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Which Pregnant Women Are at Risk?

Credit: Olesia Bilkei/Adobe

Credit: Olesia Bilkei/Adobe

By Claire Roberts & Tina Bianco-Miotto

A new screening test can identify the risk of pregnancy complications based on a genetic test in conjunction with lifestyle factors.

Women who are pregnant for the first time are largely unaware that the four main complications of pregnancy – pre­eclampsia, preterm birth, intrauterine growth restriction and gestational diabetes – occur in one-quarter of first pregnancies. Worryingly, the number of these pregnancy complications is rising, and they contribute to poor health outcomes for mothers and babies in both the short and long term.

Currently there are no effective screening tools in clinical practice that can accurately predict any complications of pregnancy in women who are pregnant for the first time. While there are models to predict some of these complications in women who have previously given birth, they rely heavily on previous pregnancy history and their use is still confined to a small number of UK hospitals. Furthermore, their accuracy is modest at best.

However, our research group has used data from nearly 3000 pregnant women in Adelaide and Auckland, their partners and babies to develop robust models to predict risk for each of the four pregnancy complications with low false positives and negatives. These will be offered as a genetic test, for which a small blood or saliva sample is required from both the pregnant woman and her partner at 12–15 weeks gestation.

We have already identified specific gene variants in both the pregnant woman and her partner that, when combined with a number of clinical, family history, dietary and lifestyle factors, predict risk. Some of these factors are highly modifiable.

In this article we will reveal what some of these factors are and offer strategies to reduce women’s risk.

Risk Factors

We are all predisposed to some sort of disease, such as heart disease, high blood pressure or some cancers. These tend to run in families, and this implicates genetic variants in their aetiology. We have identified a number of gene variants in both pregnant women and their partners that contribute to the risk of pregnancy complications.

Gene variants that associate with many diseases, including pregnancy complications, are often said to have low penetrance. This simply means that not all people who carry these variants actually get the disease.

Each person carries a unique combination of millions of gene variants, so we all have protective and deleterious gene variants that interact as a suite. Individual gene variants can affect the expression of the gene that they encode but they can also have significant effects on the expression of other genes located some distance away within the genome.

We have also found that the health of the parents of a pregnant woman can also indicate her risk for pregnancy complications. For example, a woman whose father has chronic high blood pressure is at a greater risk herself of developing pre­eclampsia, the most serious hypertensive disorder of pregnancy. Family history of miscarriage and pregnancy complications in the woman’s mother or sisters can also indicate an increased risk. These suggest that there are genetic factors common to both cardiovascular and metabolic diseases and pregnancy complications. Indeed, we have found this to be the case.

Genes are also known to interact with the environment in both health and disease. This means that an individual may harbour a number of gene variants that pre­dispose them to a particular disease but it is only concomitant exposure to certain environmental factors, such as a poor diet and physical inactivity, that reveals a vulnerability to that disease.

Gene expression can directly be influenced by nutrition. For example, zinc is a structural component of hundreds of enzymes and transcription factors that regulate gene expression, and its deficiency may compromise the function of a number of biological processes.

Environmental exposures occur in the context of the foetal, and hence placental, genome. The foetus and placenta cross-communicate with the mother, and both are at the mercy of her past and present environmental exposures, including her diet.

Furthermore, the placenta orchestrates the mother’s response to pregnancy by secreting a number of hormones and growth factors into her circulation. These are determined by the foetal and placental genome, and also respond to her health status and exposures.

Epigenetic Risks

Although a person’s DNA code is identical in every cell, differences in the DNA’s epigenetic state can determine cell and tissue type. For instance, a liver cell has different epigenetic markers than a heart cell in the same person.

There is evidence environmental factors can repress or amplify gene expression by altering a gene’s epi­genetic state. For example, active smoking alters DNA methylation in a number of genes, including tumour suppressors and genes associated with coronary artery disease.

Likewise dietary and lifestyle factors can alter the epigenetic state in a variety of human tissues, and lead to the unmasking of disease states that increase the risk of complications during pregnancy. Even the sex of the individual adds to the epigenetic web, with males and females responding differently to such exposures. We have even found that sex differences start in utero so that maternal health, foetal growth and newborn outcomes are different in women carrying a male or a female foetus.

Other Factors

Folic acid supplementation in the month prior to conception and during the first trimester of pregnancy can prevent neural tube defects such as spina bifida in babies. We have found that first trimester folic acid supplementation also protects women from developing preeclampsia, delivering preterm and having a small-for-gestational-age baby.

This suggests that folic acid supplementation may be beneficial to the placenta and how the mother adapts to pregnancy, as well as to the foetus. This has considerable biological plausibility, since folate is the pivotal factor in one-carbon metabolism, and thereby production of S-adenosyl methionine, the universal donor of methyl groups in DNA methylation. Therefore, folic acid supplementation can contribute to the appropriate epigenetic state for correct gene expression and healthy development.

We have also found that women can significantly reduce their risk of developing pregnancy complications if they eat three or more serves of fruit and/or one or more serves of green vegetables each day in the month prior to conception and during the first trimester. Fruit and vegetables contain folate as well as other micronutrients and fibre that together may help to improve the outcome of pregnancy.

Maternal smoking damages the placenta and impairs foetal growth, and is associated with foetal growth restriction and preterm birth. Maternal illicit drug use is similarly damaging. In fact, we have shown that continued use of marijuana, independent of cigarette smoking, at 20 weeks gestation is strongly associated with preterm birth.

Maternal overweight and obesity are increasingly prevalent, with more than 50% of Australian women commencing their pregnancy in these categories. A body mass index above 30 indicates obesity and significantly increases the risk for most pregnancy complications as well as long-term health issues for offspring. Obese women are more likely to deliver a baby with birth defects than lean women, and their children are more likely to be obese and develop type 2 diabetes early in life.

Screening for Those at Risk

The screening tools we have developed to predict the risk of pregnancy complications include many of these factors in different combinations for each disease. Importantly, they also point to potential new interventions.

Despite each of us being at genetic risk, our genes are just a part of the story. Although we cannot change our genomes, we can change our epigenomes and modify the effects of our genes. Fortunately, many of the factors that contribute to pregnancy complications are modifiable.

Ideally, pregnancies should be planned ahead and women should achieve a normal weight, have a good diet with recommended supplementation of micronutrients, and engage in moderate exercise both before and during pregnancy. Pre-conception planning can help to minimise the risks to maternal and infant health.

One can’t help but think that mum was right when she told us to eat our fruit and vegetables.

Claire Roberts is a NHMRC Senior Research Fellow who leads the Pregnancy and Birth Theme at The University of Adelaide, Robinson Research Institute. Tina Bianco-Miotto is a lecturer at The University of Adelaide’s School of Agriculture, Food and Wine.