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Pregnancy as a window to future health: maternal placental syndromes and short-term cardiovascular outcomes

      Background

      Cardiovascular disease is the leading cause of death among women. Identifying risk factors for future cardiovascular disease may lead to earlier lifestyle modifications and disease prevention. Additionally, interpregnancy development of cardiovascular disease can lead to increased perinatal morbidity in subsequent pregnancies. Identification and implementation of interventions in the short term (within 5 years of first pregnancy) may decrease morbidity in subsequent pregnancies.

      Objective

      We identified the short-term risk (within 5 years of first pregnancy) of cardiovascular disease among women who experienced a maternal placental syndrome, as well as preterm birth and/or delivered a small-for-gestational-age infant.

      Study Design

      We conducted a retrospective cohort study using a population-based, clinically enhanced database of women in the state of Florida. Nulliparous women and girls aged 15-49 years experiencing their first delivery during the study time period with no prepregnancy history of diabetes mellitus, hypertension, or heart or renal disease were included in the study. The risk of subsequent cardiovascular disease was compared among women who did and did not experience a placental syndrome during their first pregnancy. Risk was then reassessed among women with placental syndrome and preterm birth or delivering a small-for-gestational-age infant vs those without these adverse pregnancy outcomes.

      Results

      The final study population was 302,686 women and girls. Median follow-up time for each patient was 4.9 years. The unadjusted rate of subsequent cardiovascular disease among women and girls with any placental syndrome (11.8 per 1000 women) was 39% higher than the rate among women and girls without a placental syndrome (8.5 per 1000 women). Even after adjusting for sociodemographic factors, preexisting conditions, and clinical and behavioral conditions associated with the current pregnancy, women and girls with any placental syndrome experienced a 19% increased risk of cardiovascular disease (hazard ratio, 1.19; 95% confidence interval, 1.07–1.32). Women and girls with >1 placental syndrome had the highest cardiovascular disease risk (hazard ratio, 1.43; 95% confidence interval, 1.20–1.70), followed by those with eclampsia/preeclampsia alone (hazard ratio, 1.42; 95% confidence interval, 1.14–1.76). When placental syndrome was combined with preterm birth and/or small for gestational age, the adjusted risk of cardiovascular disease increased 45% (95% confidence interval, 1.24–1.71). Women and girls with placental syndrome who then developed cardiovascular disease experienced a 5-fold increase in health care–related costs during follow-up, compared to those who did not develop cardiovascular disease.

      Conclusion

      Women and girls experiencing placental syndromes and preterm birth or small-for-gestational-age infant are at increased risk of subsequent cardiovascular disease in short-term follow-up. Strategies to identify and improve cardiovascular disease risk in the postpartum period may improve future heart disease outcomes.

      Key words

      Related editorial, page 406.

      Introduction

      Cardiovascular disease (CVD) is the leading cause of death among women in the United States.
      • Mosca L.
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      Effectiveness-based guidelines for the prevention of cardiovascular disease in women–2011 update: a guideline from the American Heart Association.
      An increasing body of evidence indicates that pregnancy-related morbidities, including preeclampsia, placental infarction, and abruption, are associated with the development of subsequent CVD and can be referred to as maternal placental syndromes (PS).
      • Granger J.P.
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      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
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      • Sargent I.L.
      The pathogenesis of pre-eclampsia.
      Furthermore, the adverse pregnancy outcomes of preterm delivery, and infants born small for gestational age (SGA), resulting from intrauterine growth restriction, may be referred to as fetal PS and also appear to confer CVD risk.
      • Ray J.G.
      • Vermeulen M.J.
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      • Redelmeier D.A.
      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
      • Sibai B.M.
      Evaluation and management of severe preeclampsia before 34 weeks' gestation.
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      Pregnancy complications and maternal risk of ischemic heart disease: a retrospective cohort study of 129,290 births.
      • Magnussen E.B.
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      Both retrospective and prospective epidemiological studies have reported associations between hypertensive disorders of pregnancy, preterm birth (PTB), and maternal PS and an increased risk of future CVD.
      • Ray J.G.
      • Vermeulen M.J.
      • Schull M.J.
      • Redelmeier D.A.
      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
      • Smith G.C.
      • Pell J.P.
      • Walsh D.
      Pregnancy complications and maternal risk of ischemic heart disease: a retrospective cohort study of 129,290 births.
      • Magnussen E.B.
      • Vatten L.J.
      • Smith G.D.
      • Romundstad P.R.
      Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors.
      • Sibai B.M.
      • el-Nazer A.
      • Gonzalez-Ruiz A.
      Severe preeclampsia-eclampsia in young primigravid women: subsequent pregnancy outcome and remote prognosis.
      • Robbins C.L.
      • Hutchings Y.
      • Dietz P.M.
      • Kuklina E.V.
      • Callaghan W.M.
      History of preterm birth and subsequent cardiovascular disease: a systematic review.
      While most of these studies focus on long-term CVD risk, up to 15 years after giving birth, limited data exist regarding the short-term risk of CVD. CVD occurring within the first 5 years of the index delivery will likely occur in the mother’s reproductive lifespan and therefore lead to further morbidity in subsequent pregnancies. No prior research investigates the impact of PS and subsequent CVD on health care utilization or costs. We hypothesized that the short-term risk of CVD (within 5 years of first pregnancy) would be increased among women with maternal PS. Additionally we examined health care utilization and direct medical costs in the years immediately following pregnancy with and without placental complications.

      Materials and Methods

      Design, data source, and study population

      We conducted a population-based retrospective cohort study using a statewide maternal and infant longitudinally linked database.
      • Pine M.
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      Transformative use of an improved all-payer hospital discharge data infrastructure for community-based participatory research: a sustainability pathway.
      For Florida-resident births from 1998 through 2009, birth certificates were linked both to infant birth and maternal delivery hospitalization discharge records using a hierarchical deterministic linking strategy.
      • Salemi J.L.
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      After establishing events that occur at birth, we then linked in death certificates and all subsequent infant and maternal inpatient, outpatient, and emergency department discharge records available through the end of follow-up (Dec. 31, 2010). For mothers, we also linked to all hospital discharge data preceding the index pregnancy, as far back as Jan. 1, 1998. Details of the data linkage process, which achieved >92% linkage rate, and an evaluation of the validity and reliability of database have been published previously.
      • Salemi J.L.
      • Tanner J.P.
      • Bailey M.
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      • Salihu H.M.
      Creation and evaluation of a multi-layered maternal and child health database for comparative effectiveness research.
      The study population consisted initially of 318,362 nulliparous pregnant women and girls aged 15-49 years who gave birth to a live born singleton infant from Jan. 1, 2004, through Dec. 31, 2007 (Figure 1). This time frame was chosen to review medical history in the 5-year period before pregnancy, incorporate potential confounders present only on the new version of the Florida birth certificate, and allow for a minimum of 3 years of follow-up after the index delivery. Women diagnosed with prepregnancy CVD, hypertension, diabetes, or renal disease in the 5-year period before the index delivery hospitalization (n = 14,165) and those giving birth to infants with implausible gestational age-birthweight combinations based on national fetal growth curves
      • Alexander G.R.
      • Himes J.H.
      • Kaufman R.B.
      • Mor J.
      • Kogan M.
      A United States national reference for fetal growth.
      (n = 416) were excluded. The final study population consisted of 302,686 women and girls.
      Figure thumbnail gr1
      Figure 1Flow diagram representing final determination of study population
      Flow diagram representing final determination of study population of nulliparous, Florida-resident women and girls aged 15-49 years whose first singleton live birth occurred from 2004 through 2007.
      CVD, cardiovascular disease; ED, emergency department.
      Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

      PS and adverse infant outcomes

      Using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes from discharge records, supplemented with birth certificate indicators to improve sensitivity, we determined whether each mother had a PS–preeclampsia (642.4, 642.5), eclampsia (642.6 or birth certificate indicator), gestational hypertension (642.3 or birth certificate indicator), placental infarction (656.7), or placental abruption (641.2)–diagnosed during her index delivery hospitalization. Three exposures were used in analyses: (1) a 2-level “any PS” variable; (2) a 5-level variable to capture the nature and number of PS conditions; and (3) a 4-level variable that combined PS with PTB (20-37 weeks’ gestation) and SGA (birthweight <10th percentile for gestational age).

