Maternal depression – Antidepressant create an alteration of placental serotonin levels

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About one in ten women in Québec will suffer from depression during pregnancy. Without treatment, the illness carries risks for both mother and child.

Yet antidepressants are not without consequences for fetal development. The team of professor Cathy Vaillancourt at the Institut National de la Recherche Scientifique (INRS) is studying the effects of these drugs in order to identify the least harmful ones.

Professor Vaillancourt, in collaboration with the teams of Professors J. Thomas Sanderson and Nicolas Doucet of the INRS, has just modeled for the first time the interaction of commonly used antidepressants with estrogen, and more specifically with the enzyme that synthesizes the estrogen: aromatase.

It is an important contribution since estrogen production is essential to the development of the fetus and to the mother’s physiological adaptation during pregnancy.

The results of their study were recently published in The Journal of Steroid Biochemistry and Molecular Biology.

Prescribing antidepressants for pregnant women is controversial. Studies show that, when administered to mothers during pregnancy, some of these treatments are associated with a risk of heart and lung malformations in newborns. Others are thought to result in impaired cognitive development, including autism, in children.

Estrogen as a target for antidepressants

The harmful effects of antidepressants are thought to be due to their interaction with certain key hormones. Most antidepressants prescribed to pregnant women target serotonin, a hormone produced both in the brain and, as shown by Professor Vaillancourt’s team in 2017, in the placenta.

This is the family of antidepressants called selective serotonin reuptake inhibitors (SSRIs) such as Zoloft, Celexa or Prozac.

However, estrogen would also be targeted by these treatments.

“We wanted to see how the antidepressants that have been developed to block the serotonin transporter also affect aromatase. Using molecular models, we found that all the antidepressants we analyzed seemed to be able to bind directly to the enzyme and regulate its activity.

This remains to be confirmed and the precise mechanism needs to be further investigated,” reports Cathy Vaillancourt, lead author of the study.

Her doctoral student tested the effect of different types of antidepressants on placenta samples collected after delivery.

“The antidepressants we chose to test are those most commonly prescribed in pregnant women, namely sertraline (Zoloft), venlafaxine (Effexor), fluoxetine (Prozac), paroxetine (Paxil), and citalopram (Celexa),” says Andrée-Anne Hudon Thibeault “By comparing different doses and molecules, we were able to uncover some of their specificities.”

By observing the effects of antidepressants on the placenta’s hormonal system, the team can determine in advance if there will be a risk for the fetus. “Fetal development is strongly linked to the placenta. Every healthy fetus has a healthy placenta,” maintains Vaillancourt.

Safer antidepressants

Not all types of antidepressants have these harmful effects. Not all pharmacological molecules have the same hormonal affinity.

“Depending on its form, a molecule may not interact the same way with estrogen and may therefore be less harmful to the developing fetus,” asserts Professor Vaillancourt, who specializes in the involvement of maternal exposure to environmental and drugs factors in the endocrinology of the human placenta.

Prescribing antidepressants for pregnant women is controversial. Studies show that, when administered to mothers during pregnancy, some of these treatments are associated with a risk of heart and lung malformations in newborns. Others are thought to result in impaired cognitive development, including autism, in children.

It’s more a matter of the pharmacological molecule being administered and the dosage. “By testing several types of antidepressants at varying doses, our work will contribute to better choices regarding the type of antidepressant and the dose prescribed for pregnant women, while minimizing the side effects on the course of pregnancy and on fetal development,” says Andrée-Anne Hudon Thibeault, primary author and recent PhD graduate of INRS.

Discontinuing medication isn’t always advisable. Depression can have serious consequences if left untreated.

“Depression is one of the leading risk factors for suicide in pregnant women,” says Vaillancourt.

“Some studies suggest that depression can also compromise fetal development, due in part to poor lifestyle habits.”

At the same time, Professor Vaillancourt is collaborating with a team of researchers in Vancouver who are studying a cohort of pregnant women and following their children over the long term.

“This will give us a nice map of the various effects in women and the consequences for children’s heart and brain development,” says Vaillancourt.

“We’re still in the early stages of the project, but I’m confident that some antidepressants are safer and others can be developed for use during pregnancy.”

Funding: This research was supported by funding from March of Dimes and the Natural Sciences and Engineering Research Council of Canada (NSERC).


During pregnancy a woman’s body undergoes numerous changes, both physically and mentally. The overall risk of experiencing depressive symptoms during this time period is as common as in the population as a whole, approximately 10–20% [12], whereas major depressive disorder is found in around 4–7% of pregnant women [36]. Suffering from depression in pregnancy could have serious consequences for both the mother and the child.

