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J Matern Fetal Neonatal Med, Early Online: 1–4

! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.968843

ORIGINAL ARTICLE

Women with endometriosis at first pregnancy have an increased risk of

adverse obstetric outcome
Nathalie Conti1, Gabriele Cevenini2, Silvia Vannuccini1, Cinzia Orlandini1, Herbert Valensise3, Maria Teresa Gervasi4,
Fabio Ghezzi5,6, Mariarosaria Di Tommaso5,6, Filiberto Maria Severi1, and Felice Petraglia1
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Washington University Library on 12/29/14

1
Department of Molecular and Developmental Medicine, 2Department of Medical Biotechnology, University of Siena, Siena, Italy, 3Department of
Biomedicine, Obstetrics and Gynecology, Tor Vergata University, Rome, Italy, 4Obstetrics and Gynecology Unit, Department of Women and Children
Health, AOP, Padova, Italy, 5Department of Obstetrics and Gynecology, University of Insubria, Del Ponte Hospital, Varese, Italy, and 6Department of
Health Sciences, University of Florence, Florence, Italy

Abstract Keywords
Objective: To evaluate pregnancy, delivery and neonatal outcome in singleton primiparous Endometriosis, gestational diabetes,
versus multiparous women with/without endometriosis. neonatal complications, pPROM,
Methods: Multicentric, observational and cohort study on a group of Caucasian pregnant pregnancy outcome, preterm birth,
women (n ¼ 2239) interviewed during their hospitalization for delivery in five Italian small for gestational age
Gynecologic and Obstetric Units (Siena, Rome, Padua, Varese and Florence).
Results: Primiparous women with endometriosis (n ¼ 219) showed significantly higher risk of History
For personal use only.

small for gestational age fetuses (OR: 2.72, 95% CI 1.46–5.06), gestational diabetes (OR: 2.13,
95% CI 1.32–3.44), preterm premature rupture of membranes (OR: 2.93, 95% CI 1.24–6.87) and Received 3 July 2014
preterm birth (OR: 2.24, 95% CI 1.46–3.44), and were hospitalized for a longer period of time Revised 13 September 2014
(p50.0001) comparing with control group (n ¼ 1331). Multiparous women with endometriosis Accepted 21 September 2014
(n ¼ 97) delivered significantly more often small for gestational age fetuses (OR: 2.93, 95% CI Published online 9 October 2014
1.28–6.67) than control group (n ¼ 592). Newborns of primiparous women with endometriosis
needed more frequently intensive care (p ¼ 0.05) and were hospitalized for a longer period of
time (p50.0001).
Conclusions: Women with endometriosis at first pregnancy have an increased risk of impaired
obstetric outcome, while a reduced number of complications occur in the successive gestation.
Therefore, it is worthy for obstetricians to increase the surveillance in nulliparous women with
endometriosis during pregnancy.