      Cardiovascular health outcomes

      The primary outcome was incident CVD, operationalized as presence of ≥1 ICD-9-CM diagnosis codes indicative of coronary heart disease, cerebrovascular disease, peripheral artery disease, or congestive heart failure, or an ICD-9-CM procedure code for cardiac or peripheral arterial revascularization. To prevent capturing the immediate effect of the index delivery on risk of CVD,
      • Ray J.G.
      • Vermeulen M.J.
      • Schull M.J.
      • Redelmeier D.A.
      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
      assessment of CVD included encounters taking place ≥90 days after discharge from the index delivery hospitalization. Follow-up continued through Dec. 31, 2010. A detailed list of the ICD-9-CM codes used to define CVD is presented in the Appendix.

      Health care utilization indices

      We explored the associations between PS and 3 indicators of health care utilization: (1) number of encounters, (2) length of stay (LOS) across encounters, and (3) cost of providing direct medical care. The number of encounters was calculated as the number of unique inpatient, outpatient, and emergency department discharge records with date of admission ≥90 days after discharge from the index delivery hospitalization. To calculate LOS in days for any type of encounter, we subtracted the dates of admission and discharge. Same day visits were assigned an LOS of 1 day since these hospitalizations constitute a distinct stay and are billed as 1 day for room/board.

      Coffey RM, Barrett ML, Steiner S. Final Report Observation Status Related to Hospital Records. 2002. HCUP Methods Series Report #2002-3. September 27, 2002. Agency for Healthcare Research and Quality. Available at: http://www.hcup-us.ahrq.gov. Accessed December 12, 2014.

      For each woman or girl, the number of days across all admissions was summed. Hospital discharge records in our linked database contain detailed department-level charges for each encounter. Charges reflect what a hospital bills for services and are a poor estimate of actual cost.
      • Reinhardt U.E.
      The pricing of US hospital services: chaos behind a veil of secrecy.
      The degree of markup from cost to billed charges varies considerably across hospitals, departments within the same hospital, and over time. We developed an algorithm
      • Salemi J.L.
      • Comins M.M.
      • Chandler K.
      • Mogos M.F.
      • Salihu H.M.
      A practical approach for calculating reliable cost estimates from observational data: application to cost analyses in maternal and child health.
      to convert charges to cost using time-, hospital-, and department-specific cost-to-charge ratios from hospital cost reports, and further adjusted estimates for inflation to 2010 dollars using the medical care component of the Consumer Price Index.

      US Department of Labor: Bureau of Labor Statistics. Consumer Price Index: all urban consumers-(CPI-U). Available at: http://www.bls.gov/data. Accessed Dec. 18, 2014.

      Due to the lack of reliable cost-to-charge ratio to fit our data, outpatient visits were not included in determining the cost of medical care during follow-up.
      To remove the impact of subsequent pregnancies on health care utilization metrics, we excluded nonindex delivery hospitalizations. We stratified total LOS and direct medical costs into those occurring during the index delivery hospitalization and during the post-90-day follow-up period.

      Sociodemographic, behavioral, and clinical covariates

      Using both birth certificate and ICD-9-CM codes, we examined sociodemographic characteristics (age at the index delivery, race/ethnicity, nativity, education, and per-capita income), health behaviors (tobacco, alcohol, and drug use), clinical comorbidities (a 5-year history of hyperlipidemia, migraine, and lupus), prepregnancy body mass index (BMI), and gestational diabetes that could plausibly confound the associations between PS and the study outcomes. Specific ICD-9-CM codes and birth certificate indicator variables used are provided in the Appendix.

      Statistical analysis

      Descriptive statistics were used to describe the distribution of nulliparous women with and without a PS by sociodemographic, clinical, behavioral, and infant characteristics. The χ2 test (categorical data) and independent-samples t tests or Wilcoxon-Mann-Whitney tests (continuous data) were used to assess the statistical significance of bivariate associations. Kaplan-Meier curves were used to describe the risk of incident CVD for women with and without PS, and Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) that represent the association between PS and time to CVD. Women and girls were censored if they did not experience a CVD-related event by Dec. 31, 2010. Ties, in which ≥2 women or girls experience a CVD at the same recorded time, were handled using the Efron approximation. The proportional hazards assumption was assessed using plots of Schoenfeld residuals versus time; linearity was examined using plots of Martingale residuals and each covariate. To compare mean health care utilization indices across exposure and outcome groups, we used generalized linear modeling to calculate adjusted measures of association (eg, cost ratios) and 95% CIs. Due to the positively skewed nature of LOS and cost data, we considered various nonnormal distributions with the best-fitting model selected based on Akaike information criterion.
      • Hirotogu Akaike
      Information theory and an extension of the maximum likelihood principle.
      For each exposure-outcome association, 3 multivariable models were constructed to demonstrate the relative confounding effects of 3 types of factors: (1) adjusting for sociodemographic characteristics; (2) additional adjustment for 5-year history of hyperlipidemia, migraine, and lupus; and (3) additional adjustment for prepregnancy BMI, gestational diabetes, and tobacco, drug, and alcohol use during the index pregnancy.
      We conducted sensitivity analyses to evaluate the robustness of our results to alternative eligibility criteria and model inputs. Although index pregnancies in the current study were only nulliparous women and girls, subsequent pregnancies may have occurred during the follow-up period. These pregnancies could increase the risk of CVD independent of PS during the index pregnancy. Therefore, we re-ran all analyses after restricting to women and girls with no subsequent deliveries. Our cost analyses did not include outpatient visits, therefore we analyzed charges among all encounters, and compared calculated charge ratios to cost ratios. All analyses were conducted using software (SAS 9.4; SAS Institute Inc, Cary, NC) using a 5% type I error rate and 2-sided hypothesis tests. The linked database was deidentified prior to use and the study was approved by the institutional review boards of the Florida Department of Health, University of South Florida, and Baylor College of Medicine.

