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Gynecological Endocrinology
ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20
Neurodevelopmental disorders in children
exposed in utero to synthetic progestins: analysis
from the national cohort of the Hhorages
Association*
Marie-Odile Soyer-Gobillard, Laura Gaspari, Philippe Courtet, Mauricette
Puillandre, Françoise Paris & Charles Sultan
To cite this article: Marie-Odile Soyer-Gobillard, Laura Gaspari, Philippe Courtet, Mauricette
Puillandre, Françoise Paris & Charles Sultan (2019): Neurodevelopmental disorders in children
exposed in�utero to synthetic progestins: analysis from the national cohort of the Hhorages
Association*, Gynecological Endocrinology, DOI: 10.1080/09513590.2018.1512968
To link to this article: https://doi.org/10.1080/09513590.2018.1512968
Published online: 09 Jan 2019.
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ORIGINAL ARTICLE
Neurodevelopmental disorders in children exposed in utero to synthetic
progestins: analysis from the national cohort of the Hhorages Association
Marie-Odile Soyer-Gobillard
a,b
, Laura Gaspari
c
, Philippe Courtet
d
, Mauricette Puillandre
b
, Franc¸oise Paris
c
and
Charles Sultan
c
a
Centre National de la Recherche Scientifique, Sorbonne University, Universit
e P. et M. Curie (Paris 6), France;
b
Association HHORAGES-France
(Halte aux HORmones Artificielles pour les GrossessES), Asni
eres sur Oise, France;
c
Service de P
ediatrie I, Unit
ed’endocrinologie et gyn
ecologie
p
ediatrique, Universit
e de Montpellier, France;
d
D
epartement d’urgence et Post urgence Psychiatrique, CHU Montpellier and Universit
ede
Montpellier, Montpellier, France
ABSTRACT
The medical and scientific communities have not yet fully acknowledged the undesirable effects of the
synthetic hormones that have been administered to pregnant women for decades. The somatic effects of
in utero exposure to diethylstilbestrol (DES), such as genital malformations, infertility, and cancer, have
long been recognized but this has not been the case concerning psychiatric disorders. The progestins
used in contraception and hormone replacement therapy are known to affect the adult brain, but no
data exist on their effects due to in utero exposure of children. The Hhorages Association, a national
patient support group, has assembled a cohort of 1200 women who took synthetic hormones during
pregnancy. These women had a combined 1934 children. We obtained full questionnaire responses from
46 women treated with progestins only –and not an estrogenic cocktail –who gave birth to 115 chil-
dren. Three groups were observed: Group 1 (n¼18): firstborn unexposed children, Group 2 (n¼62): chil-
dren exposed in utero to synthetic progestins, and Group 3 (n¼35): children born after a previous
pregnancy treated with progestins. No psychiatric disorders were reported in Group 1 and the incidence
of psychiatric disorders was drastically elevated in Group 2. Our work shows a striking increase in psychi-
atric disorders among children exposed in utero to progestins and strongly suggests that prenatal expos-
ure is associated with a high risk of psychiatric disorders in adolescence and adulthood, whether
accompanied or not by disorders of sex development.
ARTICLE HISTORY
Received 11 July 2018
Accepted 13 August 2018
Published online 10 January
2019
KEYWORDS
Adolescence; adulthood;
prenatal progestin
exposure; psychi-
atric disorders
Introduction
Neuroactive steroids like progesterone play an important role in
shaping the CNS structure and function (neurodevelopment,
neurogenesis, and cognition) throughout the lifespan. Progesterone
exerts powerful effects on the brain, such as regulation of neuro-
genesis and astroglial and synaptic plasticity. Moreover, it regulates
the development of neuronal types like Purkinje cells and oligoden-
drocytes, as well as the myelinization process. Progesterone exerts a
significant influence on the activity of several neurotransmitters
involved to the pathophysiology of psychosis, including the dopa-
minergic, glutamatergic and GABAergic systems. In addition to
progesterone itself, it can be converted to dehydroprogesterone and
then allopregnanolone (or iso-pregnanolone) [1], potent ligands of
the GABA-A receptor. Progesterone elicits its effects by gene tran-
scription, mediated by nuclear progesterone receptors, as well as by
non-genomic mechanisms through the activation of a signal trans-
duction pathway. Preclinical studies have provided hints that neu-
rosteroids might be involved in the pathophysiology of psychosis.
