Researchers tackle foetal programming

“The unborn child’s future health is already strongly programmed in the womb,” says Professor Leea Keski-Nisula.  

Text Ulla Kaltiala Photos Raija Törrönen

The Kuopio Birth Cohort study aims to clarify the role of different maternal stress factors and exposures in intrauterine programming. The multidisciplinary study addresses many topical issues, from hormone disrupting chemicals to protective microbes.

The concept of the foetal origin of diseases was introduced in 1990 by the British epidemiologist David Barker, who noticed an association between poor foetal nutrition and cardiovascular diseases in middle age.

“The lack of nutrients is thought to prepare the foetus for sparse nutrition, even after birth. When instead the baby is well fed and gains weight rapidly, cardiometabolic risk factors begin to emerge. Today we know that maternal obesity, too, predisposes the unborn child to metabolic disorders.”

“On the positive side, keeping up exercise and a healthy diet during pregnancy is a choice we can make to give the child the best possible start in life.”

 

The Kuopio Birth Cohort (KuBiCo) study is a joint project between the University of Eastern Finland, Kuopio University Hospital and the National Institute for Health and Welfare. Led by Professor Leea Keski-Nisula, the study investigates the associations of maternal stress, medications, environmental exposures and lifestyle factors during pregnancy with the child’s subsequent health. Data is integrated from questionnaires, biosampling and clinical examinations both during and after pregnancy. So far, more than 5,000 mother-child pairs have been recruited.  

“There is growing evidence that the early-life microbial exposures affect the development of the immune system and later health,” says Dr Katri Backman, paediatrician and principal investigator in the five-year follow-up of the KuBiCo study.  

Our individual microbiome consists of all the microorganisms living in our body. Some of them may already be present during the foetal stage, but a major primary microbial colonisation happens at birth.

“For example, vaginal birth exposes the baby to a wide range of beneficial bacteria from the mother. Babies born by Caesarean delivery lack this exposure and start off with a different microbiome.”

 

Human microbiomes are also shaped by living environments. In the ongoing follow-up study, MIC-KuBiCo, researchers study the links between home indoor air microbes during pregnancy and the first years of life, the newborn microbiome, and allergy and asthma risk. Microbial mouth swabs have been collected from 70 per cent of neonates in the study, and 30 per cent of households have provided dust samples.  

“In our earlier studies, microbial diversity in indoor air has been a protective factor. Pets at home, farm environments and entry of bacteria from outdoors increase diversity, whereas the use of disinfectants at home could have the opposite effect,” notes Dr Anne Karvonen, researcher at National Institute for Health and Welfare.

With modern sequencing methods, Karvonen and colleagues have been able to identify 4,200 different bacterial species in house dust. In different homes, the amount varied from 72 to 910.  

According to Backman and Karvonen, the ultimate goal is to be able to define an optimal microbial profile and to find ways to promote it both at home and in the delivery room.

Associate Professor Jaana Rysä and colleagues use placental tissue and cell cultures to study how maternal exposure to different chemicals and drugs during pregnancy can affect the child. “In addition to passing through the placenta, many compounds can alter placental hormonal production and xenobiotic metabolism, for example, affecting foetal well-being.”  

 

One focus of interest are the nuclear receptors vital for placental function. One of the receptors they have studied is the PPAR-γ receptor, which may be important for placental immunological protection. “Consequently, immunomodulatory responses could be disturbed by any chemical acting via this receptor.”  

While blood and hair samples allow the researchers to assess real-life exposures, cell cultures can be used to study potential harm, whether caused by drugs, food toxins or environmental chemicals. Among the studied compounds are endocrine disruptors – chemicals interfering with hormone-related signalling pathways. Rysä’s group also takes part in the H2020 EDCMET project, which is designed to study the metabolic effects of endocrine disrupting chemicals, such as the industrial by-products dioxins and bisphenol A that are found in paper receipts and plastic food containers. “Endocrine disruptors have been linked to infertility, but so far, surprisingly little is known of their impact on human health, during pregnancy or otherwise.”  

“However, in many cases, alcohol and tobacco are still the worst chemicals the foetus is exposed to,” Rysä points out. In the KuBiCo study, researchers apply a new method to detect alcohol use during pregnancy. Read more on page 20.

“Severe pain must always be treated. During labour, untreated severe pain increases stress hormone concentrations in maternal circulation, which can reduce blood flow in the placenta and the foetus. In other words, severe pain is not only distressing for the mother, but it can also harm the child,” Research Director Hannu Kokki says.  

However, drugs to treat labour pain also end up in the foetus. “In this respect, the popular epidural analgesia is both effective and safe, but it’s not always suitable or available. Alternative pain relief methods are needed, and so is research on their safety.”

 

In the KuBiCo study, Kokki’s research group evaluates the foetal and newborn effects of compounds used for pain relief and anaesthesia during labour and Caesarean section. One such compound is oxycodone, increasingly used in pain relief but little evaluated in the context of labour. The group has previously shown that the elimination of oxycodone is faster in women in labour than in non-pregnant controls. When oxycodone is given in the early phases of labour, foetal exposure at birth is relatively low. They have also been the first to characterise oxycodone pharmacokinetics in very preterm neonates, and their dose recommendations are now used globally.

Pain relief in nasal spray form could be a useful option. The group has already shown that a modest dose of intranasal fentanyl can offer fast relief for the parturient and also seems to be well-tolerated by the newborn.

Preterm birth affects sleep  

Prematurely born infants still needed more daytime sleep and had more irregular sleeping patterns at the age of 12 months, compared to those born full term. Half of the one-year-olds took one daytime nap daily, whereas the rest still needed two daytime naps.

Increased risk of baby blues

Mothers diagnosed with gestational diabetes had an elevated risk of developing postpartum depression symptoms. These symptoms were observed in 16 per cent of mothers diagnosed with gestational diabetes, and in nine per cent of mothers without gestational diabetes.

Environmental intolerance

Intolerance to environmental factors was surveyed among women participating in the KuBiCo study. Forty-six per cent of the respondents reported being annoyed by chemicals, moulds or electromagnetic fields, and 33 per cent reported symptoms related to at least one of these.

Caffeine exposure revealed

Pregnant women are advised to limit their caffeine intake to 200 mg a day, equal to 2–3 cups of coffee. Over 40 per cent of mothers reported exceeding this limit. Foetal exposure to caffeine was also analysed from neonates’ hair samples, showing that mothers tended to understate their coffee consumption.

Birth size matters

Children born small for their gestational age and those born large for their gestational age had an increased risk of developing cardiometabolic disturbances in a follow-up of five to eight years. In children born large for their gestational age, avoiding excessive weight gain could prevent these outcomes.  

Cigarettes are hormone disruptors

An analysis of gene expression changes in placentas from cigarette-smoking mothers showed that smoking during pregnancy altered steroid metabolism in the placenta. According to the researchers, it seems that cigarette smoke acts as a hormone disrupter in the placenta.  

One in two went medication-free

One in two mothers used medication during pregnancy. One in five took medication for a chronic disease. The most commonly used medications were for hypothyroidism, asthma and mood disorders. In addition, one in five used antibiotics or antiallergics. Medication use did not affect the course of the pregnancy.

UEF Bulletin 2019