211

Journal of Neonatal-Perinatal Medicine 4 (2011) 211220

DOI 10.3233/NPM-2011-2756
IOS Press

The inverse association between gastroschisis

and gestational hypertension
N.R. Paynea, , K.M. Pfleghaarb , C. Blauerc,d , M. Finkelsteine and S. Olsena
a Department

of Neonatology, Childrens Hospitals and Clinics of Minnesota, Minneapolis, MN, USA

of Perinatology, Abbott Northwestern Hospital, Minneapolis, MN, USA
c School of Public Health, University of Minnesota, Minneapolis, MN, USA
d United Health Group, Golden Valley, MN, USA
e Department of Quality and Safety, Childrens Hospitals and Clinics of Minnesota, Minneapolis, MN, USA
b Department

Received 08 November 2010

Revised 17 January 2011
Accepted 2 February 2011

Abstract. Objective: Examine the relationship between maternal gestational hypertension (GH) and gastroschisis.
Study design: This retrospective, observational study used a local dataset of 30 300 NICU patients and 3 429 498 U.S. birth
certificate records to examine the prevalence of GH using univariate and logistic regression. Since body mass index (BMI) was
not available in the data, we used Monte Carlo simulation of BMI followed by logistic regression to estimate the influence of
this missing variable in the birth certificate data.
Results: In the local dataset, maternal GH was lower in mothers of gastroschisis cases compared to the mothers of all other
NICU admissions (0/188 vs. 4 351/30 112 [14.5%], p < 0.001). Adjusting for covariates, the odds ratio (OR) for GH among
mothers of gastroschisis patients was 0.04 (95% confidence interval [CI] = 0.010.28, p = 0.001). In birth certificate data, GH
was lower in mothers of gastroschisis cases compared to all others (22/927 [2.4%] vs. 144 521/3 428 571 [4.2%], p = 0.005).
Adjustment for covariates and simulated BMI also showed a lower prevalence of GH in mothers of gastroschisis cases (OR = 0.58,
95% CI = 0.350.94, p = 0.005).
Conclusion: Women delivering a live-born infant with gastroschisis may have a decreased prevalence of GH. This unique
observation warrants additional confirmatory studies. Such studies might provide insight into both GH and gastroschisis.
Keywords: Preeclampsia, pregnancy, pregnancy-associated hypertension, gastroschisis, gestational hypertension

1. Introduction
Gastroschisis is associated with unique epidemiological findings. It is more common in teenage than
in older women and its incidence has risen despite a
decline in teenage pregnancy [13]. Mothers of gastroschisis patients more often smoke, have a lower
Corresponding

author: N. Rob Payne, NICU Office, Childrens

Hospitals and Clinics of Minnesota, 2525 Chicago Avenue South,
Minneapolis, MN 55404-4518, USA. Tel.: +1 612 813 6985; Fax:
+1 612 813 7883; E-mail: rob.payne@childrensmn.org.

prepregnancy body mass index (BMI), take vasoactive medications, have genito-urinary tract infections,
are primiparous, and more frequently report a recent
change in sexual partner prior to pregnancy, compared
to women who deliver a baby without gastroschisis [1,
2, 48].
Most newborns with gastroschisis do not have other
birth defects [9]. However, almost all fetuses with
gastroschisis experience poor intrauterine growth, a
complication that develops early in gestation [1012].
Since these infants usually grow normally when provided with adequate nutrition after birth [13], we