      Results

      We identified 36,713 (13.8%) mothers with a PS during their index delivery hospitalization. Mothers with PS were more likely to be black non-Hispanic, have a high school education or less, have lower income, have a higher prepregnancy BMI, have gestational diabetes, and use illicit drugs during pregnancy (Table 1). Infants of mothers with PS were more likely to be born preterm and be SGA.
      Table 1Distribution of women with and without placental syndrome during their index pregnancies by selected maternal sociodemographic, clinical, behavioral, and infant characteristics
      Characteristic
      Binary characteristics are presented as frequency and percentage that reflect presence of condition
      Placental syndrome, N = 36,713No placental syndrome, N = 265,973P
      Generated from χ2 test of statistical independence for categorical variables, and from independent samples t test or Wilcoxon-Mann-Whitney test for continuous variables
      Follow-up time (days), median (Q1–Q3)
      Quartile
      1770 (1428–2121)1775 (1433–2129).03
      Sociodemographics
      Age, y, mean ± SD24.9 ± 6.125.1 ± 6.0<.01
      Race/ethnicity<.01
       Non-Hispanic white19,139 (52.1)131,193 (49.3)
       Non-Hispanic black8325 (22.7)47,207 (17.7)
       Hispanic7840 (21.4)72,476 (27.2)
       Non-Hispanic other1247 (3.4)13,938 (5.2)
      Nativity, foreign-born7773 (21.2)78,250 (29.4)<.01
      Education<.01
       <High school6714 (18.3)46,812 (17.6)
       High school11,619 (31.6)79,405 (29.9)
       >High school18,172 (49.5)138,134 (51.9)
      Per-capita income, US$
      Presented in thousands of dollars.
      , median (Q1–Q3)
      23.6 (18.9–28.5)23.8 (19.4–29.5)<.01
      Had another live birth13,472 (36.7)99,872 (37.5)<.01
      Comorbidities, 5-y history
       Hyperlipidemia52 (0.1)244 (0.1)<.01
       Migraine433 (1.2)2059 (0.8)<.01
       Lupus63 (0.2)230 (0.1)<.01
      Comorbidities, current pregnancy
       BMI, kg/m2, mean ± SD26.3 ± 6.524.2 ± 5.3<.01
       Prepregnancy BMI<.01
      Underweight1529 (4.2)17,677 (6.6)
      Normal15,884 (43.3)148,153 (55.7)
      Overweight8720 (23.8)51,611 (19.4)
      Obese I4603 (12.5)20,392 (7.7)
      Obese II2208 (6.0)7784 (2.9)
      Obese III1428 (3.9)4206 (1.6)
       Gestational diabetes2733 (7.4)11,384 (4.3)<.01
      Behavioral factors
       Tobacco use during pregnancy2754 (7.5)20,470 (7.7).19
       Alcohol use during pregnancy142 (0.4)978 (0.4).57
       Drug use during pregnancy425 (1.2)2444 (0.9)<.01
      Infant characteristics
       Male sex18,919 (51.5)136,179 (51.2).23
       Small for gestational age6215 (16.9)26,603 (10.0)<.01
       Preterm birth7517 (20.5)18,821 (7.1)<.01
      BMI, body mass index.
      Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.
      a Binary characteristics are presented as frequency and percentage that reflect presence of condition
      b Generated from χ2 test of statistical independence for categorical variables, and from independent samples t test or Wilcoxon-Mann-Whitney test for continuous variables
      c Quartile
      d Presented in thousands of dollars.

      PS and risk of subsequent CVD

      Women or girls with any PS were at a 39% higher risk of subsequently developing CVD than women or girls without PS (95% CI, 1.25–1.54) (Table 2). The risk was reduced to 19% after adjusting for sociodemographic, clinical, and behavioral factors, and infant sex (95% CI, 1.07–1.32). Women or girls with >1 PS condition had the highest CVD risk (HR, 1.43; 95% CI, 1.20–1.70), followed by those with eclampsia/preeclampsia alone (HR, 1.42; 95% CI, 1.14–1.76). Although women or girls with gestational hypertension alone experienced an 18% increased crude risk of CVD, the risk was not significant after adjustment for confounders. When PS was combined with PTB and/or SGA, the adjusted risk of CVD increased 45% (95% CI, 1.24–1.71) (Figure 2). Women and girls with PS without PTB or SGA did not demonstrate increased CVD risk, relative to women and girls without PS, PTB, or SGA.
      Table 2Hazard ratios and 95% confidence intervals representing association between placental syndromes during current pregnancy and subsequent cardiovascular disease
      Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system
      Exposure categoryCVD

      cases
      CVD

      rate
      Rate expressed as no. of incident CVD cases per 1000 women
      Unadjusted model

      HR (95% CI)
      Adjusted model 1
      Crude model + adjusted for maternal age, race/ethnicity, nativity, education, and income


      HR (95% CI)
      Adjusted model 2
      Adjusted model 1 + adjusted for 5-y history of hyperlipidemia, migraine, and lupus


      HR (95% CI)
      Adjusted model 3
      Adjusted model 2 + adjusted for prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex


      HR (95% CI)
      Any PS
       No22698.51.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       Yes43211.81.39 (1.25–1.54)
      HRs statistically significantly different from 1.
      1.27 (1.14–1.40)
      HRs statistically significantly different from 1.
      1.26 (1.13–1.39)
      HRs statistically significantly different from 1.
      1.19 (1.07–1.32)
      HRs statistically significantly different from 1.
      Nature/no. of PS conditions
       No PS22698.51.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       Eclampsia/preeclampsia alone8713.71.60 (1.29–1.98)
      HRs statistically significantly different from 1.
      1.48 (1.20–1.84)
      HRs statistically significantly different from 1.
      1.47 (1.18–1.82)
      HRs statistically significantly different from 1.
      1.42 (1.14–1.76)
      HRs statistically significantly different from 1.
       Gestational hypertension alone17810.01.18 (1.01–1.37)
      HRs statistically significantly different from 1.
      1.07 (0.91–1.24)1.06 (0.91–1.24)0.99 (0.85–1.16)
       Placental abruption/infarction alone3210.51.22 (0.86–1.73)1.12 (0.78–1.60)1.12 (0.78–1.60)1.09 (0.76–1.57)
       More than one placental syndrome condition13514.31.69 (1.42–2.01)
      HRs statistically significantly different from 1.
      1.54 (1.29–1.83)
      HRs statistically significantly different from 1.
      1.53 (1.28–1.82)
      HRs statistically significantly different from 1.
      1.43 (1.20–1.70)
      HRs statistically significantly different from 1.
      PS and adverse infant outcomes
       No PS, no PTB, no SGA18548.31.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       PS alone26810.71.29 (1.14–1.47)
      HRs statistically significantly different from 1.
      1.16 (1.02–1.32)
      HRs statistically significantly different from 1.
      1.16 (1.02–1.32)
      HRs statistically significantly different from 1.
      1.08 (0.95–1.23)
       PTB/SGA alone4159.61.16 (1.04–1.29)
      HRs statistically significantly different from 1.
      1.10 (0.99–1.22)1.10 (0.98–1.22)1.07 (0.96–1.20)
       PS and PTB/SGA16414.11.70 (1.45–2.00)
      HRs statistically significantly different from 1.
      1.56 (1.33–1.83)
      HRs statistically significantly different from 1.
      1.54 (1.31–1.81)
      HRs statistically significantly different from 1.
      1.45 (1.24–1.71)
      HRs statistically significantly different from 1.
      CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
      Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.
      a Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system
      b Rate expressed as no. of incident CVD cases per 1000 women
      c Crude model + adjusted for maternal age, race/ethnicity, nativity, education, and income
      d Adjusted model 1 + adjusted for 5-y history of hyperlipidemia, migraine, and lupus
      e Adjusted model 2 + adjusted for prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex
      f HRs statistically significantly different from 1.
      Figure thumbnail gr2
      Figure 2Kaplan-Meier survival estimates representing risk of cardiovascular disease across groups
      Crude Kaplan-Meier survival estimates representing risk of cardiovascular disease (CVD) across groups that differ on presence/absence of placental syndromes (PS) and adverse infant outcomes.
      PTB, preterm birth; SGA, small for gestational age.
      Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

