Original Research

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Pregnancy as a window to future health: maternal placental

syndromes and short-term cardiovascular outcomes
Mary Ashley Cain, MD; Jason L. Salemi, PhD, MPH; Jean Paul Tanner, MPH; Russell S. Kirby, PhD, MS;
Hamisu M. Salihu, MD, PhD; Judette M. Louis, MD, MPH

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-gestationalage 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, 1.07e1.32). Women and girls with >1 placental
syndrome had the highest cardiovascular disease risk (hazard ratio, 1.43;
95% confidence interval, 1.20e1.70), followed by those with eclampsia/
preeclampsia alone (hazard ratio, 1.42; 95% confidence interval,
1.14e1.76). 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, 1.24e1.71). Women
and girls with placental syndrome who then developed cardiovascular
disease experienced a 5-fold increase in health careerelated 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: cardiovascular disease, preeclampsia, preterm birth, small

for gestational age

Introduction
Cardiovascular disease (CVD) is the
leading cause of death among women in
the United States.1 An increasing body
of evidence indicates that pregnancyrelated 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).2-5 Furthermore, the
adverse pregnancy outcomes of preterm
Cite this article as: Cain MA, Salemi JL, Tanner JP, et al.
Pregnancy as a window to future health: maternal
placental syndromes and short-term cardiovascular outcomes. Am J Obstet Gynecol 2016;215:484.e1-14.
0002-9378/free
2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2016.05.047

Related editorial, page 406.

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.4,6-10
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.4,7-9,11 While most of
these studies focus on long-term CVD
risk, up to 15 years after giving birth,
limited data exist regarding the shortterm risk of CVD. CVD occurring
within the rst 5 years of the index
delivery will likely occur in the mothers
reproductive lifespan and therefore lead
to further morbidity in subsequent
pregnancies.
No prior
research

484.e1 American Journal of Obstetrics & Gynecology OCTOBER 2016

investigates the impact of PS and subsequent CVD on health care utilization or

costs. We hypothesized that the shortterm risk of CVD (within 5 years of
rst 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.12,13 For Floridaresident births from 1998 through 2009,
birth certicates were linked both to
infant birth and maternal delivery

ajog.org
hospitalization discharge records using a
hierarchical deterministic linking strategy.14 After establishing events that
occur at birth, we then linked in death
certicates 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.14 The
study population consisted initially of
318,362 nulliparous pregnant women
and girls aged 15-49 years who gave

OBSTETRICS

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
certicate, 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 curves15 (n 416)
were excluded. The nal study population
consisted of 302,686 women and girls.

FIGURE 1

Flow diagram representing final determination of study population

Original Research

PS and adverse infant outcomes

Using International Classication of
Diseases, Ninth Revision, Clinical Modication (ICD-9-CM) diagnosis codes
from discharge records, supplemented
with birth certicate indicators to
improve sensitivity, we determined
whether each mother had a PSe
preeclampsia (642.4, 642.5), eclampsia
(642.6 or birth certicate indicator),
gestational hypertension (642.3 or birth
certicate indicator), placental infarction (656.7), or placental abruption
(641.2)ediagnosed 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,4
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 dene CVD is presented
in the Appendix.

Health care utilization indices

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.

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

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TABLE 1

Distribution of women with and without placental syndrome during their index pregnancies by selected maternal
sociodemographic, clinical, behavioral, and infant characteristics
Placental syndrome, N 36,713

Characteristica
Follow-up time (days), median (Q1eQ3)

1770 (1428e2121)

No placental syndrome, N 265,973

1775 (1433e2129)

Pb
.03

Sociodemographics
Age, y, mean  SD

24.9  6.1

25.1  6.0

<.01

Race/ethnicity
Non-Hispanic white

19,139 (52.1)

131,193 (49.3)

Non-Hispanic black

8325 (22.7)

47,207 (17.7)

Hispanic

7840 (21.4)

72,476 (27.2)

1247 (3.4)

13,938 (5.2)

7773 (21.2)

78,250 (29.4)

Non-Hispanic other
Nativity, foreign-born

6714 (18.3)

46,812 (17.6)

High school

11,619 (31.6)

79,405 (29.9)

>High school

18,172 (49.5)

138,134 (51.9)

Per-capita income, US$d, median (Q1eQ3)