1934-5798/11/$27.50 2011 IOS Press and the authors. All rights reserved

212

N.R. Payne et al. / The inverse association between gastroschisis and gestational hypertension

became curious as to why many fetuses with gastroschisis have some degree of intrauterine growth
restriction. In our practice, new onset of hypertension in pregnancy, gestational hypertension (GH),
most commonly causes slow fetal growth (unpublished
observations). The increased prevalence of both gastroschisis [1, 2] and GH among very young women
[14] and the frequent growth restriction in gastroschisis fetuses led us to believe that GH would be increased
among women delivering an infant with gastroschisis.
To the contrary, we observed a decreased prevalence
of GH. This unexpected observation prompted us to
explore the association between gastroschisis and GH
in our local NICU data set and in a large cohort of birth
certificate data.
2. Materials and methods
2.1. Study design
This was a retrospective, observational, case-cohort
study of women with live births with and without gastroschisis.
2.2. Study samples
Two datasets were used for this study. Dataset #1)
Childrens Hospitals and Clinics of Minnesota maintains a database of all patients treated in the NICU since
1990 at the Minneapolis Campus and since 2004 at the
St. Paul Campus. All patients admitted from January
1, 1990, through December 31, 2008, were included
in this study. Delivery room deaths were available
after 2005, but normal newborns data were not available. Neonatal nurse practitioners or trained database
abstractors collected clinical and demographic data
concurrent with hospitalization as part of an ongoing
NICU outcomes monitoring project. Database managers verified the recorded data against the mothers
and infants medical record.
Dataset #2) We downloaded United States (U.S.)
birth certificate data for the years 2005 and 2006
including records from both the U.S. and its territories [1517]. The 2003 revision of the standard U.S.
birth certificate, but not the 1989 revision, separated
gastroschisis from omphalocele [17]. In 2005, 12 states
and in 2006, 19 states submitted birth certificate data on
the 2003 revision of the standard birth certificate [16,
17]. We analyzed only data reported using the 2003
revision. This study was approved by the Institutional

Table 1
Gestational hypertension (GH) & distribution of simulated body
mass index (BMI)a
Lean (%)

Diagnoses

Normal
Overweight/
BMI (%)
Obese (%)
(BMI < 20)b (BMI = 2026) (BMI > 26)

GH
No Gastroschisis &
No GH
Gastroschisis &
No GHc

10

48

42

14

59

27

15

83

a Data

based on the average of four studies reporting the distribution of BMI among women with and without GH [2124]; b The
four studies did not use exactly the same definition of lean, normal
BMI and overweight/obese; c Based on data of Lam, et al. [6]. We
assumed that patients with GH and gastroschisis had the same BMI
distribution as other GH patients.

Review Board of Childrens Hospitals and Clinics of

Minnesota (#0811-104).
2.3. Data denitions
For dataset #1, the local NICU database, gastroschisis was verified by the attending pediatric surgeon.
The attending obstetrician determined the presence of
GH using standard definitions [18]. Gestational age
came from obstetrical estimates based on estimated
date of confinement calculated from the first day of
the last menstrual period and corrected by early second trimester ultrasound, if available. If physical exam
indicated a gestational age >2 weeks different from
the obstetrical estimate, the estimate from the physical
exam was used. Gestational diabetes was differentiated
from chronic diabetes. Maternal smoking was considered present if the mother smoked after she knew
she was pregnant. Maternal race was assigned by selfreport or as taken from the mothers medical records.
For dataset #2, the birth certificate data, clinical
definitions were those for the 2003 revision of the
standard U.S. birth certificate [19]. GH was defined
as elevation of blood pressure above normal for age,
gender, and physiological condition diagnosed during this pregnancy and included preeclampsia and
pregnancy-induced hypertension [16, 17]. Hypertension diagnosed prior to pregnancy was specifically
excluded. Cases recorded as having eclampsia were
considered to have GH, even if GH was not recorded
as present on the birth certificate. Complete definitions
of clinical variables are available [19]. Not all states
submitted data on tobacco usage in a format comparable to that of the other states. These format differences

N.R. Payne et al. / The inverse association between gastroschisis and gestational hypertension

accounted for the many records lacking data on tobacco

usage and accounted for most of the missing data.
2.4. Simulation of BMI
We simulated BMI in the birth certificate data
as a categorical variable: lean, normal, and overweight/obese. We randomly assigned a BMI category
based on the distribution of lean, normal, and overweight/obese women in previously published reports
of GH and gastroschisis (Table 1) [6, 2023].