Almost 11% of women of childbearing age in Sweden were using antidepressant medication in 2016 [7]. The most commonly prescribed antidepressants in pregnancy are selective serotonin reuptake inhibitors (SSRIs), with a prevalence of around 2–4% in pregnant women in Europe, and 4–10% in North America [812].

Poor pregnancy outcomes, such as preterm birth and low birth weight have been reported both in women with antenatal depression and in women who used antidepressant treatment during pregnancy, and it is presently unclear whether it is the SSRI treatment or the depression itself that causes these complications [1315].

The placenta is a transitory organ that connects the fetus to the mother and acts as a bridge between the maternal and the fetal circulations. The fetal part of the placenta consists of chorionic villous trees that contain a variable amount of fetal vessels and stroma covered by a cytotrophoblast and a syncytiotrophoblast layer.

Maternal blood pools into the intervillous space and bathes the villous trees, where feto-maternal exchange takes place [16]. Anchoring villi are attached to the maternal part of the placental tissue, the decidua basalis, which is developed from uterine tissue. Placental dysfunction can have devastating consequences for both the mother and the child.

Fetal growth can be negatively affected if the placental blood supply is insufficient or if the transport of oxygen and nutrients is affected, which can lead to low birth weight, preterm birth, and birth defects [1719].

Moreover, the mother is at increased risk of developing conditions such as pre-eclampsia as a result of placental dysfunction, and a history of pre-eclampsia is also associated with abnormalities in the placenta in the current pregnancy [20].

SSRIs have the ability to cross the placenta and have been found in both cord blood and amniotic fluid [2122]. Serotonin is involved in embryogenesis [23], placentation [24], and placental vasoconstriction [25], all of which may affect the fetus.

In mice, maternal SSRI treatment has been shown to alter multidrug resistance (phosphoglycoprotein) activity both in the placenta and in the fetal and maternal blood-brain barrier, resulting in altered drug transfer into the fetal and maternal brain [26]. Another study in mice revealed a placental serotonin synthetic pathway [27], where serotonin produced in the placenta accumulates in the fetal forebrain during the developmental phase that corresponds to the first and second trimester in humans. This phase includes cortical neurogenesis, migration and initial axon targeting, which are crucial mechanisms for normal neurodevelopment [27].

Regarding the effect of maternal mental illness on placental function, several studies within a review by Gentile and Fusco describe altered gene/protein expression and epigenetic modifications in placenta from depressed mother with or without antidepressant treatment [28].

In addition, studies carried out by our research group have revealed altered gene expression in the fetal part of the placenta in women with depression during pregnancy compared with non-depressed pregnant women [2930]. Moreover, use of SSRIs during pregnancy has been found to alter placental gene expression in the fetal part compared with placental gene expression in healthy pregnancy [2930].

Oxytocin has an important endocrine role in pregnancy and parturition and methylation of the oxytocin receptor (OXTR) has been linked to mental disorders [3132]. Of interest is a study by Galbally et al. suggesting that antidepressant exposure rather than depressive symptoms during pregnancy can alter OXTR methylation in placental tissue [33]. Also, decreased expression of the imprinted gene PEG3 in the placenta have been found associated with maternal depression [34].

Investigators have also described genes involved in the hypothalamic–pituitary–adrenal (HPA) axis that are differentially expressed in placentas from mothers suffering from prenatal stress compared with healthy mothers [3539].

There are also studies describing associations between maternal depression, the placenta and child behaviour and temperament [4041]. However, much remains to be revealed concerning the biological effects of fetal exposure to maternal depression and its treatment. Specifically, more research is needed to elucidate the different effects of antenatal depression and antidepressant treatment on placental function and the offspring.

The aim of this work was to compare placental gene and protein expression in healthy women, women with antenatal depression and women on antidepressant treatment during pregnancy. For this purpose, we selected genes that have previously been shown to be involved in mood disorders, and at the same time known to be expressed in the placenta.


Source:
INRS
Media Contacts:
Julie Robert – INRS

Original Research: Closed access
“Serotonin and serotonin reuptake inhibitors alter placental aromatase”. Andrée-Anne Hudon Thibeault, Yossef López de los Santos, Nicolas Doucet, J. Thomas Sanderson et Cathy Vaillancourt.
Journal of Steroid Biochemistry and Molecular Biolog doi:10.1016/j.jsbmb.2019.105470.

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