Had another live birth

<.01
<.01

Education
<High school

<.01

23.6 (18.9e28.5)
13,472 (36.7)

23.8 (19.4e29.5)
99,872 (37.5)

<.01
<.01

Comorbidities, 5-y history

Hyperlipidemia
Migraine
Lupus

52 (0.1)

244 (0.1)

<.01

433 (1.2)

2059 (0.8)

<.01

63 (0.2)

230 (0.1)

<.01

Comorbidities, current pregnancy

BMI, kg/m2, mean  SD

26.3  6.5

24.2  5.3

Underweight
Normal

1529 (4.2)

17,677 (6.6)

15,884 (43.3)

148,153 (55.7)

Overweight

8720 (23.8)

51,611 (19.4)

Obese I

4603 (12.5)

20,392 (7.7)

Obese II

2208 (6.0)

Obese III
Gestational diabetes

<.01
<.01

Prepregnancy BMI

7784 (2.9)

1428 (3.9)

4206 (1.6)

2733 (7.4)

11,384 (4.3)

<.01

2754 (7.5)

20,470 (7.7)

.19

Behavioral factors
Tobacco use during pregnancy
Alcohol use during pregnancy

142 (0.4)

978 (0.4)

.57

Drug use during pregnancy

425 (1.2)

2444 (0.9)

<.01

Infant characteristics
Male sex

18,919 (51.5)

136,179 (51.2)

.23

Small for gestational age

6215 (16.9)

26,603 (10.0)

<.01

Preterm birth

7517 (20.5)

18,821 (7.1)

<.01

BMI, body mass index.

Binary characteristics are presented as frequency and percentage that reflect presence of condition; b Generated from c2 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.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

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Original Research

TABLE 2

Hazard ratios and 95% confidence intervals representing association between placental syndromes during
current pregnancy and subsequent cardiovascular diseasea
Exposure category

CVD CVD Unadjusted model Adjusted model 1c Adjusted model 2d Adjusted model 3e
cases rateb HR (95% CI)
HR (95% CI)
HR (95% CI)
HR (95% CI)

Any PS
No
Yes

2269

8.5 1.00 (Reference)

432 11.8 1.39 (1.25e1.54)

1.00 (Reference)
f

1.27 (1.14e1.40)

1.00 (Reference)
f

1.26 (1.13e1.39)

1.00 (Reference)
f

1.19 (1.07e1.32)f

Nature/no. of PS conditions
No PS
Eclampsia/preeclampsia alone
Gestational hypertension alone
Placental abruption/infarction alone
More than one placental syndrome condition

2269

8.5 1.00 (Reference)

1.00 (Reference)

1.00 (Reference)

1.00 (Reference)

87 13.7 1.60 (1.29e1.98)f 1.48 (1.20e1.84)f 1.47 (1.18e1.82)f 1.42 (1.14e1.76)f

178 10.0 1.18 (1.01e1.37)f 1.07 (0.91e1.24)
32 10.5 1.22 (0.86e1.73)
135 14.3 1.69 (1.42e2.01)

1.06 (0.91e1.24)

1.12 (0.78e1.60)
f

1.54 (1.29e1.83)

0.99 (0.85e1.16)

1.12 (0.78e1.60)
f

1.53 (1.28e1.82)

1.09 (0.76e1.57)
f

1.43 (1.20e1.70)f

PS and adverse infant outcomes

No PS, no PTB, no SGA

1854

8.3 1.00 (Reference)

1.00 (Reference)

1.00 (Reference)

268 10.7 1.29 (1.14e1.47)

1.16 (1.02e1.32)

PTB/SGA alone

415

1.10 (0.99e1.22)

PS and PTB/SGA

164 14.1 1.70 (1.45e2.00)f 1.56 (1.33e1.83)f 1.54 (1.31e1.81)f 1.45 (1.24e1.71)f

PS alone

9.6 1.16 (1.04e1.29)

1.00 (Reference)

1.16 (1.02e1.32)

1.10 (0.98e1.22)

1.08 (0.95e1.23)
1.07 (0.96e1.20)

CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
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.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

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.16
For each woman or girl, the number of
days across all admissions was summed.
Hospital discharge records in our linked
database contain detailed departmentlevel charges for each encounter.
Charges reect what a hospital bills for
services and are a poor estimate of actual
cost.17 The degree of markup from cost
to billed charges varies considerably
across hospitals, departments within the
same hospital, and over time. We developed an algorithm18 to convert charges
to cost using time-, hospital-, and
department-specic cost-to-charge ratios from hospital cost reports, and
further adjusted estimates for ination to
2010 dollars using the medical care
component of the Consumer Price
Index.19 Due to the lack of reliable
cost-to-charge ratio to t 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 stratied total LOS
and direct medical costs into those
occurring during the index delivery
hospitalization and during the post-90day follow-up period.