a power of 0.99 to detect a significant difference in

GH between patients with and without gastroschisis
(with alpha = 0.05). The birth certificate data had a
power of 0.82 to detect a significant difference in
GH among patients with and without gastroschisis
(with alpha = 0.05). We performed only two-sided significance tests and made no adjustment for multiple
comparisons. All analyses were performed using Stata,
v.11.1 (College Station, TX).
3. Results
3.1. Local dataset (dataset #1) univariate
analysis

2.5. Statistical analysis

We used chi-square tests for preliminary analyses and univariate logistic regression using GH and
a single covariate to determine the univariate odds
ratio (OR) and 95% confidence intervals (CI). We
repeated the simulation and univariate analysis 1000
times. To adjust for covariates, we modeled GH using
available independent variables previously reported
to be associated with GH and added the simulated
BMI. Model fit was assessed using the area under
the receiver operating characteristic curve statistic and
the Hosmer-Lemeshow goodness-of-fit test [24]. Simulation of BMI and multiple logistic regression were
repeated 10 000 times, and we report the average of
those repetitions. Analysis of our local database had

In the local dataset, there were 30 300 neonates

admitted to the two NICUs, of whom 30 178 (99.6%)
had complete data for the variables of interest. There
were 188 cases of gastroschisis. Only two gastroschisis infants had the same mother, and no adjustment
was made for this. Characteristics of gastroschisis
patients, a comparison group of 125 omphalocele
patients, and all other patients appear in Table 2.
Mothers of gastroschisis patients were less likely than
mothers of all other patients to have GH (0/188 vs.
4 351/30 112 [14.5%], p < 0.001). The 99% confidence
interval for the estimate of GH in gastroschisis patients
was 02.8%. Gastroschisis was also associated with

Table 2
NICU Patients at childrens hospitals and clinics of minnesota
Characteristic

Gestational age (Weeks)

Birth weight (grams)
Male (%)
Maternal race(%)b,c
White
Black
Hispanic
Asian
Other
Maternal age (yrs)
Chronic diabetes (%)
Gestational diabetes (%)
Multiple gestation (%)
Primipara (%)
Maternal smoking (%)
Gestational hypertension (%)
a One

213

Gastroschisis

Omphalocele

(N = 188)a

(N = 125)

All other
patients
(N = 29 865)a

35.8 2.0
2420 512b
99 (53)

36.3 2.9
2713 759
66 (53)

34.6 4.6
2488 1008
16 688 (56)

155 (83)
4 (2)
7 (4)
16 (9)
5 (3)
21.7 4.3b
0
1 (1)
5 (3)b
115 (62)b
53 (28)b
0b

113 (90)
7 (6)
1 (1)
2 (2)
2 (2)
29.2 6.1
1 (1)
4 (3)
10 (8)
41 (33)
17 (14)
10 (8)

25 741 (86)
2440 (8)
522 (2)
820 (3)
343 (1)
29.4 6.0
714 (2)
1991 (7)
6380 (21)
10 488 (35)
4323 (14)
4330 (15)

gastroschisis patient (1/188), no omphalocele patients and 122/29 987 other patients had
missing data and were excluded from subsequent analyses. The excluded gastroschisis patients
mother did not have GH; b Gastroschisis patients differed significantly from omphalocele and other
patients, p < 0.05, by Chi square or Anova tests; c May not total exactly 100% due to rounding.