      PS and health care utilization

      Table 3 describes the frequency of clinical encounters and LOS based on the presence/absence of PS, adverse pregnancy outcomes, and CVD. Women and girls with any PS had more hospital encounters and increased mean LOS than women and girls without PS. The mean number of hospital encounters, admissions, and LOS differed depending on the type of PS. Women and girls with >1 PS experienced the highest mean number of all encounters (4.1 days). 23.4% of women and girls with >1PS experienced greater than or equal to 6 hospital encounters. Women and girls with no PS had the smallest number of hospital encounters. Similarly, women and girls with >1 PS had the highest mean LOS during the index delivery (4.4 days) and during the follow-up period (5.2 days). Over 17% of these women and girls, and 12.7% of women and girls with eclampsia/preeclampsia alone, spent ≥6 days in the hospital during the index delivery, compared with 1.3% of women and girls without PS.
      Table 3Frequency and length of stay during inpatient, outpatient, and emergency department encounters, based on presence/absence of placental syndrome, adverse pregnancy outcomes, and cardiovascular disease
      Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system
      Exposure/outcome categoryAll nondelivery hospital encounters
      Includes all inpatient, outpatient, and emergency department encounters, excluding all hospitalizations in which delivery occurred.
      LOS: index deliveryLOS: other encounters
      Includes all inpatient, outpatient, and emergency department encounters, excluding all hospitalizations in which delivery occurred.
      Mean ± SD≥6 VisitsMean ± SD≥6 dMean ± SD≥21 d
      Any PS
       No3.1 ± 5.517.0%2.7 ± 1.71.3%3.8 ± 7.92.6%
       Yes3.8 ± 6.621.2%3.7 ± 2.68.9%4.7 ± 10.23.7%
      Nature/no. of PS conditions
       No PS3.1 ± 5.517.0%2.7 ± 1.71.3%3.8 ± 7.92.6%
       Eclampsia/preeclampsia alone3.9 ± 6.322.2%4.0 ± 2.912.7%5.0 ± 12.94.2%
       Gestational hypertension alone3.6 ± 6.719.8%3.2 ± 1.63.4%4.4 ± 8.93.2%
       Placental abruption/infarction alone3.8 ± 6.620.7%3.6 ± 4.37.0%4.6 ± 8.33.7%
       More than one placental syndrome condition4.1 ± 6.623.4%4.4 ± 3.117.3%5.2 ± 10.74.4%
      PS and adverse infant outcomes
       No PS, no PTB, no SGA3.0 ± 5.215.9%2.7 ± 1.00.6%3.6 ± 7.42.4%
       PS alone3.6 ± 6.520.0%3.3 ± 1.64.3%4.4 ± 8.53.3%
       PTB/SGA alone3.9 ± 6.522.3%3.2 ± 3.64.9%4.8 ± 10.23.9%
       PS and PTB/SGA4.2 ± 6.823.8%4.5 ± 3.918.8%5.4 ± 13.04.6%
      CVD
       No3.1 ± 5.417.1%2.9 ± 1.92.2%3.8 ± 7.62.6%
       Yes12.0 ± 14.961.7%3.0 ± 3.23.6%17.6 ± 30.323.6%
      PS and CVD
       No PS or CVD3.0 ± 5.216.6%2.7 ± 1.71.3%3.7 ± 7.42.5%
       PS, did not develop CVD3.7 ± 6.420.7%3.7 ± 2.68.8%4.5 ± 9.13.4%
       No PS, developed CVD11.8 ± 15.261.1%2.9 ± 3.11.7%16.9 ± 28.522.8%
       PS, developed CVD12.9 ± 13.765.0%4.0 ± 3.713.2%21.4 ± 38.327.5%
      CVD, cardiovascular disease; LOS, length of stay; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
      Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.
      a Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system
      b Includes all inpatient, outpatient, and emergency department encounters, excluding all hospitalizations in which delivery occurred.
      Women and girls with CVD had the most clinical encounters and the longest LOS during follow-up (Table 3). Approximately 65% of women and girls with PS who subsequently developed CVD had ≥6 nondelivery hospital encounters and the mean number of encounters was 12.9. Women and girls with no PS who developed CVD had the next highest number of nondelivery hospital encounters, followed by women and girls with PS who did not develop CVD, and women and girls with no PS or CVD. The presence of PS appeared to drive the length of the delivery hospitalization and development of CVD was a better predictor of the frequency and duration of clinical encounters during follow-up.