Sociodemographic, behavioral, and

clinical covariates
Using both birth certicate 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. Specic ICD-9-CM codes and

birth certicate 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 c2 test (categorical data) and independent-samples t
tests or Wilcoxon-Mann-Whitney tests
(continuous data) were used to assess the
statistical signicance 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%
condence 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

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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-tting model selected
based on Akaike information criterion.20
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
deidentied 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 identied 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.

for confounders. When PS was combined with PTB and/or SGA, the
adjusted risk of CVD increased 45%
(95% CI, 1.24e1.71) (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.

PS and health care utilization

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, 1.25e1.54) (Table 2). The
risk was reduced to 19% after adjusting
for sociodemographic, clinical, and
behavioral factors, and infant sex (95%
CI, 1.07e1.32). Women or girls with >1
PS condition had the highest CVD risk
(HR, 1.43; 95% CI, 1.20e1.70), followed
by those with eclampsia/preeclampsia
alone (HR, 1.42; 95% CI, 1.14e1.76).
Although women or girls with gestational hypertension alone experienced
an 18% increased crude risk of CVD, the
risk was not signicant after adjustment

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

FIGURE 2

Kaplan-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.

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Original Research

TABLE 3

Frequency and length of stay during inpatient, outpatient, and emergency department encounters, based on presence/
absence of placental syndrome, adverse pregnancy outcomes, and cardiovascular diseasea

Exposure/outcome category

All nondelivery hospital

encountersb

LOS: index delivery

LOS: other encountersb

Mean  SD

6 Visits

Mean  SD

Mean  SD

21 d

6 d

Any PS
No

3.1  5.5

17.0%

2.7  1.7

1.3%

3.8  7.9

2.6%

Yes

3.8  6.6

21.2%

3.7  2.6

8.9%

4.7  10.2

3.7%

Nature/no. of PS conditions
No PS

3.1  5.5

17.0%

2.7  1.7

1.3%

3.8  7.9

2.6%

Eclampsia/preeclampsia alone

3.9  6.3

22.2%

4.0  2.9

12.7%

5.0  12.9

4.2%

Gestational hypertension alone

3.6  6.7

19.8%

3.2  1.6

3.4%

4.4  8.9

3.2%

Placental abruption/infarction alone

3.8  6.6

20.7%

3.6  4.3

7.0%

4.6  8.3

3.7%

More than one placental syndrome condition

4.1  6.6

23.4%

4.4  3.1

17.3%

5.2  10.7

4.4%

No PS, no PTB, no SGA

3.0  5.2

15.9%

2.7  1.0

0.6%

3.6  7.4

2.4%

PS alone

3.6  6.5

20.0%

3.3  1.6

4.3%

4.4  8.5

3.3%

PTB/SGA alone

3.9  6.5

22.3%

3.2  3.6

4.9%

4.8  10.2

3.9%

PS and PTB/SGA

4.2  6.8

23.8%

4.5  3.9

18.8%

5.4  13.0

4.6%

No

3.1  5.4

17.1%

2.9  1.9

2.2%

3.8  7.6

2.6%

Yes

12.0  14.9

61.7%

3.0  3.2

3.6%

17.6  30.3

23.6%

No PS or CVD

3.0  5.2

16.6%

2.7  1.7

1.3%

3.7  7.4

2.5%

PS, did not develop CVD

3.7  6.4

20.7%

3.7  2.6

8.8%

4.5  9.1

3.4%

No PS, developed CVD

11.8  15.2

61.1%

2.9  3.1

1.7%

16.9  28.5

22.8%

PS, developed CVD

12.9  13.7

65.0%

4.0  3.7

13.2%

21.4  38.3

27.5%

PS and adverse infant outcomes

CVD

PS and CVD

CVD, cardiovascular disease; LOS, length of stay; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
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.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

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.
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.

