OBSTETRICS

Incidence of preeclampsia: risk factors and outcomes

associated with early- versus late-onset disease
Sarka Lisonkova, MD, PhD; K. S. Joseph, MD, PhD
OBJECTIVE: The population-based incidence of early-onset (<34
weeks) and late-onset preeclampsia (34 weeks) has not been
adequately studied. We examined the gestational ageespecic inci-
dence of preeclampsia onset and identied the associated risk factors
and birth outcomes.
STUDY DESIGN: All singleton deliveries in Washington State, 2003-
2008 (n 456,668), were included, and preeclampsia onset was
determined from hospital records linked to birth certicates. Cox and
logistic regression models were used to obtain adjusted hazard ratios
and odds ratios (AORs) for risk factors and birth outcomes,
respectively.
RESULTS: The overall preeclampsia rate was 3.1% and the incidence
increased sharply with gestation; early- and late-onset preeclampsia
rates were 0.38% and 2.72%, respectively. Among women with early-
onset preeclampsia, 12% delivered at a gestation of 34 weeks or
longer. Risk/protective factors common to both diseases included
older maternal age, Hispanic and Native-American race, smoking,
unmarried status, and male fetus. African-American race, chronic
hypertension, and congenital anomalies were more strongly associ-
ated with early-onset preeclampsia, whereas younger maternal age,
nulliparity, and diabetes mellitus were more strongly associated with
late-onset disease. Early- but not late-onset preeclampsia conferred a
high risk of fetal death (AOR, 5.8; 95% condence interval [CI],
4.0e8.3 vs AOR, 1.3; 95% CI, 0.8e2.0, respectively). The AOR for
perinatal death/severe neonatal morbidity was 16.4 (95% CI,
14.5e18.6) in early-onset and 2.0 (95% CI, 1.8e2.3) in late-onset
preeclampsia.
CONCLUSION: Early- and late-onset preeclampsia shares some
etiological features, differ with regard to several risk factors, and
lead to different outcomes. The 2 preeclampsia types should be
treated as distinct entities from an etiological and prognostic
standpoint.
Key words: birth outcomes, early onset, eclampsia, fetuses at risk,
late onset, preeclampsia
Cite this article as: Lisonkova S, Joseph KS. Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease. AmJ Obstet Gynecol
2013;209:544.e1-12.
P
reeclampsia is characterized by
elevated blood pressure and pro-
teinuria or involvement of other organs
in an exaggerated systemic inama-
tion.
1-3
In industrialized countries, pre-
eclampsia complicates approximately
3-5% of pregnancies and represents one
of the most common causes of maternal
mortality and severe maternal morbidity
including eclampsia, placental abrup-
tion, pulmonary edema, and acute renal
failure.
4-10
Infants of mothers with pre-
eclampsia are at approximately 2-fold
higher risk of neonatal death
11
and at
increased risk of neonatal morbidity
including low Apgar scores, seizures,
neonatal encephalopathy, and neonatal
intensive care admission.
11-14
However,
some previous studies have shown that
infants born at very preterm gestation
because of preeclampsia have a reduced
risk of retinopathy of prematurity,
cerebral palsy, and neonatal mortality
compared with infants born very pre-
term for other reasons.
2,15-17
Preeclampsia is a heterogeneous dis-
order with 2 distinct subtypes that have
been described based on the timing of
disease onset: early-onset preeclampsia
occurring before or at 33 weeks gesta-
tion and late-onset preeclampsia that
occurs at 34 weeks gestation or later.
18-20
Early-onset disease, in particular, confers
a high risk of life-threatening maternal
complications and fetal demise, and
early delivery is the only treatment.
20-22
Although previous publications
22-25
have described early-onset preeclamp-
sia and associated neonatal outcomes,
most reports have been based on small,
hospital-based studies and clinical
trials focusing on obstetric manage-
ment.
22,23,25
The gestational age-specic
incidence of preeclampsia, based on the
onset of symptoms and not gestational
age at delivery, has not been documented
to date at the population level. We
Fromthe Department of Obstetrics and Gynecology (both authors) and the School of Population and
Public Health (Dr Joseph), University of British Columbia, and the Childrens and Womens Hospital
and Health Centre of British Columbia (both authors), Vancouver, BC, Canada.
Received May 1, 2013; revised July 23, 2013; accepted Aug. 16, 2013.
S.L. is supported by a grant on severe maternal morbidity (MAH-114445) from the Canadian
Institutes of Health Research. K.S.J. is supported by a chair in maternal, fetal, and infant health
services research from the Canadian Institutes of Health Research (grant APR-126338).
The authors report no conict of interest.
Presented at the 26th annual meeting of the Society for Pediatric and Perinatal Epidemiologic
Research, Boston, MA, June 17-18, 2013.
Reprints not available from the authors.
0002-9378/$36.00 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.08.019
544.e1 American Journal of Obstetrics & Gynecology DECEMBER 2013
Research www.AJOG.org
therefore carried out a population-based
study to describe the gestational age-
specic incidence of preeclampsia onset
among women with singleton pregnan-
cies and to examine risk factors and birth
outcomes associated with early-onset
and late-onset disease.
MATERIALS AND METHODS
We included all singleton deliveries in
Washington State during the period from
2003 to 2008, utilizing information from
2 large population databases: (1) the
Comprehensive Discharge Abstract Da-
tabase (CHARS) which included all
hospitalizations in Washington State, and
(2) the Birth Events Record Database
(BERD), which included birth records of
all live born infants and fetal deaths.