      PS, CVD, and direct costs of medical care

      Table 4 describes the costs associated with direct medical care during inpatient and emergency department encounters for women who had PS, adverse pregnancy outcomes, and CVD. Women and girls with any PS and those with PS subgroups had higher mean hospital costs than women and girls with no PS, both during the index delivery hospitalization and during follow-up. The highest crude mean costs of care were among women and girls with PS and PTB and/or SGA. After adjusting for confounders, this cost was 55% and 34% higher than women and girls without PS, SGA, and/or PTB during the index delivery and follow-up encounters, respectively. Women and girls who then developed CVD experienced a 5-fold increase in health care–related costs during follow-up, compared to those who did not develop CVD. Prevention of PS in the 36,713 nulliparous women and girls with PS in our study population would result in estimated savings of >$63 million in the direct costs of inpatient and emergency care during the average 5-year follow-up period.
      Table 4Hospital costs associated with direct medical care during inpatient and emergency department encounters, based on presence/absence of placental syndrome, adverse pregnancy outcomes, and cardiovascular disease
      Unadjusted costs associated with direct medical care in inpatient or emergency department setting, per mother, in thousands of 2010 US dollars
      Exposure/outcome categoryNCosts
      Unadjusted costs associated with direct medical care in inpatient or emergency department setting, per mother, in thousands of 2010 US dollars
      of care during index delivery
      Costs
      Unadjusted costs associated with direct medical care in inpatient or emergency department setting, per mother, in thousands of 2010 US dollars
      of care during nondelivery encounters
      Excess cost
      Represents hospital costs associated with direct medical care that could be saved by converting each nonreference level to reference level–estimated by first calculating adjusted difference in cost between each nonreference group and reference group, and then multiplying that difference by total no. of individuals in that group. Excess costs during index delivery were combined with excess costs from other, nondelivery encounters.
      Mean ± SD≥$10,000Cost ratio
      Cost ratios presented were estimated from models with total cost as outcome, were constructed using generalized linear model with gamma distribution and log link, and were adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex
      (95% CI)
      Mean ± SD≥$10,000Cost ratio
      Cost ratios presented were estimated from models with total cost as outcome, were constructed using generalized linear model with gamma distribution and log link, and were adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex
      (95% CI)
      Any PS
       No265,9734.7 ± 2.91.7%1.00 (Reference)2.7 ± 8.76.1%1.00 (Reference)Reference
       Yes36,7136.1 ± 3.57.7%1.29 (1.28–1.30)3.5 ± 11.88.4%1.14 (1.12–1.16)63,385,729
      Nature/no. of PS conditions
       No PS265,9734.7 ± 2.91.7%1.00 (Reference)2.7 ± 8.76.1%1.00 (Reference)Reference
       Eclampsia/preeclampsia alone63696.8 ± 4.412.6%1.45 (1.43–1.46)4.0 ± 16.39.7%1.31 (1.26–1.36)18,638,687
       Gestational hypertension alone17,8525.3 ± 2.43.5%1.14 (1.13–1.14)3.1 ± 8.57.4%1.04 (1.02–1.07)13,566,092
       Placental abruption/infarction alone30376.0 ± 4.86.6%1.28 (1.26–1.29)3.3 ± 9.98.2%1.14 (1.07–1.20)5,101,735
       More than one placental syndrome condition94557.0 ± 3.912.9%1.48 (1.47–1.49)3.9 ± 13.99.6%1.22 (1.18–1.26)26,723,801
      PS and adverse infant outcomes
       No PS, no PTB, no SGA222,7554.6 ± 2.51.2%1.00 (Reference)2.5 ± 8.15.7%1.00 (Reference)Reference
       PS alone25,0675.6 ± 2.54.4%1.21 (1.20–1.21)3.1 ± 9.27.7%1.09 (1.07–1.11)29,851,037
       PTB/SGA alone43,2185.1 ± 4.64.2%1.11 (1.11–1.12)3.4 ± 11.18.1%1.16 (1.14–1.18)39,303,314
       PS and PTB/SGA11,6467.2 ± 4.914.8%1.55 (1.54–1.56)4.2 ± 16.010.1%1.34 (1.31–1.38)38,217,514
      CVD
       No299,9854.8 ± 3.02.4%1.00 (Reference)2.6 ± 8.06.1%1.00 (Reference)Reference
       Yes27015.1 ± 5.13.4%1.06 (1.04–1.08)17.4 ± 45.334.5%3.87 (3.69–4.06)21,217,327
      PS and CVD
       No PS or CVD263,7044.7 ± 2.91.7%1.00 (Reference)2.6 ± 7.85.8%1.00 (Reference)Reference
       PS, did not develop CVD36,2816.1 ± 3.57.7%1.29 (1.28–1.30)3.2 ± 9.28.1%1.12 (1.10–1.14)60,187,277
       No PS, developed CVD22694.8 ± 5.22.3%1.05 (1.03–1.07)16.0 ± 40.333.7%3.71 (3.52–3.90)16,227,502
       PS, developed CVD4326.4 ± 4.29.3%1.36 (1.31–1.42)24.6 ± 65.439.1%5.13 (4.56–5.77)5,280,306
      CI, confidence interval; CVD, cardiovascular disease; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
      Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.
      a Unadjusted costs associated with direct medical care in inpatient or emergency department setting, per mother, in thousands of 2010 US dollars
      b Cost ratios presented were estimated from models with total cost as outcome, were constructed using generalized linear model with gamma distribution and log link, and were adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex
      c Represents hospital costs associated with direct medical care that could be saved by converting each nonreference level to reference level–estimated by first calculating adjusted difference in cost between each nonreference group and reference group, and then multiplying that difference by total no. of individuals in that group. Excess costs during index delivery were combined with excess costs from other, nondelivery encounters.
      Our findings were robust to alternative eligibility criteria and model inputs. We observed no significant differences in observed associations between PS and either CVD or hospital utilization indices when we restricted our analyses to women and girls without any subsequent deliveries observed during follow-up (Supplemental Table 1, Supplemental Table 2, Supplemental Table 3). Furthermore, when we analyzed charges instead of costs, which permitted the consideration of outpatient encounters in addition to inpatient and emergency department visits, the adjusted measures of association (ie, charge ratios) were only slightly attenuated compared to the cost ratios calculated in our base case analyses (Supplemental Table 4). Finally, in an effort to distinguish differences in CVD risk between those mothers experiencing spontaneous vs induced PTB, we analyzed these as separate exposures and found almost no difference in CVD risk when considered separately vs a single exposure group.

      Comment

      This study demonstrated an increased CVD risk in short-term follow-up among women and girls with PS. The highest risk of short-term CVD was among women and girls with a PS combined with PTB and/or SGA. These findings suggest that maternal PS combined with adverse fetal outcomes of PTB or SGA may confer additional CVD risk as soon as 3-5 years after delivery. Furthermore, the study noted an increase in health care utilization and costs among those women and girls with a PS and subsequent CVD.
      Our findings of an association between maternal PS and short-term CVD risk are similar to prior reports.
      • Ray J.G.
      • Vermeulen M.J.
      • Schull M.J.
      • Redelmeier D.A.
      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
      • Veerbeek J.H.
      • Hermes W.
      • Breimer A.Y.
      • et al.
      Cardiovascular disease risk factors after early-onset preeclampsia, late-onset preeclampsia, and pregnancy-induced hypertension.
      • Lykke J.A.
      • Langhoff-Roos J.
      • Lockwood C.J.
      • Triche E.W.
      • Paidas M.J.
      Mortality of mothers from cardiovascular and non-cardiovascular causes following pregnancy complications in first delivery.
      • Brown M.C.
      • Best K.E.
      • Pearce M.S.
      • Waugh J.
      • Robson S.C.
      • Bell R.
      Cardiovascular disease risk in women with pre-eclampsia: systematic review and meta-analysis.
      • 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.
      The cardiovascular health after maternal placental syndromes (CHAMPS) study utilized a population-based retrospective cohort with a median follow-up of 8.7 years. The authors identified an increased risk of CVD among women with a PS (HR, 2.0; 95% CI, 1.7–2.2); the risk further increased among women with PS with poor fetal growth (HR, 3.1; 95% CI, 2.2–4.5)
      • Ray J.G.
      • Vermeulen M.J.
      • Schull M.J.
      • Redelmeier D.A.
      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
      . Our findings indicate that the risk may occur earlier after delivery and during their reproductive lifespan. Postpartum interventions aimed at improving cardiovascular profiles among these patients may decrease subsequent pregnancy morbidities.
      The current study provides additional insight into the severity of preterm PS and demonstrates the additive effect of PTB, SGA, and PS on the future risk of CVD. Prior reports establish a relationship between PTB and CVD risk.
      • Robbins C.L.
      • Hutchings Y.
      • Dietz P.M.
      • Kuklina E.V.
      • Callaghan W.M.
      History of preterm birth and subsequent cardiovascular disease: a systematic review.
      In contrast, studies of the association between PTB and maternal PS are limited. Lykke et al
      • Lykke J.A.
      • Langhoff-Roos J.
      • Lockwood C.J.
      • Triche E.W.
      • Paidas M.J.
      Mortality of mothers from cardiovascular and non-cardiovascular causes following pregnancy complications in first delivery.
      found a relationship between maternal PS, PTB, and SGA offspring and mortality from cardiovascular causes over a median follow-up of 14.6 years. The current study noted similar risks in a shorter follow-up period. These findings may support the theory of a more severe disease among women with PTB or severe placental disease leading to growth restriction.
      No prior information exists regarding the impact of maternal PS and subsequent CVD on future health care costs and utilization unrelated to pregnancy. The increases in cost among women with CVD and maternal PS noted in this study lend support for the necessity of early risk factor recognition and intervention in an effort to prevent future CVD.
      Our findings have several limitations. The nature of the retrospective cohort using ICD-9-CM diagnosis codes relies on accurate coding of the exposures and outcomes. The database does not identify a uniform definition of preeclampsia, eclampsia, and gestational hypertension. Therefore provider and coder discretion may lead to a nonuniform cohort. Furthermore, due to our reliance on data linkage, it was not possible to differentiate between medical encounters and outcomes that did not occur and those that happened but were not captured by data linkage (ie, missing data out migration). However, the effect of out migration on our results is likely negligible, since only about 3.6% of those aged 18-49 years move to another state after living in Florida during the previous year.

      US Census Bureau. American community survey 5-year estimates, table B07401. Available at: http://factfinder2.census.gov. Accessed April 13, 2016.

