313 (0.34)3.32.91.7–5.1
       37-3812,25628 (0.23)2.82.31.6–3.414 (0.11)1.11.00.6–1.7
       39-4153,094112 (0.21)1.81.61.3–2.084 (0.16)1.21.10.9–1.4
       42-4431,72752 (0.16)1.11.10.8–1.550 (0.16)1.01.00.7–1.3
      CI, confidence interval; HR, hazard ratio.
      Rich-Edwards. Gestation length and maternal CVD. Am J Obstet Gynecol 2015.
      a Adjusted for maternal age at delivery, year of delivery, and maternal education (less than high school, completed high school, attended university).
      Associations of gestational length with stroke mortality were less consistent, although generally elevated for both spontaneous and medically indicated preterm births (Table 2). Overall, spontaneous preterm delivery was associated with an HR of 1.5 (95% CI, 1.2–1.8) and medically indicated preterm delivery with an HR of 3.0 (95% CI, 2.0–4.3) compared with spontaneous delivery at 37–41 weeks. Women who delivered spontaneously at early term (37–38 weeks) had a 41% (19–68%) increased risk of stroke mortality compared with women delivering later in the term period (39–41 weeks). However, there was no evidence that medically indicated delivery predicted future stroke risk across the range of term deliveries. The association of gestation length with stroke was stronger for medically indicated than for spontaneous deliveries (interaction P = .01).
      Table 3 shows CVD mortality risk by preterm status in first and second births. Compared with women who bore at least 2 term infants, women who bore only 1 child had increased risk of CVD mortality, whether their first and only child was born at term (HR, 2.0; 95% CI, 1.8–2.3) or preterm (HR, 4.2; 95% CI, 3.4–5.1). Women with 2 consecutive preterm pregnancies had a 3-fold increase in CVD risk (HR, 3.3; 95% CI, 2.4–4.5). Women who had 2 deliveries and delivered preterm in only 1 of them had intermediate risks of CVD. The order of the term and preterm births did not seem to matter. There was no apparent interaction between these categories and maternal age at first birth (<30 years vs ≥30 years) in predicting CVD mortality (P = .19).
      Table 3HRs (95% CIs) for cardiovascular death by preterm status and birth order
      First birthSecond birthCVD deathsWomenHR
      Adjusted for maternal age at delivery, year of delivery, and maternal education (less than high school, completed high school, attended university).
      95% CI
      PretermNone10877864.23.4–5.1
      PretermPreterm4148193.32.4–4.5
      PretermTerm9825,3931.51.2–1.8
      TermNone62196,9192.01.8–2.3
      TermPreterm8718,0381.81.4–2.2
      TermTerm1234488,4071.0Reference
      CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio.
      Rich-Edwards. Gestation length and maternal CVD. Am J Obstet Gynecol 2015.
      a Adjusted for maternal age at delivery, year of delivery, and maternal education (less than high school, completed high school, attended university).
      To examine spontaneous deliveries that were least likely to be complicated by preeclampsia or gestational diabetes, we excluded women with pregnancies complicated by preeclampsia, fetal growth restriction, or macrosomia (as an approximation to gestational diabetes, which was not systematically recorded during this period). HRs (95% CI) for CVD mortality associated with these spontaneous deliveries were as follows: 2.1 (1.4–3.1) at 22-31 weeks; 1.9 (1.3–2.7) at 32-34 weeks; 1.4 (1.0–1.8) at 35-36 weeks; and 1.3 (1.1–1.5) for delivery at 37-38 weeks (early term delivery) compared with spontaneous delivery at 39-41 weeks.
      When we excluded women from the analysis of CVD mortality with any form of diabetes (chronic or gestational) at the time of pregnancy, we observed similar patterns of statistically significantly elevated risk of CVD mortality with a history of preterm delivery; HRs for medically indicated deliveries were somewhat attenuated (data not shown).
      We conducted sensitivity analyses to assess the degree of unmeasured confounding by smoking and obesity, which were not available from the MBRN during this period. Assuming prevalences of smoking (30%) and obesity (10%) typical of this time in Norway,

      Forey BJH, Hamling J, Thornton A, Lee P. International smoking statistics in Norway. In: International smoking statistics, 2nd ed, 2002 Sutton (UK): Wolfson Institute of Preventive Medicine and OUP; 2002. Available at: http://www.pnlee.co.uk/Downloads/ISS/ISS-Norway_121004.pdf. Accessed July 2, 2015.