Women with a diagnosis of preeclampsia
or eclampsia (henceforth referred to as
preeclampsia), including preeclampsia
superimposed on chronic hypertension
were identied from the CHARS data-
base (International Classication of Dis-
eases, ninth revision [ICD-9] diagnostic
codes 642.4, 642.5, 642.6, and 642.7).
Hospitalization records with a diag-
nosis of preeclampsia were linked to birth
records to obtain information about
gestational age at delivery, maternal
characteristics, clinical risk factors, and
birth outcomes. The number of weeks
between the hospitalization when the
preeclampsia diagnosis was made and
birth hospitalizationwas calculated based
on the CHARS and BERDrecord linkage.
Preeclampsia occurring at less than
34 weeks of gestation was identied as
early-onset disease, whereas preeclamp-
sia that occurred at 34 weeks or later was
labeled late-onset disease, irrespective of
the gestational week at delivery. Infant
birth records were also linked to CHARS
(infant) hospitalization records to iden-
tify cases of severe neonatal morbidity
(see the following text).
There were 484,111 women who were
residents of Washington State and who
delivered a singleton stillbirth or live
birth in a Washington State hospital be-
tween 2003 and 2008. Women with a
missing estimate of gestation or gesta-
tional age at delivery less than 20 weeks
and women without a linkage between
the birth/fetal death certicate (BERD
database) and maternal hospitalization
data (CHARS database) were excluded
(5.7%, n 27,443).
Maternal characteristics and clinical
risk factors examined for potential as-
sociation with preeclampsia included
maternal age (younger than 20 and
35 years old or older vs 20-34 years);
parity (number of previous live births,
none vs 1 or more); marital status (single/
widowed/separated vs married/common
law); education (less than high school
vs high school education or greater);
race (non-Hispanic white vs Hispanic,
African-American, Native-American, and
other); smoking during pregnancy (yes/
no); infertility treatment (yes/no); dia-
betes mellitus (yes/no); chronic hyper-
tension prior to pregnancy (yes/no);
infants sex (male/female); and congenital
anomalies (yes/no).
Fetal death was dened as in utero or
intrapartum death of a fetus delivered at
20 weeks gestation or later, neonatal
death was dened as a death of an infant
within 28 days after birth, and perinatal
death included fetal or neonatal death.
Using birth hospitalization data for in-
fants (obtained from the linked infants
birth and hospitalization records), the
following adverse birth outcomes were
identied based on ICD-9 codes: bron-
chopulmonary dysplasia (BPD; code
770.7), intraventricular hemorrhage
(IVH) grade III and IV (codes 772.13
and 772.14), periventricular leukomala-
cia (PVL; code 779.7), retinopathy of
prematurity (ROP; code 362.2), necro-
tizing enterocolitis (NEC; code 777.5),
and neonatal sepsis (code 771.81). Other
neonatal outcomes were identied from
birth records, namely, neonatal seizures,
Apgar score at 5 minutes, and neonatal
intensive care unit (NICU) admission.
Severe neonatal morbidity included
any of the following: a 5-minute Apgar
score of 3 or less, neonatal seizures, BPD,
IVHgrade III or IV, PVL, ROP, NEC, and
neonatal sepsis. The composite out-
come of neonatal mortality/morbidity
included both neonatal death and severe
neonatal morbidity, whereas perinatal
mortality/morbidity included perinatal
death and severe neonatal morbidity.
Small-for-gestational-age (SGA) infants
were dened as those weighing less than
the 10th percentile of the sex- and gesta-
tional ageespecic birthweight reference
for the United States,
26
whereas large-for-
gestational age infants were those weigh-
ing over the 90th percentile. We used the
clinical estimate of gestation provided in
the data source because this is more ac-
curate than gestational age estimated by
the last menstrual period.
27,28
Gestational ageespecic rates of pre-
eclampsia were calculated using ongoing
pregnancies as the denominator. c
2
tests
were used to assess the differences be-
tween rates of early-onset and late-onset
preeclampsia across maternal and clin-
ical characteristics. The Cox regression
model, with preeclampsia onset as the
outcome and gestational age as the time
axis, was used to estimate adjusted hazard
ratios (AHRs) and 95% condence in-
tervals (CIs). This enabled us to create the
appropriate risk sets, with censoring of
subjects who developed preeclampsia or
who delivered at any particular gestation.
When the proportional hazards as-
sumption was not satised, we examined
the interaction term between the risk
factor and gestational age at diagnosis
categorized as less than 34 weeks and 34
weeks or longer and obtained AHRs for
both early-onset and late-onset pre-
eclampsia separately. The Wald statistic
was used to assess statistical signicance
of the interaction terms. Shoenfeld re-
siduals were used to evaluate the pro-
portional hazards assumption of the
nal model.
29
Birth outcomes including fetal death,
perinatal death, and severe neonatal
morbidity were analyzed using the
fetuses-at-risk approach. Under this
formulation, all fetuses at a specic
gestation were considered at risk for
adverse outcomes at that gestation.
Thus, for example, all fetuses at 28 weeks
with early-onset preeclampsia were
considered to be at risk of live birth,
stillbirth, neonatal death, or severe
neonatal morbidity at 28 weeks, irre-
spective of whether they actually deliv-
ered at 28 weeks or at a subsequent
gestational week.