Severe psychiatric disorders were recently documented in chil-
dren exposed in utero to synthetic estrogens like diethylstilbestrol
(Distilbene
V
R
, DES) and ethinyl estradiol (EE) [2–4]. The actions
of these estrogens involve epigenetic mechanisms [5] and espe-
cially differential specific methylations, which were found on the
genes ZPF57 and ADAMTS9 in young psychotic patients
exposed in utero to DES [6]. In this recent work, the authors
suggested that in exposed individuals, ZFP57 gene methylation
may be associated with psychosis. The ADAMTS9 gene is impli-
cated in the control of organ shape, especially the development
and function of the uterus and reproductive organs [7], which
are often abnormal after in utero DES exposure, as well as in the
control of CNS development [8] and several kinds of cancer [9].
Synthetic progestins, widely used for contraception or hormo-
nal replacement therapy, are known to impact the adult brain
[10–11], but no data exist on the postnatal effects after in utero
exposure. The aim of this work was to determine whether pre-
natal exposure to synthetic progestins is a risk factor for psychi-
atric disorders in adolescence or adulthood.
Material and methods
Our clinical data were collected from 1200 families (1934 chil-
dren) involved in the French Hhorages Association (Halt to
CONTACT Marie Odile Soyer-Gobillard mog66@orange.fr Centre National de la Recherche Scientifique, Universit
e Paris 6 and Association HHORAGES-France,
95270 Asni
eres sur Oise, France, Asni
eres sur Oise 95270, France
Association Registered on the Epidemiological Portal of French Health Databases INSERM (French National Institute for Medical Research) and AVIESAN (National
Alliance for Life Sciences and Health) (epidemiologie-france.aviesan.fr).
This work was presented as an oral communication during the European Congress of Gynaecology, Barcelona, 2017.
ß2019 Informa UK Limited, trading as Taylor & Francis Group
GYNECOLOGICAL ENDOCRINOLOGY
https://doi.org/10.1080/09513590.2018.1512968
Synthetic Hormones for Pregnancies), a patient support group,
using a detailed questionnaire drawn up by practitioners and
researchers as described in previous papers [2,3]. We included
questions on patient sex, rank among siblings, exposure during
gestation, and somatic and psychiatric disorders of the descend-
ants. Most families had children exposed to either estrogens
alone or cocktails of estrogens and progestins, but only 46 fami-
lies (115 children) had at least one child exposed to one or more
progestins prescribed alone, without estrogens. In the extensive
questionnaires (Registration number to French National
Commission of Computer Science and Freedom, CNIL
n1006460), we obtained the family history, including the moth-
er’s hormone treatment before and during pregnancy, and the
medical records of the children’s health problems, including
diagnoses, prescriptions and treatments and/or hospitalizations.
The psychiatric disorders reported in the questionnaires were
classified as schizophrenia, bipolar disorders (maniac-depressive
psychosis), severe depression, behavior disorders, aggressiveness,
and eating disorders. The diagnoses had been made by experi-
enced psychiatrists and the patients received appropriate drugs
and psychotherapy with or without hospitalization in specialized
institutions. When suicides or suicide attempts were reported, a
second questionnaire validated by members of the Research
Group on Suicide (CHU Lapeyronie Montpellier) was sent to
the families.