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TABLE 4

Hospital costs associated with direct medical care during inpatient and emergency department encounters, based on
presence/absence of placental syndrome, adverse pregnancy outcomes, and cardiovascular diseasea

Exposure/outcome
category

Costsa of care during index delivery

Costsa of care during nondelivery

encounters

Cost ratiob
Mean  SD $10,000 (95% CI)

Cost ratiob
Mean  SD $10,000 (95% CI)

Excess costc

Any PS
No

265,973 4.7  2.9

1.7%

1.00 (Reference)

2.7  8.7

6.1%

1.00 (Reference)

Yes

36,713 6.1  3.5

7.7%

1.29 (1.28e1.30)

3.5  11.8

8.4%

1.14 (1.12e1.16) 63,385,729

Reference

Nature/no. of PS
conditions
265,973 4.7  2.9

1.7%

1.00 (Reference)

2.7  8.7

6.1%

1.00 (Reference)

Eclampsia/
preeclampsia alone

6369 6.8  4.4

12.6%

1.45 (1.43e1.46)

4.0  16.3

9.7%

1.31 (1.26e1.36) 18,638,687

Gestational
hypertension alone

17,852 5.3  2.4

3.5%

1.14 (1.13e1.14)

3.1  8.5

7.4%

1.04 (1.02e1.07) 13,566,092

Placental abruption/
infarction alone

3037 6.0  4.8

6.6%

1.28 (1.26e1.29)

3.3  9.9

8.2%

1.14 (1.07e1.20)

More than one

placental syndrome
condition

9455 7.0  3.9

12.9%

1.48 (1.47e1.49)

3.9  13.9

9.6%

1.22 (1.18e1.26) 26,723,801

222,755 4.6  2.5

1.2%

1.00 (Reference)

2.5  8.1

5.7%

1.00 (Reference)

PS alone

25,067 5.6  2.5

4.4%

1.21 (1.20e1.21)

3.1  9.2

7.7%

1.09 (1.07e1.11) 29,851,037

PTB/SGA alone

43,218 5.1  4.6

4.2%

1.11 (1.11e1.12)

3.4  11.1

8.1%

1.16 (1.14e1.18) 39,303,314

PS and PTB/SGA

11,646 7.2  4.9

14.8%

1.55 (1.54e1.56)

4.2  16.0 10.1%

1.34 (1.31e1.38) 38,217,514

299,985 4.8  3.0

2.4%

1.00 (Reference)

2.6  8.0

1.00 (Reference)

2701 5.1  5.1

3.4%

1.06 (1.04e1.08) 17.4  45.3 34.5%

No PS or CVD

263,704 4.7  2.9

1.7%

1.00 (Reference)

2.6  7.8

5.8%

1.00 (Reference)

PS, did not

develop CVD

36,281 6.1  3.5

7.7%

1.29 (1.28e1.30)

3.2  9.2

8.1%

1.12 (1.10e1.14) 60,187,277

2269 4.8  5.2

2.3%

1.05 (1.03e1.07) 16.0  40.3 33.7%

3.71 (3.52e3.90) 16,227,502

432 6.4  4.2

9.3%

1.36 (1.31e1.42) 24.6  65.4 39.1%

5.13 (4.56e5.77)

No PS

Reference

5,101,735

PS and adverse infant

outcomes
No PS, no PTB,
no SGA

Reference

CVD
No
Yes

6.1%

Reference

3.87 (3.69e4.06) 21,217,327

PS and CVD

No PS, developed
CVD
PS, developed
CVD

Reference

5,280,306

CI, confidence interval; CVD, cardiovascular disease; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
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 leveleestimated 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.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

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 caree
related costs during follow-up, compared

484.e7 American Journal of Obstetrics & Gynecology OCTOBER 2016

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

ajog.org
savings of >$63 million in the direct costs
of inpatient and emergency care during
the average 5-year follow-up period.
Our ndings were robust to alternative eligibility criteria and model inputs.
We observed no signicant 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 Tables 1-3).
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
ndings 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 ndings of an association between maternal PS and short-term CVD
risk are similar to prior reports.4,21-24
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 identied an increased
risk of CVD among women with a PS
(HR, 2.0; 95% CI, 1.7e2.2); the risk
further increased among women with PS
with poor fetal growth (HR, 3.1; 95% CI,