30,31
Two fetuses-at-
riskebased logistic regression models
were used to estimate causal associations
between early-onset and late-onset pre-
eclampsia and birth outcomes.
www.AJOG.org Obstetrics Research
DECEMBER 2013 American Journal of Obstetrics & Gynecology 544.e2
TABLE 1
Maternal characteristics and clinical factors associated with early- and late-onset preeclampsia, singleton
deliveries, Washington State, 2003-2008
Maternal
characteristics/clinical
factors
Ongoing
pregnancies
at 20 weeks Early-onset preeclampsia
Ongoing
pregnancies
at 34 weeks
a
Late-onset preeclampsia
(n [456,668) (n [1752) Rate per 1000 (n [447,822) (n [12,449) Rate per 1000
Age, y
<20 39,584 160 4.0 38,561 1627 42.2
20-34 347,105 1256 3.6 340,850 9001 26.4
35 69,979 336 4.8 68,411 1821 26.6
Race
Non-Hispanic white 323,552 1154 3.6 317,775 8914 28.1
African-American 20,045 158 7.9 19,356 690 35.6
Hispanic 56,615 210 3.7 55,533 1555 28.0
Native-American 10,625 47 4.4 10,313 372 36.1
Other 44,032 164 3.7 43,192 851 19.7
Education
Less than high school 89,238 324 3.6 87,255 2465 28.3
High school or more 359,160 1357 3.8 352,795 9752 27.6
Smoking during pregnancy
Yes 46,936 162 3.5 45,737 1131 24.7
No 403,471 1527 3.8 396,224 11,185 28.2
Marital status
Unmarried 149,369 657 4.4 145,677 4740 32.5
Married 305,666 1076 3.5 300,669 7654 25.5
Number of prior live births
0 186,980 964 5.2 182,906 8131 44.5
1 258,135 673 2.6 254,003 4043 15.9
Diabetes mellitus
Yes 25,815 207 8.0 25,110 1353 53.9
No 430,853 1545 3.6 422,712 11,096 26.2
Chronic hypertension
Yes 5560 237 42.6 5163 699 135.4
No 451,108 1515 3.4 442,659 11,750 26.5
Infertility treatment
Yes 3455 26 7.5 3339 133 39.8
No 453,213 1726 3.8 444,483 12,316 27.7
Infant sex
Male 234,224 914 3.9 229,314 6647 29.0
Female 222,441 838 3.8 218,508 5802 26.6
Lisonkova. Early- vs late-onset preeclampsia. Am J Obstet Gynecol 2013. (continued)
Research Obstetrics www.AJOG.org
544.e3 American Journal of Obstetrics & Gynecology DECEMBER 2013
These models were constructed using
ongoing pregnancies (ie, fetuses at risk)
as the denominator
32,33
; all ongoing
pregnancies at 20 weeks gestation were
included in models examining birth
outcomes following early-onset pre-
eclampsia, whereas all ongoing preg-
nancies at 34
0
weeks gestation (among
women without early-onset preeclamp-
sia) were included in the denominator
for birth outcomes following late-onset
preeclampsia.
In addition, we compared neonatal
outcomes between infants born to
mothers with and without early-onset or
late-onset preeclampsia, adjusting for
gestational age at delivery (traditional
analysis). This analysis used live births
at a particular gestational age as the
denominator and provided a predictive
(noncausal) model comparing the odds
of adverse neonatal outcomes among
mothers with and without preeclampsia,
conditional on delivery of a live-born
infant at a specic gestational age.
32,33
We further compared birth outcomes
between mothers with early-onset pre-
eclampsia who delivered at 34 weeks or
longer, and mothers with late-onset
preeclampsia (who, by denition, all
delivered at 34 weeks).
We performed sensitivity analyses
examining the effect of obesity onthe risk
of early-onset and late-onset pre-
eclampsia and its association with birth
outcomes. Obesity was dened as a body
mass index (BMI) greater than 30 kg/m
2
.
Missing values for BMI (27.7%, 14.6%,
and 13.9% in the early-onset, late-onset,
and no preeclampsia groups, respec-
tively) were imputed using multiple
imputation procedures (proc MI, SAS
software, version 9.2; SAS Institute Inc,
Cary, NC). In addition, we adjusted for
time period (year of delivery) to address
the potential effects of changes in ob-
stetric and neonatal practices.
All analyses were performed on pub-
licly accessible de-identied data. An
exemption from ethics approval was
granted by the Department of Social and
Health Services, State of Washington.
Analyses were carried out using SAS
software, version 9.2 (SAS Institute Inc.,
Cary, NC). A 2-tailed P < .05 was
considered signicant.
RESULTS
The study included 456,668 women who
delivered a singleton live birth or still-
birth between 2003 and 2008. The rate of
preeclampsia was 3.11 per 100 singleton
deliveries (14,201 of 456,668), and the
rate of eclampsia was 4.12 per 10,000
singleton deliveries (188 of 456,668).
The frequency of early-onset pre-
eclampsia was 0.38 per 100 deliveries,
and the frequency of late-onset pre-
eclampsia was 2.72 per 100 deliveries
(Table 1). The gestational ageespecic
incidence of preeclampsia increased with
pregnancy duration, from 0.01 per 1000
ongoing pregnancies at 20 weeks gesta-
tion to 9.62 per 1000 ongoing pregnan-
cies at 40 weeks gestation (Figure).
Women who were at the extremes of
maternal age (younger than 20 or 35 years
TABLE 1
Maternal characteristics and clinical factors associated with early- and late-onset preeclampsia, singleton
deliveries, Washington State, 2003-2008 (continued)
Maternal
characteristics/clinical
factors
Ongoing
pregnancies
at 20 weeks Early-onset preeclampsia
Ongoing
pregnancies
at 34 weeks
a
Late-onset preeclampsia
(n [456,668) (n [1752) Rate per 1000 (n [447,822) (n [12,449) Rate per 1000
Congenital anomalies
Yes 2249 23 10.2 1949 66 33.9
No 454,419 1729 3.8 445,873 12,383 27.8
The number of pregnancies does not add up to the total in some categories because of missing values (missing values exceeding 3% were 4.1% for education, 3.6% for smoking, and 6.6% for
number of prior live births in the early-onset preeclampsia group).
a
Ongoing pregnancies without early-onset preeclampsia.
