Pre-eclampsia and Autism: Two complications with a common root cause: In utero inflammation

Posted By Braverman IVF & Reproductive Immunology | 15-November-2018

A recent review published in the journal Developmental Neuroscience showed a strong association between offspring exposed to pre-eclampsia in utero and the higher incidence of neurodevelopmental disorders such as autism (ASD). We will take this opportunity to show you that pre-eclampsia (PE) per se is not responsible for the disruption of the fetal neurodevelopment, rather it is the maternal inflammation during early pregnancy that has dramatic and detrimental effects on brain development during the second trimester and this inflammation may contribute to pre-eclampsia occurrence during the third trimester.

The present study is referring to a recent meta-analysis (1) that includes patients with hypertensive disorders of pregnancy (HDP) including pre-eclamptic patients and examines the association between HDP and neurodevelopmental disorders. Results revealed that PE is associated with an increased risk of having a child on the spectrum (+50%).

Pre-eclampsia and Autism: two inflammatory disorders…

Pre-eclampsia (PE) affects up to 7% of pregnancies in the United States and is a leading cause of maternal death.

Characterized by hypertension and proteinuria during pregnancy, PE is associated with an impaired immune tolerance where pro-inflammatory CD4+T cells are increased while Treg cells expression is repressed.

PE is characterized by inflammation that may originate during early pregnancy with an increased secretion of pro-inflammatory cytokines and oxidative stress that injure the placenta resulting in placental insufficiency (placental ischemia) and maternal hypertension. The placental and vascular injuries induce the secretion of several circulating factors such as TNF-α, IL-6, IL-1 creating an amplification of the systemic inflammatory environment.

ASD (autism spectrum disorder) is caused by the interaction of genetic predispositions and external triggering factors.

Many studies showed that autistic subjects have a disruption in the Th1/Th2 cytokine balance with high levels of inflammatory cytokines such as IL-2, IL-12 or IFN-gamma.

In a meta-analysis (2), regrouping 17 independent studies comparing plasmatic cytokine expression between autistic individuals (n=743) and healthy controls (n=592), they found that the inflammatory cytokines IL-1 beta, IL-6 and IFN-gamma were much higher in the participants with autism than in the controls.

In addition, IL-8, eotaxin and MCP-1, factors associated with recruitment of inflammatory cells (neutrophils, monocytes) from the circulation to the site of inflammation, are also elevated in autistic subjects.

This clearly supports the theory that a T cell dysregulation (most likely arising during pregnancy) may be important in autism development (3).

…with a same cause: maternal inflammation

Maternal inflammation is one the main feature of pre-eclampsia (4) with increased levels of inflammatory cytokines, including IL-6, TNF-α, IL-12 and IL-16, causing structural and functional changes in endothelial cells, directly impacting the placentation (5).

An excessive maternal inflammatory response to pregnancy may cause preeclampsia (6).

Many studies have shown that maternal autoimmune diseases increased the risk of having a child with autism (7-10).

Most importantly, any alteration of the maternal immune system regardless of the causes leading to inflammation (such as maternal autoimmune diseases, maternal inflammatory response due to syndromes such as PCOS and endometriosis, maternal production of anti-paternal HLA antibodies) dramatically impacts the fetal environment in utero and may be a major event triggering the neuro-developmental abnormalities in the fetal brain during pregnancy (11). Particularly, IL1-7 and IL-6 seem to play a major role in the development of both diseases.

In the peripheral blood, Th17 cells have been found in higher number in PE when compared to healthy pregnancies (12). Further, a correlation between Th17 cells and IL-2- and IFNγ-producing T-cells has been shown, suggesting a strong Th17 and Th1 involvement in PE development during pregnancy.

In a rat model, when IL-17 pathway is blocked, this could reverse PE symptoms by lowering Th17 production, oxidative stress, autoantibodies secretion and hypertension (12). In a same way, increased levels of Treg cells could have similar effects on reversing the symptoms in a rat model of pre-eclampsia (13).

Autism has also been linked to maternal inflammation during pregnancy with IL-17 playing a key role in the occurrence of the disease in the offspring. In a mice model where autism is induced by maternal inflammation in utero (MIA), but where the pregnant mothers are unable to produce IL-17 (by a genetic modification), their offspring had a totally normal brain development with no autism-like behavioral abnormalities (14).

This shows that IL-17 may be one of the key pro-inflammatory cytokines injuring the fetal brain and contributing to the development of autism.

IL-6 has been shown to play a major role in the development of pre-eclampsia. Higher IL-6 levels have been reported in patients with pre-eclampsia (15-16).

The activation of the maternal endothelium, one of the major mechanisms in preeclampsia and preceding the onset of clinical symptoms, can be induced by IL-6 (17).

Further, in a mice model, infusion with IL-6 during pregnancy can induce pre-eclampsia like characteristics such as high blood pressure and renal insufficiency (18).

Dysregulation of the inflammatory cytokine IL-6 has also been reported in the maternal serum and amniotic fluid during early- or mid-gestation of autistic children (19). Unlike other cytokines, IL-6 can cross the human placenta and directly alter the placental environment thus impacting the fetus (20).

Several clinical studies suggest that IL6 levels in the amniotic fluid predict development of cerebral lesions (21-22) and impairment in spatial learning (23). In mice, studies have shown that induction of inflammation (MIA mice model) increased levels of cytokines including IL-6 in the placenta (24-26) but also in the fetal brain (27-28). This inflammation induces fetal brain injuries with autistic-like behavioral changes in the offspring (29).

Most strikingly, when inflammation is triggered during pregnancy in genetically modified mice able to secrete IL-6 but lacking placental IL-6 receptor (resulting in a non-active IL-6 signaling pathway), no behavioral abnormalities have been reported as compared to offspring from mice with an active IL-6 signaling pathway (30). This clearly shows that IL-6 pathway in placenta is required and responsible for relaying inflammatory signals to the fetal brain and impacting its development.

Maternal inflammation is a risk factor for pregnancy loss, pregnancy complications such as pre-eclampsia and could potentially disrupt fetal brain development thus leading to Autism.

It is crucial to detect, treat and reduce any maternal immune alterations regardless of the underlying causes to counteract their deleterious effects on pregnancy maintenance and fetal health.

With appropriate immune screening and adequate therapy, we, at Braverman Reproductive Immunology, can help you minimize your risk of experiencing pregnancy complications that are a result of untreated inflammatory changes.

To learn more about the common causes between pregnancy complications and autism, consult our website and read our blogs.

References