Happy Mums, Healthy Babies

“It’s the most wonderful time of your life!” is a phrase expectant mothers often hear. A pregnant woman is supposed to be filled with joy – but that’s not always the reality. For 10 to 20 percent of women, pregnancy is a psychologically challenging time: a cocktail of hormonal and physical changes, the woman’s personal history, social problems or financial strain can give rise to depression and anxiety. If the mother-to-be’s mental-health issues remain untreated, they can negatively impact not only herself but also the birth process as well as health of her baby.

Studies have shown that around half of children with depressive mothers have a higher risk of developing psychological problems. The biological mechanisms behind maternal depression in pregnancy are the focus of the Horizon Europe project, HappyMums. The large-scale project will also explore potential treatment approaches that are safe for mother and child. Seventeen universities and organizations are involved, led by the University of Milan, among them UZH research groups headed up by pharmacologists Urs Meyer and Juliet Richetto and neuro-epigeneticist Isabel Mansuy.

The reasons so many cases of depression in pregnancy go untreated are varied: for some women, internalized clichés about the wonder and bliss of motherhood prevent them from speaking up about their difficulties; on the other hand, it can be difficult for doctors to know when to diagnose depression because symptoms such as mood swings and fatigue are common occurrences during pregnancy. But even when a woman is clearly depressed, treatment options are limited. “For most medication, there is a lack of research into how it affects the fetus,” says UZH pharmacologist Richetto.

Given the paucity of research, it’s a difficult call as to whether or not anti-depressants should be prescribed. Although the evidence is clear that medication crosses into the fetus in small amounts, studies into the effects on the baby show contradictory findings. While some studies have reported damaging effects, others found no negative impact on the baby’s development.

A factor which complicates the research is that maternal depression itself can also have a damaging impact on the child, making it difficult to pinpoint clear causes when investigating medication side-effects. “We don’t yet know enough to be able to properly advise women about the consequences of taking medication,” says Richetto. Thanks to HappyMums, that is now set to change. Before researchers can start developing new treatments, they first need to gain a better understanding of the biological mechanisms: how is a susceptibility to depression passed on from mother to child? And what makes some children resilient so that they develop without problems despite having depressed mothers? To find answers to these questions, the researchers are focusing on the placenta – the organ which provides nutrients and oxygen to the fetus in the womb. Other factors that could be partially responsible for mental disorders being passed on are changes in DNA, in the womb or in the brain, as well as stress hormones. “In order to tease apart these complex interconnected potential causes, we are combining a multitude of data from clinical and preclinical research,” says Richetto.

The HappyMums trial follows thousands of mothers and their babies during and after pregnancy. The researchers gather data about the mothers’ life circumstances and medical case histories. In addition, the mothers undergo regular blood tests to measure inflammation markers and hormone levels. After the birth, clinicians analyze the babies’ blood and take samples from the umbilical cord, amniotic fluid and placenta. These samples are used to analyze the genome and any epigenetic variations. Additional MRI scans are used to observe the brain activity of mother and baby.

The data thus obtained also give indications of the biological characteristics – for example blood test results – that correlate with depression or with resilience. Knowledge of such biomarkers would make it easier for doctors to identify women at high risk of mental illness in pregnancy, or to diagnose depression in pregnant women.

The two UZH research groups led by pharmacologist Urs Meyer and neuro-epigeneticist Isabelle Mansuy became involved in the project due to their expertise in preclinical research using mice. “There are certain biological connections that can only be investigated through animal experiments, because with animals we can intervene to a greater degree,” explains Richetto, who oversaw the Meyer group’s mice experiments. Although pregnancies in mice and in humans obviously differ, they are similar enough to allow the researchers to infer key molecular processes from the mice models. For example, if a particular protein keeps appearing in a central process in the mice pregnancies, it is highly likely to also play a significant role in humans, and the researchers then know to look for it in the human study participants and their babies. “The animal models serve not only as a testing ground for causes and effects, but also give indicators for further research – there is a fruitful back and forth between the clinical and preclinical research,” says Richetto.

The same applies when it comes to discovering promising treatments. The researchers are testing and comparing a pharmacological treatment using anti-depressants and a non-pharmacological approach in mice and humans. As part of the trial, a group of mothers in Finland are either given anti-depressants or easy access to online therapy in which they can specifically work on their current problems in a practical way.

In the animal part of the trial, this cognitive behavioral therapy element is replaced by a task in which the mouse has to change a previously learned behavior with positive reinforcement through food treats. The aim of this sub-study is to give insights into the advantages and disadvantages of anti-depressants versus non-pharmacological therapies – and to find out which treatment is best for the health of mother and child.

To ensure that mothers suffering with poor mental health receive high-quality support as quickly as possible in the future, an app for pregnant women is in development. Women can use the app to store medical data and record changes in their mental or emotional state. Their physician will have access to the data via a separate user interface, enabling doctors to intervene at an early stage if the woman appears to be developing a depressive episode, and to monitor the effectiveness of the chosen treatment.

The HappyMums project will run until 2026, and the researchers hope that its findings will lead to a lasting improvement in the mental health of mothers and their children – whether through more in-depth understanding of biological processes, safer treatments for depression in pregnancy, or increased awareness of mental health problems in pregnancy.