Lisonkova. Early- vs late-onset preeclampsia. Am J Obstet Gynecol 2013.
FIGURE
Gestational ageespecic incidence of preeclampsia, singleton
deliveries, Washington State, 2003-2008
Lisonkova. Early- vs late-onset preeclampsia. Am J Obstet Gynecol 2013.
www.AJOG.org Obstetrics Research
DECEMBER 2013 American Journal of Obstetrics & Gynecology 544.e4
old or older), African-American, un-
married, and nulliparous had higher rates
of early-onset preeclampsia (Table 1).
Similarly, women who had diabetes
mellitus or chronic hypertension, used
infertility treatment to conceive, and had
an infant with a congenital anomaly also
had higher rates of early-onset pre-
eclampsia. Women who were very young
(younger than 20 years of age), unmar-
ried, nulliparous, had diabetes mellitus
or chronic hypertension, used infertility
treatment to conceive, and were pregnant
with a male fetus also had higher rates of
late-onset preeclampsia. On the other
hand women who smoked or belonged
to the other race category (ie, other
than non-Hispanic white, Hispanic,
African-American and Native-American;
Table 2) had lower rates of late-onset
disease.
Several risk factors were associated with
preeclampsia, without a signicant dif-
ference in adjusted hazard ratios for early-
and late-onset disease (Table 2). These
included smoking during pregnancy
(AHR, 0.87; 95% CI, 0.82e0.93 for both
early- and late-onset disease), unmarried
status (AHR, 1.14; 95% CI, 1.10e1.19),
older maternal age (AHR, 1.15; 95% CI,
1.10e1.21), and infants sex (AHR for
male sex, 1.10; 95% CI, 1.06e1.14).
In contrast, several risk factors dif-
fered signicantly in their association
with early- vs late-onset preeclampsia.
African-American race, chronic hyper-
tension, and congenital anomalies were
more strongly associated withearly-onset
disease, whereas young maternal age
(younger than 20 vs 20-35 years), other
race (not including African-American,
Hispanic or Native-American vs non-
Hispanic white), nulliparity, and dia-
betes mellitus were more strongly
associated with late-onset disease. Other
race had a protective effect on late-onset
disease compared with non-Hispanic
white race (AHR, 0.68; 95% CI,
0.63e0.73).
Women with chronic hypertension
had the highest risk for preeclampsia,
TABLE 2
Crude and adjusted hazard ratios for early- and late-onset preeclampsia, singleton deliveries, Washington State,
2003-2008
Demographic/clinical factors
Preeclampsia, unadjusted analysis Preeclampsia, adjusted analysis
Early onset Late onset Early onset Late onset
HR 95% CI HR 95% CI AHR 95% CI AHR 95% CI
Age, y
<20
a
1.12 0.95e1.32 1.56 1.48e1.65 0.84 0.70e1.00 1.07 1.01e1.14
20-34 Ref Ref Ref Ref
35
a
1.33 1.18e1.50 1.04 0.99e1.10 1.15 1.10e1.21 1.15 1.10e1.21
Race
Non-Hispanic white Ref Ref Ref Ref
African-American
a
2.21 1.88e2.61 1.26 1.16e1.36 1.75 1.45e2.12 1.20 1.11e1.31
Hispanic 1.01 0.96e1.06 1.01 0.96e1.06 1.07 1.01e1.13 1.07 1.01e1.13
Native-American 1.27 1.54e1.59 1.27 1.54e1.59 1.36 1.22e1.51 1.36 1.22e1.51
Other
a
1.03 0.88e1.22 0.73 0.68e0.79 0.98 0.82e1.16 0.68 0.63e0.73
Maternal education less
than high school
0.98 0.94e1.03 0.98 0.94e1.03 0.98 0.93e1.03 0.98 0.93e1.03
Smoking during pregnancy 0.91 0.86e0.96 0.91 0.86e0.96 0.87 0.82e0.93 0.87 0.82e0.93
Unmarried 1.27 1.23e1.32 1.27 1.23e1.32 1.14 1.10e1.19 1.14 1.10e1.19
No prior live births
a
1.98 1.80e2.19 2.59 2.49e2.69 2.13 1.92e2.37 2.67 2.57e2.78
Diabetes mellitus
a
2.45 2.32e2.58 2.45 2.32e2.58 1.87 1.60e2.18 2.46 2.32e2.61
Chronic hypertension
a
13.06 11.39e14.97 6.72 6.22e7.25 11.72 10.11e13.59 5.83 5.39e6.32
Infertility treatment 1.60 1.37e1.87 1.60 1.37e1.87 1.17 0.99e1.37 1.17 0.99e1.37
Infant sex (male) 1.10 1.07e1.14 1.10 1.07e1.14 1.10 1.06e1.14 1.10 1.06e1.14
Congenital anomalies
a
2.91 1.93e4.39 1.50 1.18e1.92 2.59 1.66e4.02 1.49 1.16e1.91
AHR, adjusted hazard ratio; CI, condence interval; HR, hazard ratio; Ref, referent.
a
The hazard ratios differed signicantly between early- and late-onset preeclampsia. The Wald statistic was used to assess statistical signicance of the interaction term between the risk factor and
the gestational age at preeclampsia onset.
