A case-control study of polymorphic

eruption of pregnancy
Stephanie Regnier, MD,a Virginie Fermand, CNM,b Pierre Levy, MD,c
Serge Uzan, MD,b and Selim Aractingi, MDa
Paris, France

Background: Polymorphic eruption of pregnancy (PEP) is a pruritic disease that usually occurs in
primiparous women, most commonly in the last trimester of pregnancy. The origin and pathomechanisms
still remain unknown.

Objectives: We attempted to determine the parameters that may be associated with or complicate the
course of PEP.

Methods: Data of 200 pregnant women (40 PEP and 160 control) were studied retrospectively and
compared statistically using univariable and multivariable analysis.

Results: In multivariate analysis, pregnancy with male fetuses (P = .02) and delivery by cesarean section
(P = .012) were overrepresented in the PEP group. A tendency toward more multiple gestation pregnancy
in PEP was found (P = .07). The risk of PEP was not related to excessive maternal or fetal weight gain.

Limitations: This was a retrospective study.

Conclusion: This large case-control study confirms the already suspected association of PEP with male
fetuses and cesarean deliveries in multivariate analysis. The higher rate of multiple gestation pregnancy
was also established. ( J Am Acad Dermatol 2008;58:63-7.)

n 1983, Holmes and Black1 proposed the classi-

I
fication of several unexplained dermatoses
of pregnancy pruritic urticarial papules and
plaques of pregnancy, toxemic rash of pregnancy,
early- and late-onset prurigo of pregnancy, Spangler
papular dermatitis, and toxic erythema of pregnancy
under the term ‘‘polymorphic eruption of preg-
nancy’’ (PEP). This entity is characterized by the
development of pruritic disseminated cutaneous
lesions commonly appearing during the third
From the Departments of Dermatology,a Obstetrics and Gyneco-
logy,b and Biostatistics,c Hôpital Tenon (Assistance Publique-
Hôpitaux de Paris), Unité de Formation et de Recherche Pierre
et Marie Curie, Paris 6, Université Pierre et Marie Curie.
Funding sources: None.
Conflicts of interest: None declared.
Accepted for publication August 9, 2007.
Reprint requests: Stephanie Regnier, MD, Pavillon Tarnier-Hôpital
Cochin, 89 rue d’Assas, 75006 Paris, France. E-mail: stephanie.
regnier@cch.aphp.fr.
Published online September 17, 2007.
0190-9622/$34.00
ª 2008 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2007.08.015
trimester of pregnancy. The eruption is most fre-
quently seen in primigravidas and usually presents
on the abdomen, frequently within the striae dis-
tensae.1-6 Cutaneous lesions are mainly urticarial but
vesicular or target lesions may also be seen. The PEP
incidence is 0.4% to 0.8% of pregnant women.1,3 The
origin and the pathogenesis of the disease still remain
unknown. We have conducted a retrospective clin-
ical case-control study of 40 patients with PEP and
160 pregnant control subjects to investigate the
obstetric and fetal factors that could be associated
with the development of PEP.
METHODS
The files of 40 patients who were given the
diagnosis of PEP and were followed up in our
institution between January 1994 and June 2001
were examined. The diagnosis of PEP was made
according to the classification of Holmes and Black.1
The patients included in the study had a skin pruritic
eruption occurring during the second or third trimes-
ter of pregnancy or during the first 4 weeks postpar-
tum, and had: (1) cutaneous lesions consisting of

