A new research published in the latest issue of the Journal
Molecular Psychiatry (December 2015) puts into light the key role of uterine environment and
prenatal exposure to deleterious factors in Autism development.
Indeed, the study shows that Polycystic ovary syndrome (PCOS) could increase
your risk of having a child affected by autism by 59%. Although this might
your risks are still pretty low going from 1.5% in the general population to 2% in patients with PCOS.
- What is PCOS?
Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting
about 6-10% of women of childbearing age depending on ethnicity, with
approximately 5 millions of women being concerned in the United States (1).
It is characterized by both gynecological and endocrine symptoms such as:
- chronic anovulation: missed or absence of period.
- Hyperandrogenism: higher levels of androgens (male hormones) leading to
excess of facial hair growth and acne.
- Several cysts on the ovaries
In addition, obesity, insulin resistance, and hyperinsulinemia commonly
occur in PCOS patients, increasing their susceptibility for metabolic
disorders such as type 2 diabetes or hypertension (2).
the most common endocrine cause of
infertility, a large proportion of women affected by PCOS ignore their condition and
are not yet diagnosed, due to subtle or not classical signs, until trying
and failing to conceive.
When pregnant, PCOS patients are more prone to obstetrical complications
leading to pregnancy losses in 50% of cases (3).
- PCOS and Autism in the offspring: facts
A population-based study in Sweden, including almost 24 000 children with
ASD and over 208 000 healthy control-matched children shows that PCOS
increased significantly the risks of having an autistic child (4). Maternal
PCOS was found at a higher rate in mothers of autistic children and increases
the risks of having a child with autism by 59%. When combined with obesity,
an even higher proportion of mothers with PCOS was found among mothers
of autistic children, showing that maternal obesity when combined to PCOS
doubles the risks for Autism in the child.
Nevertheless, it is important to underline
that the rate of autism remains low even in obese PCOS patients (<3%).
How can PCOS contribute to Autism development in my child?
Maternal inflammation and immune alterations are the prime factors
Immune environment during pregnancy directly impacts fetal development.
When altered, this could have detrimental consequences on fetal health
as seen in women suffering from pregnancy complications as miscarriages,
pre-eclampsia, preterm delivery or even still birth, events occurring
frequently in PCOS pregnant patients (5).
It is very well established that mothers of autistic children have a higher
frequency of plasmatic anti-brain autoantibodies (6). Patients showing
reactivity to fetal antigens by failing to generate proper tolerance to
paternal antigen may produce these anti-brain antibodies. Indeed, the
high prevalence of autism in males could be explained by an altered maternal
immune response against male-specific minor histocompatibility (HY) antigens.
These antigens are found in women following a first pregnancy with a boy
and are responsible of secondary recurrent miscarriage and other pregnancy
complications and could play a key role in male specific autism development.
- Dysregulations of inflammatory factors
Dysregulation of cytokine and chemokine levels such as IL4, IL-5, IL-6,
IL-8, IFN-γ, TNFα and MCP-1 have been reported in both PCOS patients (7) and in the maternal
serum or amniotic fluid during early- or mid-gestation of autistic children (8-9).
Having a key role during the brain development, these factors could be
responsible for the increased prevalence of autism in children of PCOS women.
Further, the high estradiol/progesterone ratio due to an anovulatory cycle
(no or low progesterone levels with steady levels of estradiol) would
likely stimulates the immune system (10).
PCOS is an
inflammatory disease as shown by increased levels of white blood cells count (WBC), C reactive
protein (CRP) or IL-6 (11) as well as increased oxidative stress (12)
and endothelial dysfunctions (13-14).
A recent prospective study comparing immune profiles in pregnant PCOS patients
to match-controlled pregnant women showed that the low-grade inflammation,
existing before the pregnancy, persists and is exacerbates by pregnancy
in PCOS patients. This was associated with obstetrical and neonatal adverse
The production of
inflammatory factors by the maternal immune system could pass through the placenta and
attack the fetal brain during a critical time of development thus impairing brain formation and
Recent studies showed that PCOS women had lower levels of
Treg cells (16), which are key actors of immune tolerance and essential to pregnancy
establishment and maintenance. This could be due to a vitamin D deficiency,
often found in PCOS and leading to decreased levels of Treg cells (17).
Some patients with insulin resistance may have "suicide" receptors
on the Treg cells that tag them to trigger their premature destruction
which also lead to failed tolerance and its associate problems in pregnancy
(study presented at the ASRI, NYC, 2014).
- Insulin resistance and hyperglycemia
PCOS is often associated with insulin resistance and hyperglycemia. Maternal
glucose can also cross the placenta inducing the production of higher
insulin levels by the fetus. Because insulin can directly impact the brain
plasticity, it is believed that
maternal hyperglycemia could be a contributing
cause to autism.
To learn more about maternal inflammation and autism, consult our website
The extreme male brain theory of autism has been developed almost 15 years
ago (18). This theory developed the idea that
in utero exposure to high levels of testosterone of maternal origin could be responsible
for autism development in the offspring.
Mothers of autistic children have been shown to have higher levels of testosterone (19).
Prenatal androgens shape neurons development and could contribute to the
development of autism (20). Testosterone also exerts epigenetic influences
(regulation of gene expression) that may result in neuronal development
alteration and disrupted synapse function and morphology (21). As PCOS
is marked by increased androgen levels, this condition could be a possible
cause of autism development in the offspring as recently shown (4) although
we strongly believe that
maternal inflammation and immune alterations are the main factors playing a key role during fetal brain development.
Therapies exist to counteract PCOS symptoms thus minimizing your risks
of having a child with autism
A large body of evidences is now documenting the efficacy of Metformin
in the treatment of PCOS associated with insulin resistance (22-23).
Metformin has pleiotropic effects on the endocrine system with:
- Significant reduction of glucose production
- Significant increase in glucose utilization
- Significant reduction in Insulin levels
- Significant increase in Insulin sensitivity
- Significant reduction in testosterone levels
Metformin restores the ovarian function with:
- Significant improvement in the frequency of menstrual cycle
- Significant improvement in ovulation (even in clomiphene-resistant women)
- Metformin and pregnancy
A multi-center, prospective, randomized, double-blind study showed an
increased in pregnancy and live birth rate in Metformin-treated PCOS patients
compared to the placebo-treated PCOS pregnant group (23).
Another one showed a significant reduction of miscarriages in PCOS women
treated with Metformin during an IVF cycle (24).
Complex interactions between immunological alterations, systemic inflammation
and endothelial dysfunction may be responsible for obstetrical complications
and autism development in the offspring (25).
By increasing Treg cells (26), lowering inflammatory factor levels (27)
and increasing vascularization (28), Metformin has beneficial effects
on pregnancy outcome and could minimize your risks of having a child affected
Myo-inositol has beneficial effects on oocyte quality and restores ovarian
function in women with PCOS (229) helping them conceive (30).
Inositol significantly reduces oxidative status leading to improvements
in glucose metabolism. By reducing hyperinsulinemia, Myo-inositol supplementation
has been demonstrated to improve pregnancy outcomes in PCOS women (31).
With its anti-inflammatory properties (32), Myo-inositol could help reduce
your risks of miscarriages, pregnancy complications and in theory could
minimize autism development in your child.
Insulin and glucose alterations as well as immune related and blood clotting
issues are commonly associated with PCOS. These imbalances could be accountable
for obstetrical complications and autism development as recently shown.
By addressing these symptoms with adequate therapies (a combination of
immune therapies and metformin/Myo-inositol), we, at
Braverman Reproductive Immunology, can help you maximizing your chances to have an uneventful pregnancy
and a healthy baby.