Lisonkova. Early- vs late-onset preeclampsia. Am J Obstet Gynecol 2013.
Research Obstetrics www.AJOG.org
544.e5 American Journal of Obstetrics & Gynecology DECEMBER 2013
with more than a 10-fold higher rate
of early-onset disease (AHR, 11.7; 95%
CI, 10.1e13.6) and an approximately
5-fold higher rate of late-onset disease
(AHR, 5.8; 95% CI, 5.4e6.3) as
compared with women without chronic
hypertension.
The rates of all adverse birth
outcomes, except for large for gesta-
tional age (LGA), were signicantly
higher among women with early-onset
preeclampsia compared with women
without early-onset disease (Table 3).
Among women with early-onset pre-
eclampsia, approximately 12%, deliv-
ered at 34 weeks gestation or later, and
almost one half of births (49.5%) were
very low birthweight (<1500 g). With
the exception of neonatal death rates, the
rates of all adverse birth outcomes were
signicantly higher among mothers
with late-onset preeclampsia compar-
ed with those without preeclampsia
(Table 3).
The rate of adverse birth outcomes
remained severalfold higher among
mothers with early-onset preeclampsia
as compared with mothers without early-
onset disease after adjustment for risk
factors (Table 4). For example, the rate of
fetal death was approximately 6 times
higher (AOR, 5.8; 95% CI, 4.0e8.3), and
the rate of perinatal death or serious
neonatal morbidity was 16 times higher
(AOR, 16.4; 95% CI, 14.5e18.6) among
women with early-onset disease.
TABLE 3
Birth outcomes associated with early- and late-onset preeclampsia, singleton deliveries, Washington State,
2003-2008
Birth outcomes
Early-onset
preeclampsia
No early-onset
preeclampsia
Late-onset
preeclampsia
No late-onset
preeclampsia
n
Rate per
1000 FAR n
Rate per
1000 FAR n
Rate per
1000 FAR n
Rate per
1000 FAR
Ongoing pregnancies 1752 454,916 12,449 435,373
Gestational age at delivery, wks
20-33 1539 878.4 7094 15.6 n/a n/a
34-36 128 73.1 26,062 57.3 2911 233.8 23,151 53.2
37-43 85 48.5 421,760 927.1 9538 766.2 412,222 946.8
Birthweight, g
<1500 867 494.9 3208 7.1 42 3.4 149 0.3
1500-2499 641 365.9 18,020 39.6 2020 162.3 12,972 29.8
2500-4499 183 104.5 424,395 932.9 10,162 816.3 413,747 950.3
4500 0 0.0 7733 17.0 166 13.3 7567 17.4
SGA (<10th percentile) 563 321.3 29,439 64.7 2007 161.2 26,800 61.6
LGA (>90th percentile) 23 13.1 52,702 115.8 1171 94.1 51,372 118.0
Apgar score at 5 min 3 78 44.5 2064 4.5 99 8.0 1328 3.1
Neonatal seizures 5 2.9 186 0.4 10 0.8 159 0.4
Neonatal sepsis 200 114.2 3468 7.6 170 13.7 2409 5.5
NICU admission 1202 686.1 22,434 49.3 1658 133.2 16,843 38.7
Fetal death 58 33.1 1648 3.6 28 2.2 631 1.4
Neonatal death 50 28.5 1071 2.4 15 1.2 402 0.9
Severe neonatal morbidity
a
367 209.5 5748 12.6 274 22.0 3758 8.6
Neonatal death/severe morbidity 381 217.5 6198 13.6 283 22.7 4020 9.2
Perinatal death 108 61.6 2719 6.0 43 3.5 1033 2.4
Perinatal death/severe morbidity 439 250.6 7846 17.2 311 25.0 4651 10.7
All differences were statistically signicant (P <.001). For early-onset preeclampsia comparisons, all ongoing pregnancies at 20 weeks of gestation were included in the denominator; for late-onset
preeclampsia comparisons, all ongoing pregnancies at 34 weeks of gestation were included in the denominator.
FAR, fetuses at risk; NICU, neonatal intensive care unit.
a
Includes any of the following: a 5 minute Apgar score of 3 or less, neonatal seizures, neonatal sepsis, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage grades 3
and 4, periventricular leukomalacia, and retinopathy of prematurity.
Lisonkova. Early- vs late-onset preeclampsia. Am J Obstet Gynecol 2013.
www.AJOG.org Obstetrics Research
DECEMBER 2013 American Journal of Obstetrics & Gynecology 544.e6
The adjusted rates of adverse birth
outcomes were also higher among
mothers with late-onset disease as
compared with mothers without pre-
eclampsia, although the differences in
rates were substantially less and some
were not statistically signicant (Table 4).
The rates of fetal, neonatal, and perinatal
death, for example, were not signi-
cantly higher among women with late-
onset preeclampsia (AOR, 1.29; 95%
CI, 0.81e1.96; AOR, 1.09; 95% CI,
0.61e1.96, and AOR, 1.19; 95% CI,
0.83e1.69, respectively). Rates of SGA,
in contrast, were signicantly elevated
among mothers with late-onset disease
(AOR, 2.68; 95% CI, 2.54e2.82).