214

N.R. Payne et al. / The inverse association between gastroschisis and gestational hypertension
Table 3
Unadjusted and adjusted odds ratios (or) for gestational hypertension in NICU patients at childrens hospitals and
clinics of minnesota
Characteristic
Gastroschisis
Omphalocele
Male
Maternal race(%)b
White
Black
Hispanic
Asian
Other
Maternal age (years)
<20
2024
2529
3034
>34
Chronic diabetes
Gestational diabetes
Multiple gestation
Multipara
Maternal smoking

Unadjusted OR (CI)a

p-value

Adjusted OR (CI)

p-value

0.03 (0.010.23)
0.52 (0.270.99)
0.84 (0.790.89)

0.001
0.045
0.902

0.04 (0.010.28)
0.58 (0.291.11)
0.86 (0.810.92)

0.001
0.102
<0.001

Referent
0.89 (0.791.01)
1.08 (0.861.37)
0.70 (0.560.88)
0.71 (0.511.00)

0.066
0.507
0.002
0.048

Referent
1.07 (0.941.21)
1.22 (0.961.55)
0.71 (0.560.89)
1.03 (0.234.65)

0.31
0.110
0.003
0.968

Referent
1.01 (0.861.19)
1.16 (1.001.35)
1. 24 (1.071.44)
1.52 (1.311.77)
2.05 (1.722.43)
1.41 (1.251.58)
1.89 (1.762.03)
0.60 (0.560.64)
0.69 (0.620.76)

0.902
0.051
0.005
0.902
<0.001
<0.001
<0.001
<0.001
<0.001

Referent
1.11 (0.941.32)
1.22 (1.041.42)
1.30 (1.111.53)
1.64 (1.401.94)
2.27 (1.902.71)
1.38 (1.221.56)
1.74 (1.621.87)
0.55 (0.520.59)
0.81 (0.730.90)

0.198
0.015
0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001

a Unadjusted Odds Ratio, CI = 95% confidence interval; b aOR = Odds Ratio adjusted for other potential risk factors.

a lower prevalence of GH compared to omphalocele

(0/187 vs. 10/125, 8.0%, p < 0.001).
3.2. Local dataset (dataset #1) multiple
regression analysis
We then examined the association of GH with gastroschisis using logistic regression controlling for other
available variables known to be associated with GH
(Table 3). There were 30 178/30 300 (99.6%) cases
with complete data. One case of gastroschisis lacked
complete data and was also excluded from the multiple regression. That patients mother did not have GH.
Significant collinearity was not present (highest variance inflation factor = 1.41). The Hosmer-Lemeshow
test had a p-value of 0.92, and the area under the
receiver operating characteristic curve was 0.63. The
adjusted OR (aOR) for GH in mothers delivering a liveborn infant with gastroschisis was 0.04 (CI, 0.010.28,
p = 0.001). The difference in GH among mothers of
omphalocele patients and all others was not significant in logistic regression (aOR = 0.58, CI, 0.301.11,
p = 0.102).
3.3. Birth certicate data (dataset #2)
univariate analysis
In the live-birth certificate data, there were 1 325
706 records in 2005, and 2 128 897 records in 2006

with information recorded on the 2003 revision of the

U.S. Standard Certificate of Live Birth from the states,
territories and possessions of the U.S (Fig. 1). Birth
certificate records coded as having both gastroschisis and omphalocele (N = 16) were excluded from the
analysis as they likely reflected coding errors or an
uncertain diagnosis. We also dropped cases with missing data for either the gastroschisis or GH variables
(N = 25 089) (Fig. 1). The remaining 3 429 498 cases
contained 927 cases of gastroschisis (2.7/10 000 live
births). Gastroschisis cases had a lower incidence of
maternal GH compared to all other patients (22/927
[2.4%] vs. 144 521/3 428 571 [4.2%], p = 0.005). By
comparison, omphalocele was associated with a higher
prevalence of GH (24/322 [7.5%] vs. 144 519/3 429
176 [4.2%], p = 0.004). GH was less common in mothers of gastroschisis patients in all maternal age groups
except for those ages 3135 (Table 4). There were few
gastroschisis patients in that age group.
3.4. Birth certicate data (dataset #2) multiple
regression analysis
Regression analyses included all available, potential covariates and the simulated BMI category. We
excluded patients with missing data (1 070 427 cases).
These cases were primarily missing data on smoking
status of the mother. The simulated distribution of BMI

N.R. Payne et al. / The inverse association between gastroschisis and gestational hypertension

