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Paris – Children conceived using assisted reproduction may be more likely to develop leukemia in the first few years of life. This is the conclusion reached by employees of the French medicines authority ANSM in a nationwide study JAMA Network Open (2024; DOI: 10.1001/jamanetworkopen.2024.9429).

Since the birth of Louise Brown in July 1978, more than 10 million children worldwide have been conceived through assisted reproduction, with fertility clinics offering not only in-vitro fertilization (IVF) and the variant ICSI (intracytoplasmic sperm injection) but also artificial insemination includes what was already possible before Louise Brown. In IVF, previously frozen embryos are increasingly being used, which makes it easier to plan the timing of treatment.

One of the known consequences of assisted reproduction is an increased rate of premature births. Paula Rios from the “Agence Nationale de sécurité du médicament et des produits de santé” (ANSM) in Saint-Denis near Paris and colleagues determined in their analysis of the French birth register EPI-MERES that 17% of children after assisted reproduction before birth 37 weeks were born compared to 6.7% after natural conception. In addition, 18.3% versus 11.8% of the children were small for their gestational age at birth.

The rate of congenital disorders was also increased at 4.1% versus 3.1%. The most likely explanation is the older age of mothers using the services of fertility clinics. In France, around 40% are over 35 years old, compared to only around 20% of women whose children were conceived naturally. As the mother ages, the risk of pregnancy complications increases and the genetic risk of children, who are more likely to be born with trisomy 21, among other things.

For several years it has been suspected that assisted reproduction could also influence the risk of cancer in children. In the first few years of life, there is an increase in malignancies, the cause of which is suspected to be disturbed embryonic development. Could the hormones used to stimulate the ovary or assisted reproductive techniques have a negative impact? To do this, Rios and colleagues compared the data from the EPI-MERES registry with the French cancer registry.

Of the 8.5 million children born between 2010 and 2021, 9,256 later developed cancer at a median age of 6.7 years. These included 292 cases of cancer in 260,236 children born after assisted reproduction.

Rios found no statistically significant accumulation for the total number of cancer cases. The only exception was acute lymphoblastic leukemia (ALL), the most common form of childhood blood cancer. 20 children developed from a cryopreserved embryo suffered from ALL.

Compared to naturally conceived children, Rios found an increase of 61%, with a significant hazard ratio of 1.61 with a 95% confidence interval of 1.04 to 2.50. The associations were not significant for children whose embryos were transferred immediately after IVF and those born after artificial insemination.

In a second analysis, which Rios restricted to children born between 2010 and 2015 and who were therefore more likely to have reached the age at which leukemia occurs, an increase in risk was detectable in children born after IVF with fresh embryo transfer became. Rios determined a hazard ratio of 1.42, which was significant with a 95% confidence interval of 1.06 to 1.92.

The study cannot prove that there is causality underlying the associations, i.e. that IVF is responsible for the leukemias. Rios was able to rule out a number of other possible risk factors such as gender, year of birth, multiple births, mother’s age at birth and deprivation index as well as length of pregnancy, birth weight, macrosomia and congenital malformations.

However, epidemiological analyzes are never perfect. It was therefore easy for the British experts interviewed by the London Science Media Center to name a few possible “confounders” that could have distorted the results. Channa Jayasena from Imperial College London misses taking the age of both parents into account. With increasing age, DNA mutations and other genetic disorders accumulate in the germ cells, which could also have influenced the risk of leukemia.

Potential peri- and postnatal risk factors for ALL were also probably not taken into account. According to Sir Mel Greaves from the Institute of Cancer Research (ICR) in London, these include a caesarean section, not breastfeeding or even the absence of older siblings. However, pediatrician Alastair Sutcliffe from the Great Ormond Street Institute of Child Health in London believes the study is overall “reliable and unbiased”.

But even if assisted reproduction increases the risk of leukemia, the risk to children would be minimal. According to the ANSM press release, there would be one additional disease for every 5,000 children conceived using assisted reproduction up to the age of 10. © rme/aerzteblatt.de