From the prognostic perspective, live-
born infants of mothers with early-onset
preeclampsia were less likely to die in the
neonatal period (AOR, 0.51; 95% CI,
0.36e0.74) compared with those born at
the same gestation to mothers without
preeclampsia (Appendix; Supplementary
Table 1). However, these infants had
higher odds of severe neonatal morbidity
(AOR, 1.35; 95% CI, 1.16e1.57), NICU
admission (AOR, 2.44; 95% CI,
2.13e2.80), and SGA (AOR, 2.78; 95%
CI, 2.46e3.13). The unadjusted odds of
LGA were lower among infants of
mothers with late-onset disease (odds
ratio, 0.78; 95%CI, 0.73e0.83), although
adjustment for gestational age and other
covariates increased the relative odds
(AOR, 1.09; 95% CI, 1.02e1.16).
Birth outcomes among women with
early-onset preeclampsia who delivered
at a gestation of 34 weeks or longer and
women with late-onset preeclampsia
were similar in terms of fetal and
neonatal death (Table 5). However, the
rates of the most common outcomes,
such as NICU admission and SGA, were
signicantly elevated among the early-
onset group (AOR, 2.22; 95% CI,
1.60e3.07; and AOR, 1.66; 95% CI,
1.24e2.23, respectively).
Sensitivity analyses showed that high
BMI was a stronger risk factor for early-
onset than for late-onset disease (AHR,
2.10; 95% CI, 1.91e2.32; and AHR, 1.71;
95% CI, 1.65e1.77, respectively), similar
to the association between chronic hy-
pertension and the preeclampsia sub-
types. The AHR for chronic hypertension
decreased after additional adjustment for
obesity (AHR, 9.4; 95%CI, 8.2e10.9; and
AHR, 2.24; 95% CI, 2.11e2.38, for early-
and late-onset preeclampsia, respec-
tively). The associations between early-
and late-onset preeclampsia and birth
outcomes were not appreciably affected
by additional adjustment for BMI except
for LGA, which was no longer signi-
cantly elevated among live-born infants
of mothers with late-onset preeclampsia
(AOR, 1.03; 95% CI, 0.97e1.10).
Additional adjustment for time period
(year of birth) did not change the results.
Women excluded from the study were
different from the study population
with regard to several risk factors for
preeclampsia. Some risk factors (such
as African-American race, no prior
live births, chronic hypertension, and
congenital anomalies) were overrep-
resented among the excluded women,
whereas other risk factors (such as older
maternal age, Hispanic and Native-
American race, single parent status, and
diabetes mellitus) were less frequent than
expected (Appendix; Supplementary
Table 2).
COMMENT
Our population-based study showed
that the gestational ageespecic inci-
dence of preeclampsia among women
with singleton pregnancies increased
sharply with gestational age. The rate of
early-onset disease (<34 weeks gesta-
tion) was substantially lower than the
rate of late-onset disease (gestation of
34 weeks): 0.38 vs 2.72 per 100 de-
liveries, respectively. Several factors,
including chronic hypertension, African-
American race, and congenital anomalies
conferred a relatively higher risk for
early-onset (as opposed to late-onset)
disease, whereas other factors such as
diabetes mellitus, nulliparity, and young
TABLE 4
Crude and AORs for birth outcomes following early- and late-onset preeclampsia, singleton deliveries,
Washington State, 2003-2008
Birth outcomes
Early-onset preeclampsia Late-onset preeclampsia
OR 95% CI AOR 95% CI OR 95% CI AOR 95% CI
SGA (<10th percentile) 7.19 6.49e7.96 6.08 5.43e6.80 2.94 2.80e3.09 2.68 2.54e2.82
LGA (>90th percentile) 0.11 0.07e0.16 0.10 0.07e0.16 0.78 0.73e0.83 0.81 0.76e0.86
Fetal death 9.42 7.22e12.3 5.79 4.03e8.33 1.55 1.06e2.27 1.26 0.81e1.96
Neonatal death 12.84 9.63e17.1 11.44 8.07e16.4 1.31 0.78e2.19 1.09 0.61e1.96
Perinatal death 10.93 8.97e13.3 8.38 6.48e10.8 1.46 1.07e1.98 1.19 0.83e1.69
Perinatal death/morbidity
a
19.07 17.08e21.29 16.41 14.48e18.60 2.37 2.11e2.67 2.02 1.78e2.28
For early-onset preeclampsia comparisons, all ongoing pregnancies at 20 weeks of gestation were included in the denominator; for late-onset preeclampsia comparisons, all ongoing pregnancies at
34 weeks of gestation were included in the denominator.
AOR, adjusted odds ratio (adjusted for race, parity, maternal age, maternal education, infants sex, marital status, infertility treatment, chronic hypertension, diabetes, and congenital anomalies); CI,
condence interval; LGA, large for gestational age; OR, odds ratio; SGA, small for gestational age.
a
Perinatal death/morbidity includes any of the following: perinatal death, 5 minute Apgar of 3 or less, neonatal seizures, neonatal sepsis, bronchopulmonary dysplasia, necrotizing enterocolitis,
intraventricular hemorrhage grades 3 and 4, periventricular leukomalacia, and retinopathy of prematurity.
Lisonkova. Early- vs late-onset preeclampsia. Am J Obstet Gynecol 2013.
Research Obstetrics www.AJOG.org
544.e7 American Journal of Obstetrics & Gynecology DECEMBER 2013
maternal age were associated with a
higher risk of late-onset preeclampsia.
Early-onset preeclampsia conferred a
substantially higher risk for adverse birth
outcomes than late-onset preeclampsia.
In contrast, the prognosis for neonatal
death among infants born to women
with early-onset preeclampsia was better
than the prognosis for infants born at the
same gestation because of other causes.
The lower risk of neonatal death among
infants born to mothers with pre-
eclampsia at preterm gestation has been
reported previously.