OBSTETRICS
2.2e4.5)4. Our ndings indicate that
the risk may occur earlier after delivery
and during their reproductive lifespan.
Postpartum interventions aimed at
improving cardiovascular proles 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.11 In
contrast, studies of the association
between PTB and maternal PS are
limited. Lykke et al22 found a relationship between maternal PS, PTB, and
SGA offspring and mortality from cardiovascular causes over a median followup of 14.6 years. The current study noted
similar risks in a shorter follow-up
period. These ndings 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 ndings 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 denition 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.25 As out migration rates

Original Research

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 followup of 4.9 years.
Although PTB and SGA offspring
were used as an exposure, in the nal
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
ndings support prior literature noting
increases in CVD risk factors following
all causes of PTB.26 Lastly, we conducted
cost analyses from a third-party payer
perspective and represent only the direct
medical costs from specic revenuegenerating 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
identied 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 ndings 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 ndings 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 ndings suggests an increase in
CVD among women and girls in subsequent pregnancies. Further studies may
determine if early identication and
intervention will be effective in the prevention of CVD and future maternal
morbidity.
n

OCTOBER 2016 American Journal of Obstetrics & Gynecology

484.e8

Original Research

OBSTETRICS

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11. Robbins CL, Hutchings Y, Dietz PM,
Kuklina EV, Callaghan WM. History of preterm
birth and subsequent cardiovascular disease: a
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2014;210:285-97.

12. Pine M, Kowlessar NM, Salemi JL, et al.

Enhancing clinical content and race/ethnicity
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14. Salemi JL, Tanner JP, Bailey M, Mbah AK,
Salihu HM. Creation and evaluation of a multilayered maternal and child health database for
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15. Alexander GR, Himes JH, Kaufman RB,
Mor J, Kogan M. A United States national
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16. Coffey RM, Barrett ML, Steiner S. Final Report
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hcup-us.ahrq.gov. Accessed December 12,
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17. Reinhardt UE. The pricing of US hospital
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18. Salemi JL, Comins MM, Chandler K,
Mogos MF, Salihu HM. A practical approach for
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Health Policy 2013;11:343-57.
19. US Department of Labor: Bureau of Labor
Statistics. Consumer Price Index: all urban
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bls.gov/data. Accessed Dec. 18, 2014.
20. Hirotogu Akaike. Information theory and an
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21. Veerbeek JH, Hermes W, Breimer AY, et al.
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onset preeclampsia, late-onset preeclampsia,
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22. Lykke JA, Langhoff-Roos J, Lockwood CJ,
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Robson SC, Bell R. Cardiovascular disease risk
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Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007;
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and long-term maternal cardiovascular health.
Ann Epidemiol 2015;25:40-5.

Author and article information

From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine
(Drs Cain and Louis), and Birth Defects Surveillance
Program, Department of Community and Family Health,
College of Public Health (Mr Tanner and Dr Kirby), University of South Florida, Tampa, FL; and Department of
Family and Community Medicine, Baylor College of
Medicine, Houston, TX (Drs Salemi and Salihu).
Received Jan. 13, 2016; revised April 27, 2016;
accepted May 26, 2016.
Supported by grant number R01HS019997 from the
Agency for Healthcare Research and Quality, which
permitted the creation of the study database.
The authors report no conflict of interest.
The primary analyses used in this article were presented at the 35th annual meeting of the Society for
Maternal-Fetal Medicine, San Diego, CA, Feb. 2-7, 2014.
Corresponding author: Mary Ashley Cain, MD.
mcain@health.usf.edu

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OBSTETRICS

Original Research

SUPPLEMENTAL TABLE 1

Comparison of hazard ratios and 95% confidence intervals representing association between placental syndromes
during current pregnancy and subsequent cardiovascular disease,a between women with and without
subsequent live birth during follow-up
Adjusted model 3b HR (95% CI)

Unadjusted model HR (95% CI)

Entire study
population,
n 302,686

Excluding women with

subsequent live births,
n 189,342

Entire study
population,
n 302,686

Excluding women with

subsequent live births,
n 189,342

No

1.00 (Reference)

1.00 (Reference)

1.00 (Reference)

1.00 (Reference)

Yes

1.39 (1.25e1.54)c

1.40 (1.22e1.61)c

1.19 (1.07e1.32)c

1.18 (1.03e1.37)c

1.00 (Reference)

1.00 (Reference)

1.00 (Reference)

1.00 (Reference)