215

Fig. 1. Selection of birth certificate records for analysis. Flow diagram of the selection of birth certificate records for analysis. There were 927
cases of gastroschisis available for univariate analyses and 676 cases for the multiple regression analysis gastroschisis. For the subgroup analyses,
we excluded cases with a maternal age >35 years because those women rarely have a baby with gastroschisis and have a higher incidence of
gestational hypertension. We also excluded cases with gestational age <33 weeks and >39 weeks. Gastroschisis patients have a mean gestational
age at birth of 36 3 weeks.

in GH and non-GH patients is shown in Table 1. The

simulated prevalence of GH in underweight women
was 3.1%, for normal weight women 3.9%, and for
overweight/obese women 7.6% (Table 5). By comparison, the overall prevalence of GH in the birth certificate
records with complete data was 4.2%. We first modeled GH in a 5% random sample (118 610 records),
which included all gastroschisis patients, using the
simulated BMI categories. There was no evidence
of collinearity among covariates (variance inflation

factors all 1.001.16). The area under the receiver

operating characteristic curve was 0.65. The HosmerLemeshow goodness-of-fit test had a p-value of 0.29.
Mothers delivering an infant with gastroschisis had an
aOR of 0.58 (CI, 0.350.95, Table 5) for GH.
Multiple logistic regression in the whole sample
following 10 000 repetitions of the BMI simulation
showed that delivering an infant with gastroschisis was
associated with an aOR of OR = 0.58 (CI, 0.350.94,
Table 5). Sensitivity testing showed that the OR for gas-

216

N.R. Payne et al. / The inverse association between gastroschisis and gestational hypertension

Table 4
Gastroschisis and gestational hypertension by maternal age groupa
Gestational hypertension (%)
Maternal age
group (Years)

Gastroschisis

All others

16
1720
2125
2630
3135
3640
4145
>45
All

1/61 (2)
6/383 (1.6)b
10/314 (3.2)
3/112 (2.7)
2/37 (5.4)
0/17 (0)
0/3 (0)
0
22/927 (2.4)c

3080/60 229 (5.4)

22 086/481 238 (4.6)
37 469/914 135 (4.1)
37 494/917 850 (4.5)
28 018/698 047 (4.0)
13 284/301 779 (4.4)
2851/52 502 (5.4)
239/2791 (8.6)
144 543/3 428 571 (4.2)

a Includes only cases with no missing data for covariates; b Difference

between gastroschisis and non-gastroschisis patients significant at

p = 0.008; c Difference between gastroschisis and non-gastroschisis
patients significant at p = 0.004.

troschisis lost its significance (CI included 1.0) when

the proportion of overweight/obese women reached
46% of all GH cases. By comparison, the average
proportion of women with GH and who were overweight/obese was 42% in the simulation, based on
previously published data [2023].
3.5. Subgroup analysis
We then performed multiple regression analysis
restricted to the records of infants born to mothers
<36 years of age, since that is the population most
likely to have a baby with gastroschisis and because the
prevalence of GH rises with age in the general population (Table 4). There were 676 cases of gastroschisis
among 2 134 405 records (Fig. 1). Univariate analysis showed less GH in gastroschisis patients (16/676
[2.4%] vs. 97 763/2 133 729 [4.6%], p = 0.006). In multiple regression analysis, gastroschisis was associated
with an adjusted OR of 0.58 (CI, 0.350.94).
Since gastroschisis patients generally deliver
preterm (mean = 36 3 weeks) and some womens
GH does not manifest until close to term, GH might
be underestimated in the gastroschisis patients mothers. To examine the effect of gestational age, we then
limited our analysis to patients born at 36 3 weeks
gestation. Again, univariate analysis showed less GH in
gastroschisis patients (13/575 [2.3%] vs. 78 359/1 550
074 [5.2%], p = 0.001). In multiple regression analyses, gastroschisis was associated with an adjusted OR
for GH of 0.48 (CI, 0.270.82).