63
64 Regnier et al J AM ACAD DERMATOL
JANUARY 2008

Table I. Obstetric characteristics of the population Whitney test for continuous variables). A multivariate
studied nonconditional logistic regression model was then
PEP Control
performed including the above-described covari-
ables when they reached a level of P value below
No. of cases 40 160
.20 in univariate analyses, in a stepwise backward
Primiparous 23 (57.5%) 70 (43.7%)
Para 2 12 (30%) 41 (25.6%) selection process. In the final step, only those for
Para 3 3 (7.5%) 27 (16.9%) which the P value was below .05 were considered as
Para [3 2 (5%) 22 (13.7%) independent variables. Because the patients were
Primigravida 16 (40%) 49 (30.6%) treated using gold-standard routine procedures,
Gravida 2 13 (32.5%) 38 (23.7%) without any additional interventions or testing, no
Gravida 3 6 (15%) 34 (21.3%) formal ethical committee approval regarding
Gravida [3 5 (12.5%) 39 (24.4%) European procedures was needed.
PEP, Polymorphic eruption of pregnancy.
RESULTS
Forty women presented with PEP during the study
period and another 160 healthy pregnant women
fixed urticarial lesions, sometimes associated with without skin disease were randomly selected as
vesicles or eczematous plaques (2) without any other control subjects.
demonstrable cause (eg, drug-induced reaction, During the study period, 16,476 women gave birth
contact or atopic dermatitis, infection, or other der- in the institution. The average age of the patients in
matoses of pregnancy); and (3) negative direct the PEP group and of the matched control subjects
immunofluorescence results for exclusion of a ges- was 31.2 years (range: 19-41 years). PEP appeared at a
tationis pemphigoid.1 All 40 patients with PEP were mean gestational age of 32 weeks of amenorrhea (15
seen by at least one author of the study. postpartum). As expected, PEP was more frequent in
The control subjects were randomly selected from the third trimester (30/40; 75%). Four patients were
the clinical files of women who gave birth in the same given the diagnosis of PEP in the second trimester
institution, at a ratio of 4:1 (160 pregnant women). (4 of 40; 10%), at 15 (n = 1), 17 (n = 1), and 19 (n = 2)
These control subjects were matched to the PEP weeks of amenorrhea, and 6 patients during the first
group according to year of delivery and maternal age. 4 weeks postpartum (6 of 40; 15%).
For each of these patients and control subjects, the The following data were initially analyzed by
following clinical and obstetric parameters were univariate analysis and are summarized in Tables I
analyzed: gravidity (defined as the number of times and II. In all, 23 women with PEP (57.5%) and 70 of
that a woman had been pregnant including early the control subjects (43.7%) were primiparous (P =
miscarriages, elective terminations, and ectopic preg- .13). Likewise, 16 women in the PEP group (40%)
nancies), parity (defined as the number of deliveries and 49 of the control group (30.6%) were primigrav-
at beyond 24 weeks of gestation), multiple gestation idas (P = .07). We noted an occurrence of 15% (6/40)
pregnancy, maternal weight gain during pregnancy, of multiple gestation pregnancies (5 twins and a
gestational age at delivery, delivery by cesarean triplet pregnancy) in the PEP group. There was only
section, prematurity (defined as delivery before the 3.1% (5/160) of multiple gestation pregnancies in the
completion of 37 weeks of amenorrhea), neonatal sex control subjects (all twins) (P = .009). Of the 5 twin
and birth weight, and other pregnancy complications pregnancies in the PEP group, two involved an
(pregnancy-induced hypertension, threatened pre- unexplained intrauterine demise of one twin, at 28
term labor, gestational diabetes). The number of and 36 weeks, respectively. No intrauterine demise
admissions (defined as an overnight stay) for indica- was recorded in the control group.
tions other than PEP was also included in the study. The mean maternal weight gain throughout preg-
In the PEP group, the gestational age at the onset of nancy (including women with multiple pregnancies)
the disease was recorded. was 13.9 6 4.7 kg for patients with PEP and 12.2 6 4.7
Finally, the sum of the collected data included 200 kg for control subjects (P = .055). The mean gesta-
women who delivered a total of 210 neonates. tional age at delivery was 38 weeks for both groups. A
preterm delivery (before 37 weeks of amenorrhea)
Statistical analysis occurred in 18.4% of patients with PEP (7 of 38) and in
Software (Statview 5.0, SAS Institute, Cary, NC) only 5.8% of control subjects (9 of 154; P = .02).
was used for the statistical analysis. Statistical evalu- The mean newborn weight was similar in both
ation was performed using univariate analyses groups (P = .13). In the PEP group, 64.5% of women
(Fisher’s test for dichotomous variables and Mann- delivered a male baby (29 of 45) compared with 48.5%
J AM ACAD DERMATOL Regnier et al 65
VOLUME 58, NUMBER 1