      Norwegian Institute of Public Health. Facts about overweight and obesity in Norway, 2011. Oslo, Norway, 2013. Available at: http://www.fhi.no/artikler/?id=102874. Accessed July 2, 2015.

      the associations of these factors with preterm delivery (relative risks [RRs] for spontaneous PTB of 1.3 for smoking and 0.8 for obesity) and CVD (RR for CVD of 1.9 for smoking and 2.0 for obesity),
      • Colditz G.A.
      • Bonita R.
      • Stampfer M.J.
      • et al.
      Cigarette smoking and risk of stroke in middle-aged women.
      • Huxley R.R.
      • Woodward M.
      Cigarette smoking as a risk factor for coronary heart disease in women compared with men: a systematic review and meta-analysis of prospective cohort studies.
      • Manson J.E.
      • Colditz G.A.
      • Stampfer M.J.
      • et al.
      A prospective study of obesity and risk of coronary heart disease in women.
      • Shah N.R.
      • Bracken M.B.
      A systematic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery.
      • Willett W.C.
      • Green A.
      • Stampfer M.J.
      • et al.
      Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes.
      we derived a smoking-corrected estimate of 1.9 and an obesity-corrected estimate of 2.0 for the association of spontaneous PTB with CVD mortality. These adjusted estimates are less than a 10% departure from the crude RR of 2.0.

      Comment

      At a median 25 years after their first birth, women who had delivered preterm were twice as likely to have died from CVD, compared with women whose first pregnancy went to term. Within preterm deliveries, the HRs for CVD risk ranged from 1.6 to 2.2 for spontaneous deliveries and from 2.7 to 4.8 for medically indicated deliveries, depending on the degree of prematurity. In particular, our study indicates for the first time that even the 12% of women who delivered early within the term period (37–38 weeks) had 41% (if spontaneous) to 60% (if indicated) increased risks of future CVD death compared with women who delivered spontaneously at 39–41 weeks.
      This study also contributed new data with respect to recurrent preterm birth and preterm birth to women who bore only 1 child. Compared with women who bore 2 term infants during the study period, women who delivered 2 preterm infants were at a 3-fold elevated risk of CVD mortality. Interestingly, women who bore only 1 infant were also at increased CVD risk, especially if that child was preterm. This is consistent with the increased CVD mortality risk observed in this cohort among women whose last observed pregnancy was preeclamptic.
      • Skjaerven R.
      • Wilcox A.J.
      • Klungsøyr K.
      • et al.
      Cardiovascular mortality after pre-eclampsia in one child mothers: prospective, population based cohort study.
      This pattern suggests that pregnancy outcomes severe enough to discourage further pregnancy may mark especially high maternal CVD risk, that women with underlying chronic disease choose to bear fewer children, and/or that subfertility is correlated with a shorter gestation and with future CVD risk.
      Preterm delivery rates vary markedly by place and time.
      • Beck S.
      • Wojdyla D.
      • Say L.
      • et al.
      The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity.
      Six percent of singleton births in this Norwegian cohort delivered 1967–1998 were preterm. The prevalence of preterm delivery in singleton pregnancies in Norway dropped to 4.9% in 2011. In contrast, the prevalence of preterm delivery among singletons in the United States in 2011 was 10.1%.
      • Martin J.A.
      • Hamilton B.E.
      • Ventura S.J.
      • Jk M.M.
      • Osterman M.
      • Mathews T.
      Births: final data for 2011.
      This variation in preterm delivery rates presumably reflects variation in the causes of preterm birth. This may be especially true for indicated deliveries because both the practice standards for medical delivery and the prevalence of the indications for medical delivery vary by place and time.
      Our analysis shows large differences in CVD mortality predicted by indicated vs spontaneous preterm delivery; this likely reflects the particular mix of underlying indications for medical delivery. The associations might be quite different for more recent preterm deliveries, which are increasingly likely to occur in the context of CVD risk factors such as obesity and hypertension.
      • Siega-Riz A.-M.
      • Laraia B.
      The implications of maternal overweight and obesity on the course of pregnancy and birth outcomes.