4. Discussion
We have shown an inverse association between GH
in the mother and gastroschisis in her live-born child.
In the local data set, GH was much less common in the
mothers of gastroschisis patients compared to all other
mothers (0/187 vs. 4351/30 112 [14.5%], p < 0.001).
In the birth certificate data, the presence of a live-born
infant with gastroschisis reduced the OR for GH by
almost half (Table 5). To our knowledge, this is the
first report of such an association.
Although the mechanism is unknown, we believe
changes in placental structure or function may mediate
this association. Shallow cytotrophoblastic invasion
of the uterine decidua and myometrium occupies a
key role in pathogenesis of GH and explains the
fetal growth restriction often seen in GH [14, 25,
26]. Abnormal placentation occurs long before the
commonly observed fetal growth restriction and maternal GH. Growth restriction also occurs commonly
in fetuses with gastroschisis [1012]. We hypothesize that placental dysfunction may also explain fetal
growth restriction in gastroschisis cases, but not lead to
GH. Slow fetal growth has two basic causes: 1) inadequate delivery of nutrients and oxygen to the fetus, as
in placental dysfunction or nutritional deficiency in the
mother, and 2) inability of the fetus to utilize nutrients
that are provided through the placenta. Most gastroschisis patients with an intact intestinal tract grow
satisfactorily when provided with adequate postnatal
nutrition [13, 27]. It seems unlikely that gastroschisis
patients cannot utilize nutrients. Some mothers of gastroschisis patients have poor nutrition and a low BMI
[2, 6], but it usually takes severe maternal malnutrition
to cause intrauterine growth restriction [28], and not
all mothers of growth-restricted gastroschisis patients
have a low BMI [6, 27, 29]. Therefore, we hypothesize that placental dysfunction frequently occurs in
mothers who have a fetus with gastroschisis. This dysfunction causes fetal growth restriction, but not GH. In
other words, both gastroschisis and GH appear to be
associated with placental dysfunction, but in the case
of gastroschisis, the dysfunction protects against rather
than predisposes to GH.
Gastroschisis and placental implantation both occur
at about the same time, early in the first trimester [14,
26, 30]. We doubt that the gastroschisis defect itself
protects against GH, although such cannot be ruled out.
It seems more likely that there is a common influence
acting both to impair placental function or structure and

Table 5
Regression analysis of gestational hypertension (GH) in birth certificate dataa

Sample size
Gastroschisis
Maternal race
Non-hispanic white
Non-hispanic black
Hispanic
Non-hispanic other
Maternal age (yrs)a
16
1720
2125
2630
3135
3640
4145
>45
Chronic diabetes
Gestational diabetes
Multiparity
Maternal smoking
Multiple gestation
Simulated BMI category
Underweight
Normal
Overweight/obese
a Includes

N (% of
total
population)

GH (%)

Whole Cohort
with BMI
Unadjusted ORb

Whole Cohort
without BMI
aORc

5% Sample
with BMI
aORd

Whole Cohort
with BMI
aOR (CI)e

2,359,071d (100)
691 (<0.1)

4.6
2.3

2,359,071 (100)
0.49 (0.300.80)

2,359,071 (100)
0.47 (0.290.78)

118,610
0.58 (0.350.95)

2,359,071
0.58 (0.350.94)

1,349,039 (57.2)
272,932 (11.6)
649,263 (27.5)
87,837 (3.7)

5.0
5.4
3.9
3.0

Referent
1.10 (1.081.12)
0.77 (0.760.78)
0.60 (0.580.63)

Referent
1.12 (1.101.14)
0.79 (0.780.81)
0.55 (0.530.58)

Referent
1.24 (1.031.22)
0.79 (0.740.85)
0.55 (0.460.66)

Referent
1.12 (1.101.14)
0.79 (0.780.81)
0.55 (0.530.58)

43,253 (1.8)
342,625 (14.5)
643,984 (27.3)
637,160 (27.0)
467,383 (19.8)
191,536 (8.1)
31,646 (1.3)
1,484 (0.1)
16,227 (0.7)
95,128 (4.0,)
1,575,663 (54.5)
288,823 (12.2)
75,254 (3.2)

