Can Fertility Treatments Contribute to Low Birth Weight and an Increased Risk of Infant Mortality?

More and more women are seeking help to get pregnant, and in recent years the number of pregnancies made possible with the help of assisted reproductive techniques has increased. In most cases, these pregnancies have a happy outcome with a healthy baby. However, previous studies show that IVF pregnancies are associated with an increased risk of low birth weight, premature birth and birth defects.

VUB Professor Claudia Spits of the Reproduction and Genetics Research Group has identified a genetic cause for the increased risk of low birth weight in babies born after assisted reproductive technologies such as IVF. Previous studies have identified treatment-related causes of low birth weight, but this is the first time the researchers have been able to identify an underlying genetic factor. Spits organized a large-scale study with Brussels IVF (the Centre for Reproductive Medicine at Brussels UZ), the Centre for Medical Genetics (CMG) at Brussels UZ and the Maastricht University Medical Centre (UMC).

Low Birth Weight As a Result of Fertility Treatments

First, the researchers examined the DNA of infants born both during spontaneous pregnancies and after fertility treatment. They found that in both groups, a greater risk of low birth weight was associated with certain mutations in mitochondrial DNA, and that these mutations were slightly more common in infants born after fertility treatment. Mitochondria are the “energy factories” in the cell that are inherited from the mother. If they do not function properly during development, they can cause a range of health problems such as cardiovascular disease and diabetes.

To determine whether these mutations are passed from mother to child, the researchers also examined the mothers’ DNA. The analysis showed that children born after fertility treatment had more new, non-transmitted mutations than babies conceived without help. In a final step, the group examined eggs obtained through hormonal stimulation and through the natural cycle to determine whether hormonal stimulation was harmful.

The mitochondrial mutations did not necessarily appear to be caused by hormonal stimulation. In particular, a combination of age-related factors in conjunction with hormonal stimulation may lead to a higher risk of abnormal oocytes. The risk of mutations in the mitochondrial DNA of the oocyte increases with age. During a normal cycle, there are mechanisms to remove mutated oocytes and select only healthy cells. However, during hormonal stimulation to boost egg production, this mechanism is switched off and mutant eggs are released.

The Spits team will conduct further studies, but these findings can be immediately applied to assisted reproductive technology (ART) treatments to limit the risk of oocytes with mutagenic mitochondria. It seems that the more eggs are retrieved after hormonal stimulation, the greater the likelihood of mutations. In the future, physicians could pay more attention to achieving a balance between an adequate egg yield and minimizing the risk of mutations.

Fertility Treatment and Mortality Risk of the Baby

Children conceived using assisted reproductive techniques such as in vitro fertilization (IVF) have a slightly higher risk of mortality in the first weeks of life than children conceived naturally. This is the result of a study by researchers at the Karolinska Institute in Sweden, which was published in the journal Fertility and Sterility. The researchers link the increased risk to a higher proportion of premature births in IVF children and emphasize that the risk of infant mortality is still very low in both groups. At over one year of age, the risk of death was similar for all children regardless of the method of conception.

In the study, the researchers selected only singleton children and compared mortality in children conceived using different types of assisted reproductive techniques with children conceived naturally. They analyzed data from 2.8 million children born in Sweden over a 30-year period. Around 43,500 of these were the result of assisted reproduction. A total of 7,236 children died before the age of one, of which only 114 were conceived with the help of artificial insemination. After adjusting for confounding factors such as the mother’s age and previous infertility, the researchers found that children conceived through IVF had a 45% higher risk of dying before the age of one than children conceived naturally. The level of risk depended on which type of assisted reproductive technique was used and how many days had passed since birth. The risk gradually decreased after the first few weeks of life, and in the first week of life, children conceived after frozen embryo transfer had more than twice the risk of death compared to children conceived naturally. However, this was only based on a small sample of children conceived with frozen embryos. After one week, the risk dropped to about the same level as for naturally conceived children. Children conceived by transfer of a fresh embryo or by intracytoplasmic sperm injection (ICSI) – in which a single sperm is injected into the egg – did not have a higher risk of death than naturally conceived children, regardless of how many days had passed since birth.

These results suggest that the type of assisted reproduction technique used may make a difference. It is therefore important to further investigate the causes or underlying mechanisms behind the risks. According to the researchers, one explanation could be that more IVF children are born prematurely than children conceived naturally, which in itself could have negative consequences. It is also possible that the underlying infertility leads to a higher risk of complications. Among the main causes of infant mortality in children conceived using assisted reproductive techniques were respiratory distress, incomplete lung development, infections and neonatal hemorrhage, which are often associated with premature births.