      Despite the presumed variation in causes of preterm birth, the reports from large registry studies consistently report relative risks of maternal CVD incidence and/or mortality associated with total preterm delivery ranging from 1.4 to 2.5.
      • Bonamy A.-K.E.
      • Parikh N.I.
      • Cnattingius S.
      • Ludvigsson J.F.
      • Ingelsson E.
      Birth characteristics and subsequent risks of maternal cardiovascular disease: effects of gestational age and fetal growth.
      • Catov J.M.
      • Wu C.S.
      • Olsen J.
      • Sutton-Tyrrell K.
      • Li J.
      • Nohr E.A.
      Early or recurrent preterm birth and maternal cardiovascular disease risk.
      • Hastie C.E.
      • Smith G.C.
      • Mackay D.F.
      • Pell J.P.
      Maternal risk of ischaemic heart disease following elective and spontaneous pre-term delivery: retrospective cohort study of 750 350 singleton pregnancies.
      • Irgens H.U.
      • Reisæter L.
      • Irgens L.M.
      • Lie R.T.
      Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study.
      • Smith G.
      • Pell J.P.
      • Walsh D.
      Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129 290 births.
      • Davey Smith G.
      • Hart C.
      • Ferrell C.
      • et al.
      Birth weight of offspring and subsequent cardiovascular mortality of the parents.
      • Kessous R.
      • Shoham-Vardi I.
      • Pariente G.
      • Holcberg G.
      • Sheiner E.
      An association between preterm delivery and long-term maternal cardiovascular morbidity.
      • Davey Smith G.
      • Whitley E.
      • Gissler M.
      • Hemminki E.
      Birth dimensions of offspring, premature birth, and the mortality of mothers.
      Previous studies examining the risk of stroke associated with a history of delivering preterm have reported relative risks of 1.9,
      • Irgens H.U.
      • Reisæter L.
      • Irgens L.M.
      • Lie R.T.
      Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study.
      1.9,
      • Pell J.P.
      • Smith G.C.
      • Walsh D.
      Pregnancy complications and subsequent maternal cerebrovascular events: a retrospective cohort study of 119,668 births.
      1.7 (excluding preeclampsia and small for gestational age),
      • Catov J.M.
      • Wu C.S.
      • Olsen J.
      • Sutton-Tyrrell K.
      • Li J.
      • Nohr E.A.
      Early or recurrent preterm birth and maternal cardiovascular disease risk.
      and 2.1–3.1 (depending on the degree of accompanying fetal growth restriction).
      • Bonamy A.-K.E.
      • Parikh N.I.
      • Cnattingius S.
      • Ludvigsson J.F.
      • Ingelsson E.
      Birth characteristics and subsequent risks of maternal cardiovascular disease: effects of gestational age and fetal growth.
      However, none of these studies distinguished between indicated and spontaneous delivery. We found that spontaneous preterm delivery predicted a nearly 50% increase in stroke mortality compared with a spontaneous term delivery, whereas medically indicated preterm delivery predicted nearly a 3-fold increased stroke risk.
      Two studies have considered total CVD in relation to spontaneous or medically indicated preterm deliveries. An Israeli study reported increased odds ratios of complex cardiovascular events (largely CHD) for women with a history of ever having had a spontaneous preterm delivery compared with women who had delivered only term infants. Although they did not formally test interactions between delivery type and prematurity, the authors reported higher odds ratios (ORs) of CVD after spontaneous preterm delivery (OR, 3.8; 95% CI, 2.2–6.6) than after induced preterm labor (OR, 2.6; 95% CI, 0.5–12.5).
      • Kessous R.
      • Shoham-Vardi I.
      • Pariente G.
      • Holcberg G.
      • Sheiner E.
      An association between preterm delivery and long-term maternal cardiovascular morbidity.
      In Scotland, Hastie et al
      • Hastie C.E.
      • Smith G.C.
      • Mackay D.F.
      • Pell J.P.
      Maternal risk of ischaemic heart disease following elective and spontaneous pre-term delivery: retrospective cohort study of 750 350 singleton pregnancies.
      reported that spontaneous preterm delivery had an HR of 2.1 for CHD mortality compared with spontaneous term delivery, which agrees closely with the HR of 2.0 for the same comparison in our cohort.