Introduction whether these abnormalities may impair decidualization

and placentation during pregnancy [5]. Since these processes
Endometriosis is a benign gynecologic disease, affecting up to
may be crucial for pregnancy implantation and development,
10% of the women during their reproductive life, with an
it was hypothesized that pregnancy outcome may be
increasing incidence [1]. The ectopic localization of endo-
affected in women with endometriosis [6]. Nevertheless,
metrial tissue outside uterus causes two main symptoms, pain
studies on the relationship between endometriosis and preg-
and infertility, but endometriosis is associated with significant
nancy outcome are conflicting, with some studies reporting an
deterioration of quality of life and represents a significant
increased risk of complications (preterm birth, preeclampsia
public health issue [2]. Indeed, women with endometriosis
and antepartal bleeding/placental complications) [6–10] and
show an increased incidence of gastrointestinal, urinary and
others showing some (placenta previa) [11] or no association
psychiatric disorders with long-term implications on auto-
[12–15]. However, these studies followed different criteria,
immune or cancer risk [3].
mostly evaluating retrospectively large databases from birth
It is well accepted that endometrium of women with
register [6] or from infertile women undergoing pregnancy
endometriosis is abnormal [4] while the debate is open
with or without assisted reproductive technology (ART)
[8,10,12,13]. No studies distinguished the parity of these
women.
Address for correspondence: Felice Petraglia, MD, FRCOG, Obstetrics The present study aimed to evaluate, during the time of
and Gynecology Unit, Department of Molecular and Developmental
hospitalization, pregnancy, delivery and neonatal complica-
Medicine, University of Siena, S. Maria alle Scotte, viale Bracci 53100,
Siena, Italy. Tel: +39 0577 233.453. Fax: +39 0577 233.454. E-mail: tions in women with endometriosis achieving first or second
felice.petraglia@unisi.it pregnancy.
 2 N. Conti et al.
Methods
This is a multicentric, observational and cohort study,
including a group of Caucasian singleton pregnant women
(n ¼ 2239) attending five Italian Gynecologic and Obstetric
Units: Siena, Rome, Padua, Florence and Varese. The
permission of the Local Human Investigation Committee
was granted for the study. All women were studied after
delivery during the post-partum hospitalization, collecting
informations about gynecological and reproductive history
and data on the ongoing pregnancy, delivery and neonatal
outcome. The study group consisted of women who presented
a history of endometriosis (n ¼ 316), distinguishing primiparas
(n ¼ 219) and multiparas (n ¼ 97). The diagnosis of endo-
metriosis had been confirmed before first pregnancy by
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pathology following surgical removal of the lesions, resulting
ovarian (35%), mixed ovarian and peritoneal (25%), mixed
ovarian and deep (21%) and deep endometriosis (19%).
Data on the time interval between surgery and pregnancy
and between first and second pregnancy, as well as the
other medical treatment, were not collected. As control group
(n ¼ 1923) all other women were included, subdivided
into primiparas (n ¼ 1331) and multiparas (n ¼ 592) accord-
ing to the present state. Exclusion criteria were endocrine,
autoimmune, systemic diseases such as hypertension or
diabetes and uterine disorders for both groups.
Obstetric complications were: small for gestational age
fetuses (SGA) (condition in which the fetus fails to reach
For personal use only.
his potential growth and birth weight is below the 10th centile
for gestational age), gestational hypertension (systolic
blood pressure over 140 mmHg or diastolic blood pressure
over 90 mmHg, developing after 20 weeks of gestation),
preeclampsia (hypertension developing after 20 weeks of
gestation with proteinuria), gestational diabetes (carbohydrate
intolerance with onset or recognition in pregnancy, with
positive oral glucose tolerance test), premature rupture of
membranes (pPROM) (rupture of membranes before 37
weeks of gestation) and spontaneous preterm birth (PTB)
(live birth before 37 completed weeks of gestation after
spontaneous labor).
At delivery data were collected on gestational age,
prelabor rupture of membranes (PROM), mode of delivery
(spontaneous vaginal delivery, operative vaginal delivery
and caesarean section), post-partum hemorrhage (blood loss
estimated to be 4500 ml within 24 h of vaginal delivery
or 4750 ml after caesarean section) and days of maternal
hospitalization. Data collected on neonates were: weight at
birth, sex, neonatal intensive care unit (NICU) admission and
days of hospitalization.
Statistical analysis
Analysis of data was performed using MedCalcÕ Package
(Version 12.4.0.0). Statistically significant differences were
determinated using Student’s t-test, Mann–Whitney U test or
Fisher’s exact test as appropriate. Logistic regression was
used to calculate odds ratio (OR), presented with 95%
confidence intervals (CI) to evaluate the association between
endometriosis and obstetrics complications, before and after
adjustment for infertility and use of ART. p values less than
0.05 were considered to indicate statistical significance.
J Matern Fetal Neonatal Med, Early Online: 1–4
Results
Cases and controls had no statistically significant differences
in terms of age, pregravidic and gravidic BMI both in
primiparous and multiparous women. Undergoing ART was
more common in women with endometriosis versus controls
both at first gestation (35.0% versus 5.8%) and subsequent
gestations (15% versus 4.1%) (p50.01). Multivariate analysis
did not show any influences of ART on pregnancy, delivery
and neonatal outcome.
Women with endometriosis at first pregnancy showed
significantly higher incidence of SGA (p ¼ 0.002), with
10.6% versus 4.1% and OR of 2.72. Pregnant women
affected by endometriosis at first pregnancy showed a rate
of 13.3% of gestational diabetes versus 6.7% in healthy ones
(p ¼ 0.002) with OR 2.13. The OR for pPROM and PTB in
primiparas affected by endometriosis was 2.93 (p ¼ 0.001)
and 2.24 (p ¼ 0.0005), respectively. Compared with women
without endometriosis, women at first pregnancy
delivered approximately one week before healthy con-
trols, with a median of 39 weeks of gestation (p ¼ 0.0002)
and were hospitalized for a longer period of time (p50.0001)
(Table 1).
Newborns of women with endometriosis at first pregnancy
needed more frequently NICU (p ¼ 0.05), with a OR 1.86 and
were hospitalized for a longer period of time (p50.0001)
(Table 1), because of a high incidence of prematurity (35%)
and defective fetal growth (28%). Multiparous women with
endometriosis showed significantly more often SGA
(p ¼ 0.001) with a OR 2.93 (Table 1).
Discussion
The present study showed that women with endometriosis at
first pregnancy have more complications than in the subse-
quent gestations, with greater risk of SGA babies, gestational
diabetes, pPROM and PTB, with longer hospitalization
both for mother and neonate. When women with endometri-
osis had a second pregnancy they showed a reduced risk,
however, with prolonged maternal and neonatal hospitaliza-
tion. Therefore, in case of endometriosis at first pregnancy
should require more surveillance: an information which may
be useful to the endometriosis patients and to the obstetricians
to do a better counselling and make clinical decisions.
An increased incidence of adverse pregnancy outcome fits
with previous retrospective cohort study from a Swedish
Register showing that women with endometriosis showed an
increased incidence of PTB, preeclampsia and antepartal
bleeding/placental complications [7]. Also in agreement
with our data are the ART patients who showed that women
with ovarian endometriosis had an increased rate of PTB
and SGA babies [8]. Conversely, other studies have shown
no association with adverse obstetric outcomes both in
pregnancies achieved with IVF [13] and in those with
spontaneous conception [14] or mix population [11,12]. Our
study neither observed the decrease in risk of preeclampsia
[15,16], nor the increased incidence of hypertensive dis-
orders [7]. The possible explanation for the different results
are: (1) the different methods (database versus interviews) and
(2) the distinction between first and second pregnancy after a
history of endometriosis.
 DOI: 10.3109/14767058.2014.968843 Endometriosis and obstetric outcome 3
Table 1. Pregnancy, delivery and neonatal outcomes in first pregnancy and subsequent pregnancies, in women with or without endometriosis, including
percentage, for binary variables, median, for quantitative variables and odds ratio (OR) and related confidence intervals (CI) of statistically significant
(p50.05) variables.