      As out migration rates are likely nondifferential across exposure groups, any bias in our reported measures of association is likely to be small and toward the null. Inclusion criteria were limited to data collected following the inclusion of prepregnancy BMI in the data set, leading to a median follow-up of 4.9 years.
      Although PTB and SGA offspring were used as an exposure, in the final analysis we did not discern between spontaneous vs induced PTB. When analyzed separately almost no difference in CVD risk was noted and therefore we utilized PTB as a single exposure. Our findings support prior literature noting increases in CVD risk factors following all causes of PTB.
      • Perng W.
      • Stuart J.
      • Rifas-Shiman S.L.
      • Rich-Edwards J.W.
      • Stuebe A.
      • Oken E.
      Preterm birth and long-term maternal cardiovascular health.
      Lastly, we conducted cost analyses from a third-party payer perspective and represent only the direct medical costs from specific revenue-generating centers associated with the institutional portion of the hospital stay. Our estimates of the excess maternal and infant costs associated with PS, adverse pregnancy outcomes, and CVD are conservative and likely understated the potential savings to society.
      Our study included several strengths. The database used included a large number of women and girls with the identified exposures. The ability to adjust for multiple CVD risk factors, including prepregnancy BMI, allowed for a more accurate picture of disease risk. The cohort included a large percentage of overweight and obese women as well as racial/ethnic minorities, which made the findings applicable to these populations. Finally, our unprecedented evaluation of hospital costs and health care utilization further demonstrated the health care burden among this group of women.
      Our findings show an increase in CVD risk among women and girls with maternal PS. PTB and/or SGA offspring further increase CVD risk among women with PS. The short-term nature of these findings suggests an increase in CVD among women and girls in subsequent pregnancies. Further studies may determine if early identification and intervention will be effective in the prevention of CVD and future maternal morbidity.

      Appendix

      Supplemental Table 1Comparison of hazard ratios and 95% confidence intervals representing association between placental syndromes during current pregnancy and subsequent cardiovascular disease,
      Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system
      between women with and without subsequent live birth during follow-up
      Exposure categoryUnadjusted model HR (95% CI)Adjusted model 3
      Crude model + adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex
      HR (95% CI)
      Entire study population, n = 302,686Excluding women with subsequent live births, n = 189,342Entire study population, n = 302,686Excluding women with subsequent live births, n = 189,342
      Any PS
       No1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       Yes1.39 (1.25–1.54)
      HRs statistically significantly different from 1.
      1.40 (1.22–1.61)
      HRs statistically significantly different from 1.
      1.19 (1.07–1.32)
      HRs statistically significantly different from 1.
      1.18 (1.03–1.37)
      HRs statistically significantly different from 1.
      Nature/no. of PS conditions
       No PS1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       Eclampsia/preeclampsia alone1.60 (1.29–1.98)
      HRs statistically significantly different from 1.
      1.45 (1.07–1.97)
      HRs statistically significantly different from 1.
      1.42 (1.14–1.76)
      HRs statistically significantly different from 1.
      1.29 (0.95–1.75)
       Gestational hypertension alone1.18 (1.01–1.37)
      HRs statistically significantly different from 1.
      1.24 (1.01–1.53)
      HRs statistically significantly different from 1.
      0.99 (0.85–1.16)1.04 (0.84–1.28)
       Placental abruption/infarction alone1.22 (0.86–1.73)1.32 (0.84–2.08)1.09 (0.76–1.57)1.18 (0.74–1.88)
       More than one placental syndrome condition1.69 (1.42–2.01)
      HRs statistically significantly different from 1.
      1.66 (1.31–2.10)
      HRs statistically significantly different from 1.
      1.43 (1.20–1.70)
      HRs statistically significantly different from 1.
      1.38 (1.09–1.76)
      HRs statistically significantly different from 1.
      PS and adverse infant outcomes
       No PS, no PTB, no SGA1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       PS alone1.29 (1.14–1.47)
      HRs statistically significantly different from 1.
      1.29 (1.09–1.54)
      HRs statistically significantly different from 1.
      1.08 (0.95–1.23)1.07 (0.90–1.29)
       PTB/SGA alone1.16 (1.04–1.29)
      HRs statistically significantly different from 1.
      1.20 (1.04–1.39)
      HRs statistically significantly different from 1.
      1.07 (0.96–1.20)1.14 (0.99–1.32)
       PS and PTB/SGA1.70 (1.45–2.00)
      HRs statistically significantly different from 1.
      1.76 (1.42–2.17)
      HRs statistically significantly different from 1.
      1.45 (1.24–1.71)
      HRs statistically significantly different from 1.
      1.51 (1.21–1.87)
      HRs statistically significantly different from 1.
      CI, confidence interval; HR, hazard ratio; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
      Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.
      a Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system
      b Crude model + adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex
      c HRs statistically significantly different from 1.
      Supplemental Table 2Frequency and length of stay during inpatient, outpatient, and emergency department encounters, based on presence/absence of placental syndrome, adverse pregnancy outcomes, and cardiovascular disease,
      Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system
      restricted to women without subsequent live birth during follow-up (n = 189,342)
      Exposure/outcome categoryAll nondelivery hospital encounters
      Includes all inpatient, outpatient, and emergency department encounters, excluding all hospitalizations in which delivery occurred.
      LOS: index deliveryLOS: other encounters
      Includes all inpatient, outpatient, and emergency department encounters, excluding all hospitalizations in which delivery occurred.
      Mean ± SD≥6 VisitsMean ± SD≥6 dMean ± SD≥21 d
      Any PS
       No2.5 ± 4.713.0%2.8 ± 1.91.3%3.1 ± 7.61.8%
       Yes3.0 ± 5.216.2%3.7 ± 2.79.4%3.9 ± 9.02.5%
      Nature/no. of PS conditions
       No PS2.5 ± 4.713.0%2.8 ± 1.91.3%3.1 ± 7.61.8%
       Eclampsia/preeclampsia alone3.0 ± 5.116.8%4.1 ± 2.813.1%4.1 ± 9.93.1%
       Gestational hypertension alone2.8 ± 4.915.0%3.2 ± 1.63.7%3.6 ± 8.22.2%
       Placental abruption/infarction alone3.0 ± 5.715.7%3.8 ± 4.87.6%3.7 ± 7.02.4%
       More than one placental syndrome condition3.2 ± 5.618.1%4.4 ± 3.117.9%4.2 ± 10.32.8%
      PS and adverse infant outcomes
       No PS, no PTB, no SGA2.4 ± 4.412.3%2.7 ± 1.00.6%3.0 ± 7.01.6%
       PS alone2.8 ± 4.815.5%3.3 ± 1.64.5%3.6 ± 7.42.1%
       PTB/SGA alone3.0 ± 5.816.5%3.2 ± 4.05.2%3.8 ± 10.12.7%
       PS and PTB/SGA3.3 ± 5.817.7%4.6 ± 4.019.8%4.5 ± 11.73.3%
      CVD
       No2.5 ± 4.513.1%2.9 ± 2.02.3%3.1 ± 7.11.7%
       Yes10.8 ± 14.856.6%3.1 ± 3.93.4%17.7 ± 24.621.5%
      PS and CVD
       No PS or CVD2.4 ± 4.512.7%2.8 ± 1.81.3%3.0 ± 7.01.7%
       PS, did not develop CVD2.9 ± 5.015.8%3.7 ± 2.79.4%3.7 ± 7.92.3%
       No PS, developed CVD10.8 ± 15.256.6%3.0 ± 4.11.6%17.1 ± 33.420.9%
       PS, developed CVD10.8 ± 12.556.4%3.9 ± 2.712.8%20.9 ± 40.124.8%
      CVD, cardiovascular disease; LOS, length of stay; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
      Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.
      a Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system
      b Includes all inpatient, outpatient, and emergency department encounters, excluding all hospitalizations in which delivery occurred.
      Supplemental Table 3Comparison of hospital costs associated with direct medical care during inpatient, outpatient, and emergency department encounters, based on presence/absence of placental syndrome, adverse pregnancy outcomes, and cardiovascular disease,
      Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system
      between women with and without subsequent live birth during follow-up
      Exposure/outcome categoryCosts accrued during index delivery