2,16,17
This differ-
ence in prognosis, however, was condi-
tional on a live birth and not evident
in the causal fetuses-at-risk analysis
(Table 4). Furthermore, the rates of
NICU admission and SGA were signi-
cantly higher among infants born to
mothers with early-onset preeclampsia.
Approximately 12% of the women with
early-onset preeclampsia delivered at a
gestation of 34 weeks or longer.
Our population-based study exam-
ined gestational ageespecic rates of
preeclampsia in a large cohort of sin-
gletons. Overall rates of preeclampsia
were consistent with previous estimates
from industrialized countries, which
have reported preeclampsia rates be-
tween 3 and 5 per 100 deliveries
2,3
and
eclampsia rates between 2.7 and 8.2 per
10,000 deliveries.
2,7
Although the causes of preeclampsia
are not known, placental dysfunction has
been implicated in its origins,
18,20,34
and
placental morphology studies suggest
that preeclampsia is a heterogeneous
entity.
34-36
Our results showthat effect of
risk factors such as race/ethnicity, nulli-
parity, chronic hypertension, and dia-
betes vary according to the subtype of
preeclampsia. For example, congenital
anomalies were more strongly associated
with early-onset disease, suggesting the
presence of associated placental abnor-
malities that affect perfusion and result
in early-onset disease. In contrast, a
stronger positive association between
diabetes mellitus and late-onset pre-
eclampsia suggests that relative placental
insufciency is more likely to occur in
diabetic pregnancies with a larger fetus.
We also observed a stronger association
between early-onset disease and SGA (as
compared with late-onset disease and
SGA), likely because of the profound
effects of poor placental perfusion early
in gestation and differences in disease
severity.
20,37
Our study has a few limitations.
Gestational age at the onset of pre-
eclampsia was estimated based on the
time between hospital admission for
preeclampsia and hospital admission for
delivery. We were not able to capture
women with preeclampsia who were not
hospitalized and those who did not deliver
in the hospital. However, such missed
cases of preeclampsia were likely milder
cases that did not result in serious com-
plications requiring hospitalization. In
some cases, the onset of preeclampsia may
have occurred a few days before the
admission to the hospital. The delay be-
tween the onset of preeclampsia and
admission to the hospital may have
resulted insome misclassicationof early-
onset disease as late-onset preeclampsia.
As with any administrative database,
the accuracy of diagnoses was contingent
on documentation and abstraction from
medical records. However, it has been
shown that linkage between hospitali-
zation data and birth/infant death cer-
ticates increases data accuracy and that
the accuracy of major obstetric diagnoses
and procedures is relatively high in
Washington States linked data le.
38
TABLE 5
Crude and adjusted odd ratios for birth outcomes contrasting
early-onset vs late-onset preeclampsia, singleton deliveries
at gestation of 34 weeks, Washington State, 2003-2008
Birth outcomes
Early-onset preeclampsia
with delivery at gestation
34 weeks (n [213)
Late-onset
preeclampsia
(n [12,449) P value
a
Gestational age at delivery, wks
34-36 128 (60.1) 2911 (23.4) < .01
37-43 85 (39.9) 9538 (76.6)
Birthweight, g
<1500 2 (0.95) 42 (0.34) < .01
1500-2499 70 (33.3) 2020 (16.2)
2500-4499 138 (65.7) 10,162 (81.6)
4500 0 (0.00) 166 (1.33)
SGA (<10th percentile) 44 (21.0) 2007 (16.1) < .01
LGA (<90th percentile) 11 (5.24) 1171 (9.41) < .01
Apgar score at 5 min 3
b
2 (0.94) 99 (0.80)
NICU admission
b
55 (25.8) 1658 (13.4) < .01
Fetal death 0 (0.00) 28 (0.22) .49
Neonatal death
b
0 (0.00) 15 (0.12) .61
Severe neonatal morbidity
b,c
7 (3.29) 274 (2.21) .41
Neonatal death/severe
morbidity
b
7 (3.29) 283 (2.28) .46
Perinatal death 0 (0.00) 43 (0.35) .79
Perinatal death/severe
morbidity
7 (3.29) 311 (2.50) < .047
LGA, large for gestational age; NICU, neonatal intensive care unit; SGA, small for gestational age.
a
P value based on c
2
or Fisher exact test;
b
Excludes fetal deaths;
c
Includes any of the following: a 5 minute Apgar score of 3
or less, neonatal seizures, neonatal sepsis, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemor-
rhage grades 3 and 4, periventricular leukomalacia, and retinopathy of prematurity.
Lisonkova. Early- vs late-onset preeclampsia. Am J Obstet Gynecol 2013.
www.AJOG.org Obstetrics Research
DECEMBER 2013 American Journal of Obstetrics & Gynecology 544.e8
Other potential weaknesses of the
study include limited information about
risk factors, such as BMI. Sensitivity
analyses showed that high BMI had a
stronger association with early- vs late-
onset preeclampsia (similar to chronic
hypertension), suggesting that metabolic
syndrome (associated with high BMI)
may play a stronger role in early-onset vs
late-onset disease.
We did not have detailed information
about antenatal screening, and obstetric
and neonatal care practices in the
different hospitals in Washington state
including use of aspirin among women
at high risk for preeclampsia. Potential
inaccuracies in diagnosis and differences
in intervention between physicians and
hospitals may have resulted in some
nondifferential misclassication of risk
factors and outcomes and led to some
dilution in observed associations.
Finally, subjects excluded from the
study because of missing information or
unlinked records were signicantly
different from those included in the
study, with respect to some maternal
characteristics, although the fraction
excluded was small (5.7%).