First pregnancy Subsequent pregnancy

Endometriosis No endometriosis Endometriosis No endometriosis
(n ¼ 219) (n ¼ 1331) OR 95% CI (n ¼ 97) (n ¼ 592) OR 95% CI
Selected conditions in pregnancy
Small for gestational age fetus 10.6 4.1 2.72 1.46–5.06 10.5 3.8 2.93 1.28–6.67
(SGA) (%)
Gestational hypertension (%) 3.7 5.8 1.1 4.2
Preeclampsia (%) 2.2 1.2 1 0.5
Gestational diabetes (%) 13.3 6.7 2.13 1.32–3.44 11.6 9.7
Premature rupture of membranes 3.6 1.2 2.93 1.24–6.87 2.5 1.5
(pPROM) (%)
Preterm birth (%) 17.8 8.8 2.24 1.46–3.44 8.2 8.8
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Delivery
Induction of labour (%) 16.0 19.9 7.2 11.5
Prelabor rupture of membranes 32.2 28.2 20.0 27.3
(PROM) (%)
Caesarean section (%) 29.1 25.3 17.8 16.9
Gestational age at delivery (ws) 39 40 39 39
Operative vaginal delivery (%) 3.4% 3.0% 2.7% 2.5%
Post-partum haemorrage (%) 9.4 7.8 9.3 10.2
Days of hospitalization (days) 4 3 3.3 3.0
Neonatal outcome
Neonatal gender 47.4 versus 52.6 versus 49.5 versus 50.5 versus
(Male versus Female) (%) 49.6 47.4 50.5 49.5
Neonatal weight (g) 2905 ± 317 3150 ± 320 3240 ± 614 3240 ± 552
NICU admission (%) 7.7 4.9 1.86 1.06–3.28 6.1 5.1
Days of hospitalization (days) 4 3 3.2 3
For personal use only.