      Cost ratio (95% CI)
      Crude model + adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex
      Costs accrued during nondelivery encounters

      Cost ratio (95% CI)
      Crude model + adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex
      Entire study population, n = 302,686Excluding women with subsequent live births, n = 189,342Entire study population, n = 302,686Excluding women with subsequent live births, n = 189,342
      Any PS
       No1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       Yes1.29 (1.28–1.30)
      Cost ratios statistically significantly different from 1.
      1.30 (1.29–1.31)
      Cost ratios statistically significantly different from 1.
      1.14 (1.12–1.16)
      Cost ratios statistically significantly different from 1.
      1.13 (1.10–1.15)
      Cost ratios statistically significantly different from 1.
      Nature/no. of PS conditions
       No PS1.00 (Reference)1.00 (Reference)1.00 (Reference)
       Eclampsia/preeclampsia alone1.45 (1.43–1.46)
      Cost ratios statistically significantly different from 1.
      1.45 (1.43–1.47)
      Cost ratios statistically significantly different from 1.
      1.31 (1.26–1.36)
      Cost ratios statistically significantly different from 1.
      1.32 (1.26–1.39)
      Cost ratios statistically significantly different from 1.
       Gestational hypertension alone1.14 (1.13–1.14)
      Cost ratios statistically significantly different from 1.
      1.14 (1.13–1.15)
      Cost ratios statistically significantly different from 1.
      1.04 (1.02–1.07)
      Cost ratios statistically significantly different from 1.
      1.04 (1.01–1.08)
      Cost ratios statistically significantly different from 1.
       Placental abruption/infarction alone1.28 (1.26–1.29)
      Cost ratios statistically significantly different from 1.
      1.30 (1.27–1.32)
      Cost ratios statistically significantly different from 1.
      1.14 (1.07–1.20)
      Cost ratios statistically significantly different from 1.
      1.01 (0.94–1.09)
       More than one placental syndrome condition1.48 (1.47–1.49)
      Cost ratios statistically significantly different from 1.
      1.49 (1.47–1.50)
      Cost ratios statistically significantly different from 1.
      1.22 (1.18–1.26)
      Cost ratios statistically significantly different from 1.
      1.17 (1.13–1.22)
      Cost ratios statistically significantly different from 1.
      PS and adverse infant outcomes
       No PS, no PTB, no SGA1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       PS alone1.21 (1.20–1.21)
      Cost ratios statistically significantly different from 1.
      1.21 (1.20–1.22)
      Cost ratios statistically significantly different from 1.
      1.09 (1.07–1.11)
      Cost ratios statistically significantly different from 1.
      1.05 (1.02–1.08)
      Cost ratios statistically significantly different from 1.
       PTB/SGA alone1.11 (1.11–1.12)
      Cost ratios statistically significantly different from 1.
      1.12 (1.12–1.13)
      Cost ratios statistically significantly different from 1.
      1.16 (1.14–1.18)
      Cost ratios statistically significantly different from 1.
      1.15 (1.13–1.18)
      Cost ratios statistically significantly different from 1.
       PS and PTB/SGA1.55 (1.54–1.56)
      Cost ratios statistically significantly different from 1.
      1.57 (1.55–1.58)
      Cost ratios statistically significantly different from 1.
      1.34 (1.31–1.38)
      Cost ratios statistically significantly different from 1.
      1.36 (1.31–1.42)
      Cost ratios statistically significantly different from 1.
      CVD
       No1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       Yes1.06 (1.04–1.08)
      Cost ratios statistically significantly different from 1.
      1.08 (1.06–1.10)
      Cost ratios statistically significantly different from 1.
      3.87 (3.69–4.06)
      Cost ratios statistically significantly different from 1.
      4.57 (4.28–4.88)
      Cost ratios statistically significantly different from 1.
      PS and CVD
       No PS or CVD1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       PS, did not develop CVD1.29 (1.28–1.30)
      Cost ratios statistically significantly different from 1.
      1.30 (1.29–1.31)
      Cost ratios statistically significantly different from 1.
      1.12 (1.10–1.14)
      Cost ratios statistically significantly different from 1.
      1.11 (1.08–1.13)
      Cost ratios statistically significantly different from 1.
       No PS, developed CVD1.05 (1.03–1.07)
      Cost ratios statistically significantly different from 1.
      1.09 (1.06–1.11)
      Cost ratios statistically significantly different from 1.
      3.71 (3.52–3.90)
      Cost ratios statistically significantly different from 1.
      4.42 (4.12–4.76)
      Cost ratios statistically significantly different from 1.
       PS, developed CVD1.36 (1.31–1.42)
      Cost ratios statistically significantly different from 1.
      1.31 (1.24–1.38)
      Cost ratios statistically significantly different from 1.
      5.13 (4.56–5.77)
      Cost ratios statistically significantly different from 1.
      5.75 (4.89–6.77)
      Cost ratios statistically significantly different from 1.
      CI, confidence interval; CVD, cardiovascular disease; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
      Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.
      a Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system
      b Crude model + adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex
      c Cost ratios statistically significantly different from 1.
      Supplemental Table 4Comparison of charges (for inpatient, outpatient, and emergency department) vs costs (for inpatient and emergency department only)
      Exposure/outcome categoryIndex delivery

      Cost ratio (95% CI)
      Adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex
      Nondelivery encounters