Exposure category
Any PS

Nature/no. of PS conditions
No PS

1.42 (1.14e1.76)

Eclampsia/preeclampsia alone

1.60 (1.29e1.98)

Gestational hypertension alone

1.18 (1.01e1.37)c

1.24 (1.01e1.53)c

0.99 (0.85e1.16)

Placental abruption/infarction alone

1.22 (0.86e1.73)

1.32 (0.84e2.08)

1.09 (0.76e1.57)

More than one placental syndrome condition

1.69 (1.42e2.01)

1.45 (1.07e1.97)

1.66 (1.31e2.10)

1.43 (1.20e1.70)

1.29 (0.95e1.75)
1.04 (0.84e1.28)
1.18 (0.74e1.88)

1.38 (1.09e1.76)c

PS and adverse infant outcomes

No PS, no PTB, no SGA
PS alone
PTB/SGA alone
PS and PTB/SGA

1.00 (Reference)

1.00 (Reference)

1.29 (1.14e1.47)

1.16 (1.04e1.29)

1.70 (1.45e2.00)

1.00 (Reference)

1.00 (Reference)

1.29 (1.09e1.54)

1.08 (0.95e1.23)

1.07 (0.90e1.29)

1.20 (1.04e1.39)

1.07 (0.96e1.20)

1.76 (1.42e2.17)

1.45 (1.24e1.71)

1.14 (0.99e1.32)
c

1.51 (1.21e1.87)c

CI, confidence interval; HR, hazard ratio; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
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.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

OCTOBER 2016 American Journal of Obstetrics & Gynecology

484.e10

Original Research

ajog.org

OBSTETRICS

SUPPLEMENTAL TABLE 2

Frequency and length of stay during inpatient, outpatient, and emergency department encounters, based on
presence/absence of placental syndrome, adverse pregnancy outcomes, and cardiovascular disease,a restricted
to women without subsequent live birth during follow-up (n [ 189,342)

Exposure/outcome category

All nondelivery hospital

encountersb

LOS: index delivery

LOS: other encountersb

Mean  SD

6 Visits

Mean  SD

Mean  SD

6 d

21 d

Any PS
No

2.5  4.7

13.0%

2.8  1.9

1.3%

3.1  7.6

1.8%

Yes

3.0  5.2

16.2%

3.7  2.7

9.4%

3.9  9.0

2.5%

2.5  4.7

13.0%

2.8  1.9

1.3%

3.1  7.6

1.8%

Nature/no. of PS conditions
No PS
Eclampsia/preeclampsia alone

3.0  5.1

16.8%

4.1  2.8

13.1%

4.1  9.9

3.1%

Gestational hypertension alone

2.8  4.9

15.0%

3.2  1.6

3.7%

3.6  8.2

2.2%

Placental abruption/infarction alone

3.0  5.7

15.7%

3.8  4.8

7.6%

3.7  7.0

2.4%

More than one placental syndrome condition

3.2  5.6

18.1%

4.4  3.1

17.9%

4.2  10.3

2.8%

No PS, no PTB, no SGA

2.4  4.4

12.3%

2.7  1.0

0.6%

3.0  7.0

1.6%

PS alone

2.8  4.8

15.5%

3.3  1.6

4.5%

3.6  7.4

2.1%

PTB/SGA alone

3.0  5.8

16.5%

3.2  4.0

5.2%

3.8  10.1

2.7%

PS and PTB/SGA

3.3  5.8

17.7%

4.6  4.0

19.8%

4.5  11.7

3.3%

No

2.5  4.5

13.1%

2.9  2.0

2.3%

3.1  7.1

1.7%

Yes

10.8  14.8

56.6%

3.1  3.9

3.4%

17.7  24.6

21.5%

No PS or CVD

2.4  4.5

12.7%

2.8  1.8

1.3%

3.0  7.0

1.7%

PS, did not develop CVD

2.9  5.0

15.8%

3.7  2.7

9.4%

3.7  7.9

2.3%

No PS, developed CVD

10.8  15.2

56.6%

3.0  4.1

1.6%

17.1  33.4

20.9%

PS, developed CVD

10.8  12.5

56.4%

3.9  2.7

12.8%

20.9  40.1

24.8%

PS and adverse infant outcomes

CVD

PS and CVD

CVD, cardiovascular disease; LOS, length of stay; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
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.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