From the questionnaires completed by the families and
returned to the Hhorages Association, it appears that one or sev-
eral progestins were prescribed and administered to pregnant
mothers as shown in the numerous conserved medical prescrip-
tions. The prescribed pharmaceuticals were: 17a-hydroxyproges-
terone caproate (synthetic progestin, SP): 32 (Note: withdrawn in
2000 but re-authorized in 2011), 17a-hydroxyprogesterone hepta-
noate (SP): 10 (Note: withdrawn in 2002), chlormadinone acetate
(SP derived from hydroxyprogesterone): 11 (Note: withdrawn on
1970), dydrogesterone (6-dehydroprogesterone, synthetic isomer
of progesterone): 4 (Note: against total indication for pregnant
women; not withdrawn), ‘natural progesterone’(derived from
soybean, micronized): 4 (Note: not withdrawn), Norethisterone
Base (SP): 1 (Note: against total indication for pregnant women;
withdrawn in 1998). Total: 62.
Results
In the entire national Hhorages cohort of 1934 children, we
detected 46 families in which at least one child had been exposed
to one or several synthetic progestins.
As shown in Table 1, among the 115 children born from
these 46 mothers, we observed three well-differentiated groups:
Group 1: 18 firstborn unexposed children (9 boys þ9 girls) free
of disorders, Group 2: 62 children exposed to synthetic proges-
tins (40 boys þ22 girls), and Group 3: 35 children (21 boys þ14
girls) born after a previous exposure, free of disorders except 1.
Group 1 þGroup 3 (18 þ35 ¼53 children) served as intra-famil-
ial controls. Among the 62 children exposed to synthetic proges-
tins (see the list of medications in Material and methods), 49
presented psychiatric disorders (79.03%), whereas only 6 (4 boys
þ2 girls) presented somatic disorders alone (9.67%) and 7 (5
boys þ2 girls) presented no disorder (11.29%).
In Group 2, among the 49 patients affected by psychiatric dis-
orders, 10 suffered from both somatic and psychiatric disorders
and 39 from psychiatric disorders alone. Among the psychiatric
disorders, we noted: schizophrenia: 29 (25 boys þ4 girls); severe
depression, bipolar disorder: 16 (6 boys þ10 girls); and behavior
disorders, aggressiveness, eating disorders: 4 (0 boys þ4 girls)
(Table 2). It should be noted that boys mostly suffered from
schizophrenic psychosis (25 boys versus 4 girls), whereas girls
mostly suffered from bipolar disorder (10 girls versus 6 boys).
The questionnaires completed by the families and returned to
the Hhorages Association revealed that one or several progestins
were prescribed and administered to the pregnant mothers, with
the most frequently prescribed drugs being hydroxyprogesterone
caproate, heptanoate alone, or heptanoate in a cocktail with
other progestins.
In Group 3, among the 35 post-exposed children –that is,
born after a previous exposed pregnancy –only one presented a
psychiatric disorder as severe depression.
In Group 2, composed of children exposed to progestins,
schizophrenia (n¼29), and bipolar disorder and severe depres-
sion (n¼16) made up most of the psychiatric disorders, whereas
eating disorders (n¼2) and behavior disorders (n¼2) were less
numerous. Seven series of suicide attempts (a series comprising
between 2 and 15 suicide attempts per person) were also counted
and one death, as shown in Table 3, which presents the psychi-
atric disorders along with their prevalence in the general popula-
tion [12,13].
Discussion
Although selection biases (family–patient association) may some-
what affect the impact of our data, the high prevalence of psychi-
atric disorders in the exposed subjects is quite striking. It should
be noted that the intra-familial controls (18 firstborn unexposed
versus 62 exposed) presented no disease and among the 35 post-
exposed (born after a previous treated pregnancy) only one psy-
chiatric disorder was observed. Among the 115 children born
from 46 families of the Hhorages cohort, 42 unexposed children
had no psychiatric disorders, while of the 62 exposed children,
only 7 were without psychiatric disorders (55 with a disorder).
Table 1. Classification of the three groups of Hhorages children born from 46
families in which at less one child per family has been exposed in utero
to progestins.
115 children
Group 1 Group 2 Group 3
Firstborn unexposed Exposed to synthetic progestins Post-exposed
(n=18) (n=62)n=
35
Psychiatric disorders
0 disorder n=49 (79.03%) n=1
0 disorder n=7 (11.29%)
Somatic disorders only:
n=
6
(9.67%)
Table 2. Total number of psychiatric disorders among the 62 children exposed
to progestins.