      The contrast between medically indicated and spontaneous preterm deliveries echoes previously reported differences between hypertensive and normotensive deliveries. Preeclampsia is a primary indication for medical delivery, associated with a doubling of CVD risk in mothers.
      • Bellamy L.
      • Casas J.-P.
      • Hingorani A.D.
      • Williams D.J.
      Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.
      • McDonald S.D.
      • Malinowski A.
      • Zhou Q.
      • Yusuf S.
      • Devereaux P.J.
      Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses.
      Compared with normotensive term births, preeclamptic preterm delivery is associated with relative risks as small as 1.8 for stroke
      • Lykke J.
      • Paidas M.
      • Damm P.
      • Triche E.
      • Kuczynski E.
      • Langhoff-Roos J.
      Preterm delivery and risk of subsequent cardiovascular morbidity and type II diabetes in the mother.
      but as high as 4.5 for CHD
      • Smith G.
      • Pell J.P.
      • Walsh D.
      Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129 290 births.
      and 8.1 for total CVD mortality.
      • Irgens H.U.
      • Reisæter L.
      • Irgens L.M.
      • Lie R.T.
      Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study.
      Preterm birth uncomplicated by preeclampsia has been associated with more modest relative risks of CVD, ranging from 1.2 to 3.0.
      • Catov J.M.
      • Wu C.S.
      • Olsen J.
      • Sutton-Tyrrell K.
      • Li J.
      • Nohr E.A.
      Early or recurrent preterm birth and maternal cardiovascular disease risk.
      • Irgens H.U.
      • Reisæter L.
      • Irgens L.M.
      • Lie R.T.
      Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study.
      • Catov J.M.
      • Bodnar L.M.
      • Ness R.B.
      • Barron S.J.
      • Roberts J.M.
      Inflammation and dyslipidemia related to risk of spontaneous preterm birth.
      In our dataset, spontaneous preterm delivery was associated with increased CVD mortality, whether or not the pregnancy was complicated by preeclampsia.
      This data set had several limitations, some of which reflect medical practices of the era. Gestational diabetes was not routinely screened until late in this period, so we were unable to account for possible confounding by gestational diabetes. However, gestational diabetes is not a strong risk factor for either medically indicated or spontaneous preterm delivery.
      • Villar J.
      • Papageorghiou A.T.
      • Knight H.E.
      • et al.
      The preterm birth syndrome: a prototype phenotypic classification.
      Furthermore, we observed that women with spontaneous preterm births uncomplicated by preeclampsia, small for gestational age, and large for gestational age still had elevated CVD risk; this restriction would have eliminated many diabetic pregnancies. Finally, analysis excluding women with diabetes before pregnancy showed a similar pattern.
      The MBRN did not start collecting data on smoking during pregnancy until 1998, after the births in this analysis had occurred. However, our sensitivity analysis and at least 3 previous studies have shown through an adjustment or sensitivity analysis
      • Bonamy A.-K.E.
      • Parikh N.I.
      • Cnattingius S.
      • Ludvigsson J.F.
      • Ingelsson E.
      Birth characteristics and subsequent risks of maternal cardiovascular disease: effects of gestational age and fetal growth.
      • Catov J.M.
      • Wu C.S.
      • Olsen J.
      • Sutton-Tyrrell K.
      • Li J.
      • Nohr E.A.
      Early or recurrent preterm birth and maternal cardiovascular disease risk.
      • Pell J.P.
      • Smith G.C.
      • Walsh D.
      Pregnancy complications and subsequent maternal cerebrovascular events: a retrospective cohort study of 119,668 births.
      that smoking explains little of the association between preterm delivery and CVD mortality; this is consistent with the modest association of smoking with risk of preterm birth, estimated in a metaanalysis as a relative risk of 1.3.
      • Shah N.R.
      • Bracken M.B.
      A systematic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery.
      As is typical of registries, there were no data available on CVD risk factors, such as body mass index. However, sensitivity analysis suggested that adjustment for obesity would have yielded less than a 10% change in the association of spontaneous preterm delivery with CVD mortality.
      Finally, we were not able to validate the registry reports of gestational length or type of delivery against medical records. Even so, we could exclude obviously misclassified gestation lengths by using gestational age- and sex-specific birthweight distributions as a standard.