484.e11 American Journal of Obstetrics & Gynecology OCTOBER 2016

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OBSTETRICS

Original Research

SUPPLEMENTAL TABLE 3

Comparison 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,a between women with and without subsequent live birth during follow-up

Exposure/outcome category

Costs accrued during index delivery

Cost ratio (95% CI)b

Costs accrued during nondelivery encounters

Cost ratio (95% CI)b

Entire study
population,
n 302,686

Excluding women with

subsequent live births,
n 189,342

Entire study
population,
n 302,686

1.00 (Reference)

1.00 (Reference)

Excluding women with

subsequent live births,
n 189,342

Any PS
No
Yes

1.00 (Reference)
1.29 (1.28e1.30)

1.30 (1.29e1.31)

1.00 (Reference)
c

1.13 (1.10e1.15)c

1.31 (1.26e1.36)c

1.32 (1.26e1.39)c

1.14 (1.12e1.16)

Nature/no. of PS conditions
No PS

1.00 (Reference)

1.00 (Reference)
c

1.00 (Reference)

Eclampsia/preeclampsia alone

1.45 (1.43e1.46)

Gestational hypertension alone

1.14 (1.13e1.14)c

1.14 (1.13e1.15)c

1.04 (1.02e1.07)c

1.04 (1.01e1.08)c

Placental abruption/infarction alone

1.28 (1.26e1.29)c

1.30 (1.27e1.32)c

1.14 (1.07e1.20)c

1.01 (0.94e1.09)

1.22 (1.18e1.26)c

1.17 (1.13e1.22)c

1.00 (Reference)

1.00 (Reference)

More than one placental syndrome

condition

1.48 (1.47e1.49)

1.45 (1.43e1.47)

1.49 (1.47e1.50)

PS and adverse infant outcomes

No PS, no PTB, no SGA

1.00 (Reference)

1.00 (Reference)
c

1.05 (1.02e1.08)c

PS alone

1.21 (1.20e1.21)

PTB/SGA alone

1.11 (1.11e1.12)c

1.12 (1.12e1.13)c

1.16 (1.14e1.18)c

1.15 (1.13e1.18)c

PS and PTB/SGA

1.55 (1.54e1.56)c

1.57 (1.55e1.58)c

1.34 (1.31e1.38)c

1.36 (1.31e1.42)c

1.00 (Reference)

1.00 (Reference)

1.00 (Reference)

1.00 (Reference)

1.21 (1.20e1.22)

1.09 (1.07e1.11)

CVD
No
Yes

1.06 (1.04e1.08)

1.08 (1.06e1.10)

3.87 (3.69e4.06)

4.57 (4.28e4.88)c

PS and CVD
No PS or CVD

1.00 (Reference)

1.00 (Reference)
c

1.00 (Reference)
c

1.00 (Reference)
c

1.11 (1.08e1.13)c

PS, did not develop CVD

1.29 (1.28e1.30)

No PS, developed CVD

1.05 (1.03e1.07)c

1.09 (1.06e1.11)c

3.71 (3.52e3.90)c

4.42 (4.12e4.76)c

PS, developed CVD

1.36 (1.31e1.42)c

1.31 (1.24e1.38)c

5.13 (4.56e5.77)c

5.75 (4.89e6.77)c

1.30 (1.29e1.31)

1.12 (1.10e1.14)

CI, confidence interval; CVD, cardiovascular disease; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
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.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

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OBSTETRICS

SUPPLEMENTAL TABLE 4

Comparison of charges (for inpatient, outpatient, and emergency department) vs costs (for inpatient
and emergency department only)
Index delivery
Cost ratio (95% CI)b
Exposure/outcome category

Charges

Nondelivery encounters
Cost ratio (95% CI)b
Costs

Charges

Costs

Any PS
No
Yes

1.00 (Reference)
1.40 (1.39e1.40)

1.00 (Reference)
c

1.29 (1.28e1.30)

1.00 (Reference)
c

1.12 (1.10e1.14)

1.00 (Reference)
c

1.14 (1.12e1.16)c

Nature/no. of PS conditions
No PS

1.00 (Reference)

1.00 (Reference)

1.00 (Reference)

1.00 (Reference)