      Cost ratio (95% CI)
      Adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex
      ChargesCostsChargesCosts
      Any PS
       No1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       Yes1.40 (1.39–1.40)
      Cost ratios statistically significantly different from 1.
      1.29 (1.28–1.30)
      Cost ratios statistically significantly different from 1.
      1.12 (1.10–1.14)
      Cost ratios statistically significantly different from 1.
      1.14 (1.12–1.16)
      Cost ratios statistically significantly different from 1.
      Nature/no. of PS conditions
       No PS1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       Eclampsia/preeclampsia alone1.60 (1.59–1.62)
      Cost ratios statistically significantly different from 1.
      1.45 (1.43–1.46)
      Cost ratios statistically significantly different from 1.
      1.22 (1.18–1.27)
      Cost ratios statistically significantly different from 1.
      1.31 (1.26–1.36)
      Cost ratios statistically significantly different from 1.
       Gestational hypertension alone1.19 (1.19–1.20)
      Cost ratios statistically significantly different from 1.
      1.14 (1.13–1.14)
      Cost ratios statistically significantly different from 1.
      1.05 (1.03–1.07)
      Cost ratios statistically significantly different from 1.
      1.04 (1.02–1.07)
      Cost ratios statistically significantly different from 1.
       Placental abruption/infarction alone1.35 (1.33–1.37)
      Cost ratios statistically significantly different from 1.
      1.28 (1.26–1.29)
      Cost ratios statistically significantly different from 1.
      1.14 (1.08–1.20)
      Cost ratios statistically significantly different from 1.
      1.14 (1.07–1.20)
      Cost ratios statistically significantly different from 1.
       More than one placental syndrome condition1.65 (1.63–1.67)
      Cost ratios statistically significantly different from 1.
      1.48 (1.47–1.49)
      Cost ratios statistically significantly different from 1.
      1.18 (1.15–1.21)
      Cost ratios statistically significantly different from 1.
      1.22 (1.18–1.26)
      Cost ratios statistically significantly different from 1.
      PS and adverse infant outcomes
       No PS, no PTB, no SGA1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       PS alone1.29 (1.28–1.30)
      Cost ratios statistically significantly different from 1.
      1.21 (1.20–1.21)
      Cost ratios statistically significantly different from 1.
      1.09 (1.07–1.11)
      Cost ratios statistically significantly different from 1.
      1.09 (1.07–1.11)
      Cost ratios statistically significantly different from 1.
       PTB/SGA alone1.11 (1.11–1.12)
      Cost ratios statistically significantly different from 1.
      1.11 (1.11–1.12)
      Cost ratios statistically significantly different from 1.
      1.14 (1.12–1.15)
      Cost ratios statistically significantly different from 1.
      1.16 (1.14–1.18)
      Cost ratios statistically significantly different from 1.
       PS and PTB/SGA1.70 (1.69–1.72)
      Cost ratios statistically significantly different from 1.
      1.55 (1.54–1.56)
      Cost ratios statistically significantly different from 1.
      1.27 (1.24–1.30)
      Cost ratios statistically significantly different from 1.
      1.34 (1.31–1.38)
      Cost ratios statistically significantly different from 1.
      CVD
      Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system
       No1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       Yes1.06 (1.04–1.08)
      Cost ratios statistically significantly different from 1.
      1.06 (1.04–1.08)
      Cost ratios statistically significantly different from 1.
      3.46 (3.31–3.62)
      Cost ratios statistically significantly different from 1.
      3.87 (3.69–4.06)
      Cost ratios statistically significantly different from 1.
      PS and CVD
       No PS or CVD1.00 (Reference)1.00 (Reference)1.00 (Reference)1.00 (Reference)
       PS, did not develop CVD1.40 (1.39–1.40)
      Cost ratios statistically significantly different from 1.
      1.29 (1.28–1.30)
      Cost ratios statistically significantly different from 1.
      1.11 (1.09–1.13)
      Cost ratios statistically significantly different from 1.
      1.12 (1.10–1.14)
      Cost ratios statistically significantly different from 1.
       No PS, developed CVD1.05 (1.03–1.07)
      Cost ratios statistically significantly different from 1.
      1.05 (1.03–1.07)
      Cost ratios statistically significantly different from 1.
      3.40 (3.24–3.56)
      Cost ratios statistically significantly different from 1.
      3.71 (3.52–3.90)
      Cost ratios statistically significantly different from 1.
       PS, developed CVD1.46 (1.40–1.53)
      Cost ratios statistically significantly different from 1.
      1.36 (1.31–1.42)
      Cost ratios statistically significantly different from 1.
      4.13 (3.69–4.61)
      Cost ratios statistically significantly different from 1.
      5.13 (4.56–5.77)
      Cost ratios statistically significantly different from 1.
      CI, confidence interval; CVD, cardiovascular disease; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
      Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.
      a Composite indicator including diagnosis of ischemic heart disease, cerebrovascular disease, peripheral artery disease, congestive heart failure, and certain operations on cardiovascular system
      b Adjusted for maternal age, race/ethnicity, nativity, education, income, 5-y history of hyperlipidemia, migraine, and lupus, prepregnancy body mass index, gestational diabetes, tobacco use, drug use, and infant sex
      c Cost ratios statistically significantly different from 1.
      AppendixDiagnosis and procedure codes used to identify selected clinical and behavioral conditions
      ConditionICD-9-CM code
      Presence of ≥1 of listed codes serves as positive indication of condition–“x” indicates that all subcodes with listed code prefix are part of the condition's definition
      Birth certificate indicator
      Reflects use of variable on birth certificate to supplement identification through ICD-9-CM codes–if used, positive indication on birth certificate serves as positive indication of condition regardless of presence of 1 of listed ICD-9-CM codes
      Placental syndromes
      Assessment made using only index maternal delivery hospitalization
       Preeclampsia642.4x, 642.5xNo
       Eclampsia642.6xYes
       Gestational hypertension642.3xYes
       Placental infarction656.7xNo
       Placental abruption641.2xNo
      Cardiovascular outcomes
      Assessment made using 5-y history relative to admission date of index maternal delivery hospitalization (for exclusion criteria) or using all encounters ≥90 d postdischarge from index delivery hospitalization (for determination of primary study outcome)
       Coronary heart disease410–414x, 429.2, V45.81, V45.82No
       Cerebrovascular disease430–438xNo
       Peripheral artery disease440.2x, 440.3x, 440.8, 440.9, 443.9No
       Congestive heart failure398.91, 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 428xNo
       Cardiac or peripheral artery revascularization procedure36.0x, 36.1x, 36.3x, 37.41, 37.60, 37.91, 37.95, 37.99, 38.1x, 38.3x, 38.4x, 39.22, 39.23, 39.62, 39.64, 39.65, 39.66, 39.71, 39.73, 39.74No
      Clinical comorbidities
      Assessment made using 5-y history relative to admission date of index maternal delivery hospitalization.
       Chronic hypertension401–405x, 642.0x, 642.1x, 642.2x, 642.7xYes
       Prepregnancy diabetes249x, 250x, 648.0xYes
       Renal disease580–589x, 646.2xNo
       Hyperlipidemia272.0, 272.1, 272.2, 272.3, 272.4No
       Migraine346xNo
       Systemic lupus erythematosus710.0No
      Behavioral factors
      Assessment made using only index maternal delivery hospitalization
       Tobacco use305.1, 649.0x, 989.84Yes
       Alcohol use291x, 303x, 305.0x, 425.5, 760.71, V11.3Yes
       Drug use292.0x, 292.1x, 292.2x, 292.8x, 304x, 305.2x, 305.3x, 305.4x, 305.5x, 305.6x, 305.7x, 305.9x, 648.3x, 655.5x, 760.72, 779.5, 760.75, 965.00, 965.02, E935.1, E850.1No
      ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.
      Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.
      a Presence of ≥1 of listed codes serves as positive indication of condition–“x” indicates that all subcodes with listed code prefix are part of the condition's definition
      b Reflects use of variable on birth certificate to supplement identification through ICD-9-CM codes–if used, positive indication on birth certificate serves as positive indication of condition regardless of presence of 1 of listed ICD-9-CM codes
      c Assessment made using only index maternal delivery hospitalization
      d Assessment made using 5-y history relative to admission date of index maternal delivery hospitalization (for exclusion criteria) or using all encounters ≥90 d postdischarge from index delivery hospitalization (for determination of primary study outcome)
      e Assessment made using 5-y history relative to admission date of index maternal delivery hospitalization.

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      Linked Article

      • Progressive uterorenal denervation may contribute to both placental and cardiovascular syndromes?
        American Journal of Obstetrics & GynecologyVol. 216Issue 4
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          Cain et al1 find that women experiencing “placental syndromes” are at increased risk of serious cardiovascular disease within 5 years. We believe they have a common source of injury, namely, progressive autonomic denervation. Both uterus and kidneys receive sympathetic nerves from the same thoracic segments (T10-12). Persistent physical efforts during defecation are a common source of progressive autonomic injury in Western populations where they complicate 20-30% of Western bowel movements.2 With the introduction of Western fast foods and removal of squat toilets over the past 25 years, it is becoming a major source of recent, cardiovascular morbidity in China.
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