The mechanism of action of endometriosis in determining
an adverse pregnancy outcome may be an abnormal endo-
metrium, resulting in suboptimal endometrial receptivity and
impaired placentation during first pregnancy, even though no
study has yet been performed on placenta from women with
endometriosis [5]. However, this hypothesis of defective
placentation is valid for explaining reduced fetal growth and
an increased risk of SGA [8]. The increased incidence of PTB
related to endometriosis may be explained by a chronic
inflammation state, which is common in endometriosis and
PTB [17]. Increased expression of inflammatory pathways in
the endometrium of endometriosis (corticotropin-releasing
hormone [18], growth factors and cytokines [19]) are the
same factors implicated in decidua and trophoblast of PTB
[20]. A major hormonal change common in endometriosis and
PTB is progesterone receptor (PR) isoforms A more expressed
than PR-B [21,22]. In endometriosis, the promoter of PR-B is
hypermethylated in concomitance with reduced PR-B expres-
sion [23] as well as in PTB [24].
The increased incidence of pPROM in women with
endometriosis at first pregnancy is related to a physical/
microbial inflammatory event weakening fetal membranes
and increasing prostaglandins (PGs), causing collagen deg-
radation within fetal membranes, also through the action
of metalloproteinases (MMP-9) and collagenase [25]; in
women with endometriosis increased levels of PGs and
inflammatory cytokines locally activate MMP-9 and matrix-
degrading enzymes and are responsible for the invasiveness
of lesions [26,27].
The state of chronic, low-grade subclinical inflammation
may also explain the increased incidence of gestational
diabetes in primiparous women with endometriosis [28].
Women with endometriosis at first pregnancy and their
neonates had a longer hospitalization. The higher need for
NICU admission and the longer hospitalization are related to
a higher incidence of prematurity and defective fetal growth.
Previous studies showed an increased incidence of post-
partum hemorrhage in endometriosis, even though adjusting
for confounding factor such as IVF [11,29]. Aberrant
expression of integrins and HOX-genes [30–32] provide a
rationale for the increased risk of placental complications
observed [11,29].
Pregnancy, delivery and neonatal complications showed
in women with endometriosis at first pregnancy disappear
in the successive one, suggesting an important role of
pregnancy in inducing hormonal and immunological modifi-
cations. All women at first pregnancy showed higher rates of
maternal, obstetrical and neonatal complications, with a
higher tendency to gestational hypertension/preeclampsia,
intrauterine growth retardation and preterm birth [33]. The
beneficial effect of a natural pregnancy on endometriosis
has been well established for a long time [34] and this is the
first study to show an effect of pregnancy in endometriosis
influencing positively the outcome of subsequent gestations.
Specific local or systemic antepartum hormonal changes
including steadily rising serum levels of progesterone during
pregnancy may be the cause of an improvement of most
cases of endometriosis [35], probably reducing the hyperin-
flammatory state at the basis of pregnancy complications
endometriosis-induced. However, because of the low number
of women and the lack of information on the management
of endometriotic patients between surgery and pregnancy,
a prospective large study will be necessary to confirm our
observations.
 4 N. Conti et al.
In conclusion, the rate of obstetrics disorders was signifi-
cantly higher during first pregnancy, while these conditions
did not occur in second pregnancy of multiparous women.
This observation suggests a protective role of pregnancy in
endometriosis towards subsequent pregnancies, probably
through hormonal and immunological modification. As
consequence, the patient with endometriosis achieving first
pregnancy should be considered at increased risk. Further
studies will elaborate the possible measures to suggest to
these patients in order to reduce the risk. The clear message
is that a link between endometriosis and current pregnancy
exists, and that these gynecological patients require an
accurate obstetric care.
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Declaration of interest
This study was in part supported by MIUR Grant entitled
‘‘Preterm birth: molecular, biochemical and biophysical
markers of the feto-placental unit’’ (prot.20102CHST5).
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