      Our understanding of the risk factors linking CVD and length of gestation, especially spontaneously delivered pregnancies, is weak. Infection and inflammation play a large role in spontaneous preterm delivery.
      • Romero R.
      • Espinoza J.
      • Gonçalves L.F.
      • Kusanovic J.P.
      • Friel L.
      • Hassan S.
      The role of inflammation and infection in preterm birth.
      Several studies have found that maternal plasma C-reactive protein levels in pregnancy predict spontaneous preterm delivery,
      • Hvilsom G.B.
      • Thorsen P.
      • Jeune B.
      • Bakketeig L.S.
      C-reactive protein: a serological marker for preterm delivery?.
      • Lohsoonthorn V.
      • Qiu C.
      • Williams M.A.
      Maternal serum c-reactive protein concentrations in early pregnancy and subsequent risk of preterm delivery.
      • Moghaddam Banaem L.
      • Mohamadi B.
      • Asghari Jaafarabadi M.
      • Aliyan Moghadam N.
      Maternal serum c-reactive protein in early pregnancy and occurrence of preterm premature rupture of membranes and preterm birth.
      particularly if women also have high cholesterol or triglyceride levels.
      • Catov J.M.
      • Bodnar L.M.
      • Ness R.B.
      • Barron S.J.
      • Roberts J.M.
      Inflammation and dyslipidemia related to risk of spontaneous preterm birth.
      C-reactive protein levels predict elevated CVD risk.
      • Danesh J.
      • Wheeler J.G.
      • Hirschfield G.M.
      • et al.
      C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease.
      • Ridker P.M.
      • Hennekens C.H.
      • Buring J.E.
      • Rifai N.
      C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.
      Although C-reactive protein levels have been associated with a history of eclampsia and indicated preterm delivery,
      • Hastie C.E.
      • Smith G.C.
      • Mackay D.F.
      • Pell J.P.
      Association between preterm delivery and subsequent C-reactive protein: a retrospective cohort study.
      • Hubel C.A.
      • Powers R.W.
      • Snaedal S.
      • et al.
      C-reactive protein is elevated 30 years after eclamptic pregnancy.
      they were not associated with a history of spontaneous preterm delivery in a small study (n = 30 cases) of women 1–29 years after pregnancy.
      • Hastie C.E.
      • Smith G.C.
      • Mackay D.F.
      • Pell J.P.
      Association between preterm delivery and subsequent C-reactive protein: a retrospective cohort study.
      The Avon Longitudinal Study of Parents and Children found no evidence of dyslipidemia, glucose intolerance, elevated blood pressure, or inflammation (including C-reactive protein) in a group of 139 women studied at a mean 18 years after preterm delivery.
      • Fraser A.
      • Nelson S.M.
      • Macdonald-Wallis C.
      • et al.
      Associations of pregnancy complications with calculated cardiovascular disease risk and cardiovascular risk factors in middle age: the Avon longitudinal study of parents and children.
      The various associations of preterm delivery, preeclampsia, gestational diabetes, and fetal growth restriction with CVD suggest that further research into their common causes may shed new light on the pathology and etiology of pregnancy complications as well as CVD. Knowledge generated in this arena is already changing clinical practice. For example, 2 organizations have recommended accelerated glucose screening among women with a history of gestational diabetes.
      American Diabetes Association
      Standards of medical care in diabetes—2008.
      • Metzger B.E.
      • Buchanan T.A.
      • Coustan D.R.
      • et al.
      Summary and recommendations of the fifth international workshop-conference on gestational diabetes mellitus.
      The American College of Obstetricians and Gynecologists and the American Heart Association have recommended that preeclampsia be considered a cardiovascular risk factor.
      American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy
      Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy.
      • Mosca L.
      • Benjamin E.J.
      • Berra K.
      • et al.
      Effectiveness-based guidelines for the prevention of cardiovascular disease in women–2011 update: a guideline from the American Heart Association.
      Our findings suggest that spontaneous preterm delivery may also merit attention as a CVD risk factor. A better understanding of the mechanisms linking gestational length of spontaneously delivered pregnancies with CVD may yield novel risk factors and opportunities for the prevention of both preterm delivery and CVD.

      Acknowledgment

      The authors’ institutions had no role in the design and conduct of the study; the collection, management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript.

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