Life in utero: Predisposing the unexposed

pregnant graphicWe think of life in utero (during pregnancy) as a quiescent environment for the developing foetus. However the reality is that maintaining pregnancy is a dynamic and continuous process. The conventional model is that normal human pregnancy lasts for approximately 40 weeks, and the final stages of labour take place in the last 12-24 hours. There is now a rising view among obstetricians that a “not in labour” stage should also be considered which lasts from 1 to 39 weeks. This is because the mother’s body is actively keeping the uterine muscles relaxed and stretched to accommodate the foetus, and remodelling the cervix to keep it tightly shut during pregnancy to prevent preterm labour. The maternal system accomplishes this because the placenta secretes progesterone and oestrogens into the maternal circulation at levels up to 100 times more than in pre-pregnancy.

The placenta is a strange organ, its main role is to facilitate nutrient exchange between the maternal and foetal circulatory systems, but in doing so it opens up the possibility of accommodating unwelcome agents that can disrupt normal development (teratogens) into the foetus. Teratogens can include alcohol, drugs (inducing medications) and even viruses.

Teratogenic effects of alcohol

Alcohol can freely pass through the placenta and into the foetus which cannot breakdown alcohol efficiently due to the lower affinity for ethanol by the fetal dehydrogenase enzymes Thus the effects of alcohol are amplified in the developing foetus which may lead to foetal alcohol spectrum disorder (FASD). Infants that suffered from FASD in utero exhibit poor decision making skills, learning disabilities, hyperactivity, poor social awareness and even egocentricity in later life. Alcohol is described as having the most serious neurodevelopmental effects of all abusive substances. This is for two reasons, firstly it concentrates in the developing brain and secondly it prevents nerve cell migration and development. The NHS recommends that pregnant women should only drink a maximum of 2 units of alcohol per week, but abstain completely during the first trimester. There is a good reason for this; the first 12 weeks of pregnancy is when the primary structures of the embryo are formed. Interestingly, brain development takes place throughout pregnancy and even post utero, so there is also a strong case for abstaining from alcohol until delivery.

The thalidomide catastrophe

Many prescription drugs such as metformin and paracetamol can cross the placenta without harm to the foetus. However in the 1960’s the drug thalidomide was prescribed as a treatment for morning sickness in early pregnancy. During weeks 4-8 of pregnancy the placenta peaks its production of hCG hormone, high levels of hCG cause morning sickness in pregnant women. Coincidentally, upper limb development also takes place between weeks 4-8, which is the same time that the women took thalidomide to alleviate morning sickness. It was eventually discovered that thalidomide causes growth restriction of the upper and lower limbs because it reduces the vascularisation of limb tissue during its development. Estimates suggest that 20,000 babies were affected by thalidomide. Contrary to popular belief, thalidomide was tested on animals such as rodents during trials, however it was not tested extensively enough on pregnant animals and so it was wrongly assumed to be safe in pregnant women.

The Barker hypothesis

The in utero environment lasts up to 40 weeks for the developing foetus and the exposures of the mother can predispose the foetus to develop abnormally, but can the maternal environment predispose the foetus to certain diseases that appear in adult life? In 1995, Dr David Barker, professor of clinical epidemiology at the University of Southampton, showed that babies with low birth weight (<5.5 pounds) were at greater risk of developing coronary heart disease than newborns of normal weight. This was the first rigorous study to show that the in utero environment can predispose a newborn to certain chronic diseases. Further studies have also supported the hypothesis. We now know that maternal malnutrition can cause the developing foetal heart muscles to slow their growth, and therefore hinder heart development in utero. Due to the reduction in heart muscle cells (cardiomyocytes) through apoptosis, the heart will have reduced capacity to repair itself in later life in response to arterial wall damage.

Fortunately the placenta is excellent at preventing the transmission of most bacteria and viruses including HIV, the virus that causes AIDS. Instead, maternal to foetal transmission of HIV commonly occurs during mixing of blood at delivery, implicating the importance of high quality obstetric facilities. Pregnancy is a time of intense physiological change. Empowering women with the knowledge of how their environment and individual exposures can affect their child can incentivise mothers to take precautionary measures to promote healthy pregnancy outcomes.

Image: courtesy of Dr Scott Semple, University of Edinburgh

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