The strengths of our study include a
large study population and gestational
ageespecic incidence rates dened us-
ing the onset of disease. The population
perspective obtained by using statewide
information minimized potential selec-
tion bias that may be present in hospital-
based studies, especially those that
include selected hospital patients.
30-33
The large study size offered statistical
power for analysis of rare adverse birth
outcomes. Finally, the use of the fetuses-
at-risk approach in addition to tradi-
tional perinatal modeling provides the
causal and prognostic perspectives on
the relation between preeclampsia and
birth outcomes.
In summary, population-based data
on singleton deliveries in Washington
State between 2003 and 2008 showed
that the incidence of preeclampsia
increased sharply with gestational age.
Even though some risk factors were
common to both early- and late-onset
disease, several risk factors had quanti-
tatively different associations with the 2
subtypes of preeclampsia. Early-onset
preeclampsia had far greater adverse ef-
fects on the fetus and infant compared
with late-onset disease. Our study thus
conrms the heterogeneity of pre-
eclampsia and shows that the timing of
disease onset is one important indicator
of disease severity and possibly of disease
etiology. Research studies should treat
the 2 preeclampsia subtypes as distinct
entities from an etiological and prog-
nostic standpoint. -
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APPENDIX
SUPPLEMENTARY TABLE 1
Crude and AORs for neonatal outcomes among live newborns, following early- and late-onset preeclampsia,
singleton deliveries, Washington State, 2003-2008
a
Neonatal outcomes
Early-onset preeclampsia Late-onset preeclampsia
OR 95% CI AOR
a
95% CI OR 95% CI AOR
a
95% CI
SGA (<10th percentile) 6.51 5.62e7.54 2.78 2.46e3.13 2.94 2.80e3.09 2.13 2.02e2.24
LGA (>90th percentile) 0.27 0.14e0.52 0.46 0.29e0.74 0.78 0.73e0.83 1.09 1.02e1.16
Apgar score at 5 min 3 0.46 0.36e0.59 0.84 0.64e1.10 2.62 2.14e3.22 1.98 1.59e2.46
NICU admission 1.90 1.66e2.17 2.44 2.13e2.80 3.82 3.62e4.03 1.65 1.55e1.76
Severe neonatal morbidity
b
0.82 0.72e0.94 1.35 1.16e1.57 2.59 2.29e2.93 1.57 1.37e1.79
Neonatal death 0.29 0.22e0.39 0.51 0.36e0.74 1.31 0.78e2.19 0.71 0.39e1.28
Neonatal death/severe morbidity 0.75 0.66e0.85 1.18 1.01e1.37 2.50 2.21e2.82 1.51 1.32e1.72
Regression models adjusted for gestational age, race, parity, maternal age, maternal education, infants sex, marital status, infertility treatment, chronic hypertension, diabetes, and congenital
anomalies.
AOR, adjusted odds ratio; CI, condence interval; LGA, large for gestational age; NICU, neonatal intensive care unit; OR, odds ratio; SGA, small for gestational age.
a
Prognostic model comparing neonatal outcomes conditional on live birth, adjusted for gestational age at delivery. Fetal death was not included in the prognostic model because such deaths occur
before birth;
b
Includes any of the following: a 5 minute Apgar score of 3 or less, bronchopulmonary dysplasia, necrotizing enterocolitis, neonatal seizures, neonatal sepsis, intraventricular
hemorrhage grades 3 and 4, periventricular leukomalacia, and retinopathy of prematurity.
Lisonkova. Early- vs late-onset preeclampsia. Am J Obstet Gynecol 2013.
Research Obstetrics www.AJOG.org
544.e11 American Journal of Obstetrics &Gynecology DECEMBER 2013
SUPPLEMENTARY TABLE 2
Demographic and clinical characteristics, singleton deliveries with and
without inclusion criteria, Washington State, 2003-2008
a
Demographic/clinical risk factors
Included Excluded
P value
b
n [456,668 (%) n [27,443 (%)
a
Age, y
<20 39,584 (8.67) 2285 (8.33) < .01
20-34 347,105 (76.01) 22,217 (80.96)
35 69,979 (15.32) 2687 (9.79)
Race
Non-Hispanic white 323,552 (70.85) 19,056 (69.44) < .01
African-American 20,045 (4.39) 2455 (8.95)
Hispanic 56,615 (12.4) 2735 (9.97)
Native-American 10,625 (2.33) 488 (1.78)
Other 44,032 (9.64) 2480 (9.04)
Maternal education less
than high school
89,238 (19.54) 3683 (13.42) < .01
Smoking during pregnancy 46,936 (10.28) 2766 (10.08) < .01
Single parent 149,369 (32.71) 5213 (19.00) < .01
No prior live births 186,961 (40.94) 12,801 (46.65) < .01
Diabetes mellitus 25,815 (5.65) 1279 (4.66) < .01
Chronic hypertension 5560 (1.22) 499 (1.82) < .01
Infertility treatment 3455 (0.76) 145 (0.53) < .01
Infant sex (male) 234,224 (51.29) 14,063 (51.24) .98
Congenital anomalies 2249 (0.49) 353 (1.29) < .01
Some numbers do not add because of missing values; all missing values were less than 3%.
a
Excluded were women who delivered outside the hospital, those without a linkage between birth/fetal death certicate and
hospitalization le, and those without a missing estimate of gestation at delivery;
b
P values are based on c
2
test.
Lisonkova. Early- vs late-onset preeclampsia. Am J Obstet Gynecol 2013.
www.AJOG.org Obstetrics Research
DECEMBER 2013 American Journal of Obstetrics & Gynecology 544.e12