Study explores cancer risk in children

In a recent study published in JAMA Network Open, researchers compared the risk of cancer in children born by medically assisted reproduction (MAR) to infants conceived naturally.

Study: Medically Assisted Reproduction and Risk of Cancer Among Offspring. Image Credit: Antonio Guillem/Shutterstock.com

Background

Childhood cancers are a global health problem, with early onset after birth and embryologic traits indicating that they may arise before conception. MAR therapies like assisted reproduction technologies (ART) are putative risk factors for pediatric cancer due to their epigenetic disruption potential.

Studies have found an increased risk of unfavorable perinatal outcomes such as preterm delivery, low birth weight, and fetal development defects. However, the long-term consequences of reproductive therapies on child health are unclear, with conflicting results.

About the study

In the present study, researchers investigated whether cancer risk differed between infants born through medically assisted reproduction and those conceived naturally.

The researchers obtained data from the French National Mother-Child Register (EPI-MERES) for live births in France from 1 January 2010 to 31 December 2021 (follow-up through 30 June 2022).

They analyzed data between 1 December 2021 and 30 June 2023. The study’s exposure was ART usage, including artificial insemination (AI), fresh embryonic transfer (ET), and frozen ET (FET).

The team classified infants as born after MAR if their conception date was within three weeks of the MAR procedure and naturally conceived otherwise. They used the recorded embryo transfer (ET) date as the ART procedure date. Children were born following fresh ET if the interval between oocyte retrieval and ET was less than three weeks.

The researchers compared cancer risk, overall and stratified by cancer subtype, between children born following MAR and those conceived spontaneously by performing Cox proportional regression modeling to derive the hazard ratios (HRs), adjusted for mother and child factors at birth.

Study covariates included birth year, sex, singleton or multiple births, birth weight, gestational length, an indicator of fetal growth, maternal age at index childbirth, and the French census-based deprivation index of the municipality of residence at birth as a proxy for household socioeconomic status.

The team recognized primary congenital anomalies using the International Classification of Diseases, 10th edition (ICD-10) codes.

They identified childhood malignancies using the French National Registry of Childhood Malignancies (RNCE) and the International Classification of Childhood Cancer, Third Edition (ICCC-3) codes. They determined MAR procedures and dates using CCAM codes for oocyte retrieval, ET, and AI. 

Case patients were children with cancer meeting one or more of the following criteria: had at least two hospitalizations with cancer diagnosis, at least one hospitalization with cancer diagnosis and one hospitalization for oncologic treatment or a diagnosis of childhood cancer, or one hospitalization with cancer diagnosis followed by death within six months. 

The researchers used alternative techniques to assess cancer risk in infants born between 2010 and 2015. They used partial likelihood tests to compare the predicted risk for several MAR methods.

Sensitivity analyses were limited to singletons, and additional sensitivity analyses considered the first coded diagnosis group as the cancer diagnosis. They assessed leukemia risk overall and by subtype acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)].

Results

The study comprised 8,526,306 pediatric individuals, the average age being six years; 96% were singletons, 51% were males, 12% were small for gestational age (SGA) at delivery, and 3.0% were born with congenital deformities.

In total, 3.1% (n=260,236) of offspring were born after medically assisted reproduction, including 1.6% (n=133,965) following fresh ET, 0.8% (n=66,165) following FET, and 0.7% (n=60,106) after AI.

The researchers detected 9,256 case-patients after seven years (median) of follow-up, among whom 165 took birth after ET, 57 after FET, and 70 after AI.

The overall cancer risk was similar for children conceived spontaneously and those taking birth following fresh ET (HR, 1.1), frozen ET (HR, 1.0), or artificial insemination (HR, 1.1).

However, children born following FET had a higher risk of ALL [20 case-patients, HR 1.6, and a risk difference (RD) of 23 per million individual years] than children conceived spontaneously.

Furthermore, among infants born in the 2010-2015 period, leukemia risk was increased for those taking birth following embryonic transfer (45 case-patients, hazard ratio, 1.4; adjusted RD, 20 per million individual years).

The team also discovered a non-significant rise in the likelihood of central nervous system (CNS) malignancies following AI. Leukemia accounted for 29% of cases, with ALL accounting for the vast majority (79%). The results of the sensitivity analysis were constant.

Conclusions

The study found that infants born following MAR had a higher leukemia risk than those conceived spontaneously, particularly ALL after FET. However, the overall cancer risk was similar between children born following MAR and those conceived spontaneously.

The study emphasizes the need to monitor the risk of ALL as the use of ART continues to expand. The non-significantly elevated risk of CNS malignancies following AI merits additional research.

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