Table II. Univariate analysis of maternal-fetal informations and comorbidity

PEP Control P value
Parity, mean 1.8 6 1 2.1 6 1.4 .13
Gravidity, mean 2.2 6 1.5 2.7 6 1.8 .07
Maternal weight gain, mean 13.9 6 4.7 12.2 6 4.7 .055
Newborn birth weight, mean 3.03 6 0.7 3.2 6 0.5 .13
No. of hospitalisations 1.2 6 0.9 0.4 6 0.6 \.0001
Multiple gestation pregnancy 6/40 (15%) 5/160 (3.1%) .009
Prematurity (8 lost data) 7/38 (18.4%) 9/154 (5.8%) .02
Male fetuses (210 newborn) 29/45 (64.5%) 80/165 (48.5%) .06
Cesarean section 16/40 (40%) 21/160 (13.1%) \.0001
Hypertension 7/40 (17.5%) 12/160 (7.5%) .06
Threatened premature labor 7/40 (17.5%) 21/160 (13.1%) .47
Gestational diabetes 9/40 (22.5%) 9/160 (5.625%) .0027

PEP, Polymorphic eruption of pregnancy.

of control subjects (80 of 165 ; P = .06). Interestingly,
the number of cesarean sections in the PEP group
(16/40, 40%) was significantly higher than in the
control group (21/160, 13.1% ; P = .0001). The precise
reasons for cesarean section were retrieved in 13 of
16 cases and consisted in inadequate progression of
labor (n = 4), breech presentation (n = 2), previous
uterine scar (n = 1), fetal-pelvic disproportion (n = 1),
fetal bradycardy (n = 2), macrosomia (n = 1), unsuc-
cessful induction of labor (n = 1), and pre-eclampsia
and nonreassuring fetal heart rate (n = 1).
The incidence of pregnancy-induced hyperten-
sion and threatened premature labor was not differ-
ent between the two groups, whereas gestational
diabetes appeared to be overrepresented in PEP
group (P = .027).
Number of pregnant women admitted to hospital
(excluding PEP admission) was significantly higher
in the PEP group (P \.0001).
In the final multivariate model, only 3 parameters
were significantly associated with PEP (Table III):
presence of a male fetus (P = .026); delivery by
cesarean section (P = .002); and number of admis-
sions (P = .032).
The level of multiple gestation pregnancies was
higher in patients with PEP than in control subjects
(odds ratio: 3.5, 0.8-14.6), but this difference did not
reach significance (P = .07).
DISCUSSION
Using multivariate analysis in this case-control
study, our results showed that PEP was associated
with a higher prevalence of male babies, and a greater
incidence of cesarean section. Hospital admissions
(for nondermatologic conditions) and multiple ges-
tation pregnancies were also more frequent in the
PEP group. The incidence of PEP in single pregnancy
Table III. Final multivariate nonconditional logistic
regression model
Odds ratio,
adjusted 95% CI P
Female 0.4 0.2; 0.9 .041
Cesarean 3.3 1.4; 7.9 .005
No. of hospitalizations 2.6 1.6; .2 .0001
(coded as a continuous
variable)
CI, Confidence interval.
is reported in the literature as 1 in 200 (0.5%). In our
study, the incidence of PEP appears to be 0.25%,1,3 In
our institution, all the pregnant women with skin
lesions are referred to our clinic. However, women
presenting with milder skin conditions (eg, discrete
cutaneous lesions) may have not been referred to a
dermatologist and a bias toward more severe PEP
could have resulted in this series. In this study, we
used strict criteria for the diagnosis of PEP consisting
of the classic clinical signs and symptoms and neg-
ative direct immunofluorescence finding to exclude
nonblistering gestational pemphigoid.3,6,7 In addi-
tion, this was a monocentric study where all women
were examined by the same two dermatologists (S. R.
and S. A.) who always used the same diagnostic
criteria. The time of PEP onset was analogous to
previous studies by Roger et al,3 Aronson et al,5
Vaughan Jones et al,6 Holmes,8 and Rudolph et al.9
As previously described, PEP predominantly af-
fects primiparous women (57.5%) in the third tri-
mester of pregnancy (75%).1-6
The association of PEP with male fetal sex has
already been described but these studies locked
matched-control subjects.6,10 The significance of
such male preponderance remains unexplained.6,10