5.4
4.9
4.5
4.5
4.5
4.9
6.0
10.0
12.8
10.3
3.8
4.2
10.2

Referent
0.90 (0.860.94)
0.81 (0.780.85)
0.83 (0.790.86)
0.81 (0.780.85)
0.90 (0.860.94)
1.10 (1.041.17)
1.93 (1.622.29)
3.07 (2.933.22)
2.49 (2.442.55)
0.58 (0.570.59)
0.89 (0.870.91)
2.44 (2.372.51)

Referent
1.00 (0.961.05)
1.05 (1.011.10)
1.07 (1.031.12)
1.07 (1.021.12)
1.18 (1.221.24)
1.41 (1.331.51)
1.86 (1.562.23)
3.31 (3.163.47)
2.58 (2.522.64)
0.54 (0.530.54)
0.88 (0.870.90)
2.52 (2.462.59)

Referent
1.01 (0.83 1.23)
1.06 (0.871.29)
1.09 (0.891.32)
1.08 (0.881.33)
1.19 (0.961.48)
1.43 (1.071.90)
1.75 (0.754.11)
3.32 (2.684.12)
2.59 (2.342.86)
0.54 (0.500.57)
0.89 (0.810.97)
2.51 (2.242.81)

Referent
1.01 (0.96 1.05)
1.05 (1.011.10)
1.07 (1.031.12)
1.07 (1.021.12)
1.18 (1.121.24)
1.42 (1.331.51)
1.87 (1.562.23)
3.31 (3.163.48)
2.58 (2.522.64)
0.54 (0.530.54)
0.88 (0.870.90)
2.52 (2.462.59)

326 304 (13.8)

1 328 703 (58.5)
651 766 (27.6)

3.1
3.9
7.6

Referent
1.14 (1.121.16)
2.18 (2.162.20)

ND
ND
ND

Referent
1.14 (1.041.25)
2.19 (1.992.41)

Referent
1.14 (1.121.16)
2.18 (2.132.23)

all cases with no missing data for covariates. Data on BMI was simulated, and the results represent 1000 simulations; b Univariate odds ratio determined by logistic regression,
CI = 95% confidence interval. BMI data represent the results of 1000 simulations; c Adjusted odds ratio determined by multiple logistic regression including all variables listed in the first
column of the table as covariates. Results represent the mean of 1000 5% samples followed by simulations of BMI and logistic regression. CI = 95% confidence interval; d Of the 3,429,498
records available, 2,359,071 (68.8%) had no missing or Unknown covariate data items. Most of the missing data was for maternal cigarette smoking. Two states did not submit useable
data for this field on birth certificates for 2006 [12]. Results shown represent the mean of 10,000 simulations of BMI followed by logistic regression. CI = 95% confidence interval.

N.R. Payne et al. / The inverse association between gastroschisis and gestational hypertension

Feature

217

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N.R. Payne et al. / The inverse association between gastroschisis and gestational hypertension