Schizophrenia (25 boys, 4 girls) 29
Maniac-depressive psychosis (bipolar disorder), severe
depression (6 boys, 10 girls)
16
Behavior disorders, aggressiveness, eating disorders (0 boys, 4 girls) 4
Somatic disorders only (4 boys, 2 girls) 6
With no disorder (5 boys, 2 girls) 7
Total number of exposed children 62
2 M.-O. SOYER-GOBILLARD ET AL.
As shown in Table 3, our data demonstrate that the prevalence
of psychiatric disorders in patients who were exposed in utero to
progestins was significantly different from the prevalence of the
same disorders in the general population: schizophrenia:
29 ¼46.77% versus 1% in the general population, behavior disor-
ders: 2 ¼3.22% versus 3% in the general population, bipolar dis-
order and severe depression: 16 ¼25.80% versus 6.3% in the
general population, eating disorders: 2 ¼3.22% versus 1.6%, sui-
cides or suicide attempts: 7 ¼11.29% versus 0.3% in the general
population, and death: 1 ¼1.6% versus 0.02% in the general
population. Seven in utero exposed patients (11.29%) presented
no disorder.
We compared our data with the recent results [4] obtained
from the Hhorages cohort in which we analyzed 1002 patients
who were exposed in utero to the synthetic estrogens diethylstil-
bestrol and ethinyl estradiol. Of the 720 patients exposed in
utero, 250 boys and 353 girls showed severe psychiatric disor-
ders: schizophrenia, bipolar disorder, severe depression, behavior
disorders, eating disorders, suicide attempt series (612 ¼85%)
and death (32 ¼4.4%). Psychiatric disorders were the same in
the groups exposed to estrogens or progestins, with minor differ-
ences: for boys, the number of cases of bipolar disorder seemed
less high in patients exposed to progestins than in patients
exposed to synthetic estrogens, with behavior disorders more
prevalent in the latter category. In both categories, schizophrenia
was the most prevalent disorder for boys. For girls, however, the
proportions of psychiatric cases were nearly the same in the two
categories. Bipolar disorder and severe depression were the most
abundant disorders in the two categories.
Cumulative evidence from experimental, hormonal, genetic,
and epidemiological studies suggests a neurodevelopmental ori-
gin of most psychiatric disorders. Environmental disturbances
are known to increase brain disorder risk, interacting with a gen-
etic predisposition. During fetal life, neuronal differentiation,
migration, and interaction are managed by molecular processes,
regulating the dopaminergic, glutamatergic, and GABAergic sys-
tems. While the GABA system is the major inhibitory neuro-
transmitter in postnatal life, GABA-A receptor activation is
excitatory during fetal life. In addition to progesterone itself, pro-
gesterone is converted to dehydroprogesterone and then to allo-
pregnanolone (or iso-pregnanolone), potent ligands of the
GABA-A receptor. These neurosteroids are known to be involved
in neuronal and glial development and plasticity, and the regula-
tion of mood and affection. Any neurodevelopmental disruption
of this system can induce a dysfunction of cell migration and
synaptic integration and may have marked consequences leading
to chronic disability.
The data regarding the impact of synthetic progestins on the
developing brain are currently conflicting. In adults, progestins
have been suggested to exert neuroprotective effects in several
animal models of neurological disease [14]. After two years of
treatment with progestogen via a COC combination (Oral
Contraceptive Combination), impaired social behavior was
observed in female rats [15]. This combination was also able to
alter GABA receptor exposure, increasing the exposure of the
gamma2-subunit in the cerebral cortex and thus affecting anxiety
behavior. According to this group, progestin may alter brain
function in animal models. In 2016, Willing and Wagner [16]
showed that exposure to synthetic progestins during develop-
ment could impair brain function later in life. These authors
noted that many regions of the developing brain are sensitive to
progestins, including the mesocortical dopamine pathway, a
neural circuit important in rats for complex cognitive behavior
later in life. They found that rats exposed to synthetic progestins
during development expressed impaired cognitive flexibility with
increased perseveration later in life. Although this data cannot be
extrapolated to humans, these authors pointed out the risk of
developmental-behavioral effects of synthetics progestins pre-
scribed for pregnant women.