Eclampsia/preeclampsia alone

1.60 (1.59e1.62)c

1.45 (1.43e1.46)c

1.22 (1.18e1.27)c

1.31 (1.26e1.36)c

Gestational hypertension alone

1.19 (1.19e1.20)c

1.14 (1.13e1.14)c

1.05 (1.03e1.07)c

1.04 (1.02e1.07)c

Placental abruption/infarction alone

1.35 (1.33e1.37)c

1.28 (1.26e1.29)c

1.14 (1.08e1.20)c

1.14 (1.07e1.20)c

More than one placental syndrome condition

1.65 (1.63e1.67)c

1.48 (1.47e1.49)c

1.18 (1.15e1.21)c

1.22 (1.18e1.26)c

1.00 (Reference)

1.00 (Reference)

1.00 (Reference)

1.00 (Reference)

PS and adverse infant outcomes

No PS, no PTB, no SGA

1.09 (1.07e1.11)c

PS alone

1.29 (1.28e1.30)

PTB/SGA alone

1.11 (1.11e1.12)c

1.11 (1.11e1.12)c

1.14 (1.12e1.15)c

1.16 (1.14e1.18)c

1.34 (1.31e1.38)c

PS and PTB/SGA

1.70 (1.69e1.72)

1.21 (1.20e1.21)
1.55 (1.54e1.56)

1.09 (1.07e1.11)
1.27 (1.24e1.30)

CVDa
No
Yes

1.00 (Reference)
1.06 (1.04e1.08)

1.00 (Reference)
c

1.06 (1.04e1.08)

1.00 (Reference)
c

3.46 (3.31e3.62)

1.00 (Reference)
c

3.87 (3.69e4.06)c

PS and CVD
No PS or CVD

1.00 (Reference)

1.00 (Reference)
c

1.00 (Reference)
c

1.00 (Reference)
c

1.12 (1.10e1.14)c

PS, did not develop CVD

1.40 (1.39e1.40)

No PS, developed CVD

1.05 (1.03e1.07)c

1.05 (1.03e1.07)c

3.40 (3.24e3.56)c

3.71 (3.52e3.90)c

5.13 (4.56e5.77)c

PS, developed CVD

1.46 (1.40e1.53)

1.29 (1.28e1.30)
1.36 (1.31e1.42)

1.11 (1.09e1.13)
4.13 (3.69e4.61)

CI, confidence interval; CVD, cardiovascular disease; PS, placental syndrome; PTB, preterm birth; SGA, small for gestational age.
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.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.

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Original Research

APPENDIX

Diagnosis and procedure codes used to identify selected clinical and behavioral conditions
ICD-9-CM codea

Birth certificate indicatorb

Preeclampsia

642.4x, 642.5x

No

Eclampsia

642.6x

Yes

Gestational hypertension

642.3x

Yes

Placental infarction

656.7x

No

641.2x

No

Coronary heart disease

410e414x, 429.2, V45.81, V45.82

No

Cerebrovascular disease

430e438x

No

Peripheral artery disease

440.2x, 440.3x, 440.8, 440.9, 443.9

No

Congestive heart failure

398.91, 402.01, 402.11, 402.91, 404.01, 404.03,

404.11, 404.13, 404.91, 404.93, 428x

No

Cardiac or peripheral artery revascularization

procedure

36.0x, 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, 39.74

No

Chronic hypertension

401e405x, 642.0x, 642.1x, 642.2x, 642.7x

Yes

Prepregnancy diabetes

249x, 250x, 648.0x

Yes

Renal disease

580e589x, 646.2x

No

Hyperlipidemia

272.0, 272.1, 272.2, 272.3, 272.4

No

Migraine

346x

No

710.0

No

Condition
Placental syndromes

Placental abruption
Cardiovascular outcomes

Clinical comorbiditiese

Systemic lupus erythematosus

Behavioral factors

Tobacco use

305.1, 649.0x, 989.84

Yes

Alcohol use

291x, 303x, 305.0x, 425.5, 760.71, V11.3

Yes

Drug use

292.0x, 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, E850.1

No

ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.

Presence of 1 of listed codes serves as positive indication of conditionex indicates that all subcodes with listed code prefix are part of the conditions definition; b Reflects use of variable on birth
certificate to supplement identification through ICD-9-CM codeseif used, positive indication on birth certificate serves as positive indication of condition regardless of presence of 1 of listed ICD-9CM 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.
Cain et al. Placental syndromes and cardiovascular disease. Am J Obstet Gynecol 2016.
a

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