66 Regnier et al
In the study by Holmes8 more female than male
fetuses (58%) were associated with PEP. The higher
rate of male fetuses in women with PEP found in
multivariate analysis remains an unanswered phe-
nomenon that is not reported in other diseases
linked to pregnancy such as gestational diabetes
mellitus or intrahepatic cholestasis. The predomi-
nance of male fetuses in pregnancy-induced hyper-
tension was suggested once, but not confirmed in
a more recent study.11,12 Interestingly, Ohel et al13
have reported that hypertensive disorders were sig-
nificantly associated with PEP. In our study, we noted
a higher rate of pregnancy-induced hypertension
in the PEP group, although that was not statistically
significant.
Surprisingly, we found that PEP was significantly
associated with a greater risk of cesarean section
(40%, 16/40). Indications for cesarean section in the
PEP group were mainly inadequate progression of
labor (4/13). Previously, Yancey et al10 noted two
cesarean sections in a group of 20 patients with PEP
and more recently Ohel et al13 noted higher rates of
cesarean delivery in PEP but these data were not
identified as independent factors associated with PEP.
Mascaro et al14 have previously reported similar
results in pregnant women with herpes gestationis,
another specific skin disease of pregnancy. The
reason for these cesarean sections was not given.
Of note, control matching did not take into account
past obstetric events that may influence some of the
reasons for cesarean sections.
Multiple gestation pregnancies were more fre-
quent in the PEP group (15%) than in control group
(3.1%), but this difference was about to reach signif-
icance in the multivariate analysis (P = .07). The rate
estimated in our study is increased as compared with
that reported by Cohen et al4 (10%), Roger et al2 (9%),
and Ohel et al,13 but was similar to the results of
Vaughan Jones et al,6 Rudolph et al,9 or Kroumpouzos
and Cohen.15 Cohen et al4 have suggested that
abdominal skin distention or factors related to it may
play a role in the development of PEP. They found a
significantly higher incidence of PEP with increased
maternal weight gain and newborn birth weight, and
an increased twin rate.4
Some authors had proposed that mechanical
distention of the skin could be implicated in its
pathogenesis because women presenting with PEP
were more frequently primiparae with increased
maternal and fetal weight gain when compared
with control subjects.4 However, this result was not
confirmed.2,6 Abdominal wall distention is higher in
multiple gestation pregnancies. As in other studies,
we did not find an increased maternal or newborn
weight gain in women with PEP.2,9 Maternal weight
J AM ACAD DERMATOL
JANUARY 2008
gain showed a strong trend with PEP on univariate
analysis only (P = .055).
Finally, another unsuspected result was that
women with PEP were more often admitted to
hospital, for various reasons other than skin symp-
toms. These were various and included gestational
diabetes, threatened premature labor, or pre-
eclampsia (P = .032). However, none of these
diseases appeared frequent enough in the analysis
to be significantly associated with PEP. These results
do not rely on any easy explanation and should
be re-evaluated in future studies. As previous case-
control studies on PEP did not target hospital admis-
sions, these original data are not in contradiction
with previous literature.
Conclusion
PEP is relatively common in comparison with
other dermatoses occurring during pregnancy. The
association of PEP with multiple gestation preg-
nancy and male babies was described and con-
firmed here. In addition, an increased risk of
cesarean section appears possible although remains
unexplained.
REFERENCES
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VOLUME 58, NUMBER 1

12. Toivanen P, Hirvonen T. Sex ratio of newborns: preponderance
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