Negative mood symptoms have been reported by Andreen
et al. [17] in women as a result of progesterone during the luteal
phase of the menstrual cycle or progestin in COC. The symp-
toms are believed to be mediated via the action of allopregnano-
lone on the GABA-A system. In male patients with early
psychosis, Belvederi Murri et al. [18] reported a lower level of
progesterone and suggested that this hormone is involved in the
pathophysiology of psychotic disorders. This hypothesis is sup-
ported by the antipsychotic-like effects observed in animal mod-
els of schizophrenia. Recently Slopien et al. [19] reported a
reduction in circulating allopregnanolone levels that correlate
with depressive symptoms. Conversely, healthy women reported
increased anxiety and mood disorders after long-acting subder-
mal implant of progestogens.
In 2011, Guest et al. [20] reported an elevated concentration
of progesterone in a group of 236 first and recent onset of
schizophrenia patients and suggested that steroid hormones
influence brain function, underlying schizophrenia, and major
depressive disorders. Moreover, Buoli et al. found high DHAS
levels in patients with a history of psychotic symptoms, suggest-
ing a role of steroids in the etiology of psychosis and mood dis-
orders [21].
Lastly, citing the French National Agency of Medicine [22],
the independent medical journal ‘Prescrire’, reported that 2714
adverse effects were signaled in the last year by women using
Mirena
V
R
, an intrauterine device containing levonorgestrel, a well-
known progestin [23]. In 85% of the cases, the side effects were
mainly related to psychiatric disorders, such as anxiety
and depression.
Although a direct relationship cannot be formulated, a link
between progestin treatment during fetal life and later psychiatric
disorders in offspring should be considered. Since progestins are
known to induce GABA receptor activity/neural activation before
Table 3. Prevalence of psychiatric disorders and comparison with the general population.
Group 1 Group 2 Group 3
Firstborn unexposed Progestin exposed Post-exposure General population
(n¼18) (n¼62) (n¼35)
Schizophrenia (0%) (n¼29) (46.77%) (0%) (1%)
Behavioural disorders (0%) (n¼2) (3.22%) (0%) (3%)
Bipolar disorder, depression (0%) (n¼16) (25.80%) (n¼1) (2.8%) (6.3%)
Eating disorders (0%) (n¼2) (3.22%) (0%) (1.6%)
Suicides (0%)
Attempts (n¼7) (0%) (n¼7) (11.29%) (0%) (0.3%)
Death (n¼1) (0%) (n¼1) (1.6%) (0%) (0.02%)
With no disorder (n¼7) (11.29%)
GYNECOLOGICAL ENDOCRINOLOGY 3
birth, it is likely that the GABAergic system contributes to
schizophrenia, anxiety, depression, panic disorders, epilepsy, aut-
ism, and other disorders [24]. Disruption of GABA signaling in
early development alters cell migration and cortical architecture,
which then may lead to chronic disability in postnatal life. Our
results point out the postnatal consequences of synthetic proges-
tin treatment during fetal life and highlight the potential impact
of synthetic progestin. They highlight the need for reevaluation
of the potential outcome of progestin administration dur-
ing gestation.
Acknowledgments
The authors acknowledge Professor M. Dolan (University of
Massachusetts, Amherst, USA) for critical reading of the manuscript
as well as the Hhorages board for its ongoing support and precious
collaboration concerning the files and relations with families. The
authors also warmly acknowledge the patient families of the
Hhorages Association for their ongoing support and participation
via their testimonies.
Disclosure statement
The authors declare that they have no conflict of interest concerning
this work, the Hhorages Association being exclusively financed by
memberships and donations.
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