Australasian Science: Australia's authority on science since 1938

The Risky Business of Being Male

Foetus

Male and female babies may need to be treated differently in the neonatal intensive care unit.

By Vicki Clifton

Female babies are more likely to survive a stressful pregnancy.

The earliest known English report of sex specific differences in foetal and neonatal outcomes was reported by Dr Josef Clarke in 1786. Clarke examined birth outcomes at the Lying-in Hospital in Dublin from 1757–84, recording the outcomes of more than 20,000 deliveries. He reported that male babies were more likely to die than females before and after birth.

These findings have been reported consistently in the literature to the present day. Males are 20% more likely to experience a poorer outcome during pregnancy than females, but we still don’t know why this occurs.

Our research group has been examining sex-specific mechanisms that affect the growth of male and female babies. We are interested in foetal growth because of its link to disease later in life.

Prof David Barker of the University of Southampton has reported that low birthweight babies (weighing less than 2500 g) are likely to die from complications related to diabetes and cardiovascular disease in old age. This suggests that what happens in the womb can determine what you die of in old age.

We are interested in what happens to female babies relative to male babies in the womb in the presence of a stress during pregnancy. The main stress we have studied is the impact of maternal asthma on the baby.

Effects of Maternal Asthma
Our studies of maternal asthma indicate that male and female foetuses have different strategies to cope with an adverse environment or event. We found that if the mother had asthma, female foetal growth was reduced, especially if the mother did not use inhaled steroids during pregnancy. However, when asthma was treated with inhaled steroids during pregnancy, female foetal growth was comparable to the non-asthmatic population.

These data suggest that the inflammatory effects of asthma affect mechanisms associated with female foetal growth. It also tells us that the treatment for asthma is protective and allows the baby to grow normally.

Conversely we have found that the male foetus continues to grow normally in the presence of chronic maternal asthma. It is only when asthma worsens with an acute asthma attack that the male foetus shows signs of being in trouble. The male foetus does one of three things. He either stops growing and is born growth-restricted, delivers preterm or dies.

Our findings indicate that males employ strategies that allow them to continue to grow normally in a stressful environment, but this places them at risk if there is a second stressful event, such as an acute asthma attack.

Females, however, adapt to a stressful environment by reducing their growth so that they are smaller but not growth-restricted. This allows them to survive any further complications like an asthma attack, which could result in a decrease in the supply of nutrition or oxygen as the pregnancy progresses.

But how does this difference between male and female babies occur?

The Placenta
We think that the difference between males and females is due to differences in placental function. The placenta is a foetal organ that mediates the transfer of oxygen and nutrients from mother to foetus during pregnancy. It is a very important organ, and when it doesn’t work optimally the baby doesn’t grow normally.

We have collected data showing that genes and proteins in the placenta differ based on the sex of the foetus. Steroids produced from the foetal–placental unit also vary depending on the sex of the foetus. Furthermore, placental structure and cell types present in the placenta vary depending on the sex of the foetus. These findings indicate that the placenta functions in a sex-specific manner, and may also respond to a stress like asthma in a sex-specific manner.

When a mother is stressed she produces high levels of the hormone cortisol. Cortisol plays an important role at the end of pregnancy, maturing foetal organs and slowing foetal growth. But when the mother is stressed, the foetus can be exposed to high levels of cortisol too early in pregnancy and this can reduce the growth of the foetus.

The Placenta Is a Stress Mediator
The placenta tries to control the transfer of cortisol from mother to foetus with the enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), which metabolises active cortisol into inactive cortisone. In asthmatic mothers we found that placental 11β-HSD2 activity decreased in the presence of a female foetus but did not change in the presence of a male foetus. This means the female baby is exposed to more cortisol early in the pregnancy, and may explain why she is smaller relative to the female babies of non-asthmatic mothers.

Male foetuses are exposed to similar concentrations of cortisol to girls and yet they still grow normally while the girls reduce their growth. We think the boys turn off their ability to respond to cortisol in the presence of a stress, and turn up the production of placental growth factors to help them grow in an unfavourable environment. Meanwhile the girls turn on placental pathways that reduce growth, such as cytokine pathways.

We are still working on the exact mechanism, but what we know from this work is that the response by the girls to maternal stress is protective and ensures their survival. But the boys take a risk: they ignore the stress and try to continue to grow. If nothing else happens in the pregnancy then they are fine but if something goes wrong then they are in trouble.

What Does It All Mean?
Our work in asthma during pregnancy shows that a male and female foetus can be exposed to the same stress in pregnancy but respond in different ways with different mechanisms.This work has relevance to our basic scientific understanding of foetal growth and development, and is changing how we view how a foetus grows.

Clinically we now know that we should monitor a mother’s asthma during pregnancy closely. When asthma is controlled with an inhaled steroid, both male and female babies grow normally without any complications. Thus the poor outcomes we see with male babies could be avoided with a suitable asthma management plan for the mother, which can be obtained from a general practitioner.

Our work also has us thinking about how we treat male and female babies in the neonatal intensive care unit when they deliver preterm. It is possible we should consider sex-specific therapies for preterm babies to improve their chances of survival.

A/Prof Vicki Clifton is NHMRC Research Fellow at the Robinson Institute, University of Adelaide.