predisposing to gastroschisis. This common influence

remains unknown. However, we believe that the placenta holds clues to this association. We are currently
studying the placentas from mothers of gastroschisis
patients to identify possible abnormalities.
It is interesting to note that maternal smoking, like
gastroschisis, has been associated with a reduced birth
weight and risk of GH [6, 14, 26, 3133], but only
if smoking continues after conception [31, 33]. Our
findings are consistent with these previous observations. Maternal smoking was associated with a lower
OR for GH in both the local data (OR 0.81, CI,
0.730.90) and the birth certificate data (OR 0.88, CI,
0.870.90). GH is associated with elevated circulating levels of anti-angiogenic factors, such as soluble
fms-like tyrosine kinase-1 (sFlt-1) or soluble vascular
endothelial growth factor (VEGF) receptor 1, as it is
also known [14, 25]. Elevated levels of sFlt-1 appear to
downregulate VEGF activity and are associated with
vasoconstriction and endothelial dysfunction, hallmarks of GH. In contrast to the elevated levels seen
in GH, smoking is associated with lower levels of sFlt1 in pregnancy and by implication, upregulated VEGF
activity [3436]. Similarly, GH is associated with lowered levels of placental growth factor (PIGF), which is
thought to upregulate VEGF activity [14, 25]. Smokers
have higher levels of PIGF compared to nonsmokers
[35, 36]. Thus, smoking may protect against GH by
altering the balance of anti-angiogenic factors such as
sFlt-1 and angiogenic factors such as PIGF. The mechanism by which this might occur in GH and whether
angiogenic levels are abnormal in gastroschisis pregnancies is not known. It is tempting to speculate that
immunological factors may underlie both GH and gastroschisis as both are associated with a short duration
of cohabitation prior to conception [7, 14, 25].
There are several limitations to our study. First,
gastroschisis occurs relatively rarely. Examining a
putative association between GH and gastroschisis
requires a large data set. To address this, we examined this association in two different data sets, a local
cohort and a national cohort including over 3 million
records with 927 cases of gastroschisis. Not a single
case of GH was found among the women delivering
an infant with gastroschisis in the local cohort. The
99% CI of the estimate of GH in mothers of our gastroschisis patients, 0/187, ranged from 0 to 2.9% and
did not overlap the 4.6% prevalence of GH in the birth
certificate data.
Another potential limitation is that birth certificate
data may underreport birth defects and GH [37, 38].

However, birth defects that are readily visible in the

delivery room, such as gastroschisis are less likely to be
omitted from birth certificates compared to less visible
birth defects [38]. Case ascertainment of gastroschisis seemed reasonable at 2.7/10 000, comparable to
a recently published population-based study, which
found a similar incidence [1]. It is likely, however, that
GH is somewhat underreported in birth certificate data.
Some studies report a higher incidence of GH than we
found in the birth certificate data [14, 26]. Such underreporting would invalidate our results only if GH were
selectively underreported in patients delivering a baby
with gastroschisis. We doubt that this occurred. The
prevalence of GH in another abdominal wall defect,
omphalocele, was higher than that seen in gastroschisis and higher than in the birth certificate data overall.
Thus, we do not believe that selective underreporting
of GH in gastroschisis patients accounted for these
findings.
The most serious limitation is the lack of data on
BMI in both data sets. This information was not available in the birth certificate data or the local data set.
Monte Carlo simulation suggested that the reported
difference in BMI between the mothers of gastroschsis
patients and other mothers did not explain our observations (Table 5). Previously published data suggested
that mothers of gastroschisis patients have a BMI
approximately 2 Kg/M2 lighter than controls [27, 29]
and that each 1 Kg/M2 increase in BMI would increase
the risk of GH by about 0.5% [39]. In the birth certificate data, adjusting for the lower BMI in the mothers
of gastroschisis patients would increase the prevalence
of GH in the mothers of gastroschisis patients to 3.4%
(2.4% + (0.5%/Kg/M2 * 2 Kg/M2 ), still less than the
observed prevalence of GH in the whole cohort (4.2%).
In summary, this study reports a novel, inverse association between gastroschisis and GH in two data sets
using both univariate and multiple regression analysis.
We believe the uniqueness of our observations warrants
examination of this association in another data set to
confirm our findings. We also hypothesize that placental structure or function may mediate the association
between gastroschisis and a lowered risk of GH.

Acknowledgments
The authors express appreciation to the neonatal nurse practitioners and NICU data managers for
collecting and recording patient data, and to the neonatologists of the St. Paul Campus of the Childrens

N.R. Payne et al. / The inverse association between gastroschisis and gestational hypertension

Hospitals and Clinics of Minnesota for allowing inclusion of their patients.

[17]

Financial disclosure
Dr. Payne was partially supported by Perinatal
Epidemiology Training Grant, 5 T32 HD046377 to
Michigan State University.

[18]

[19]

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