What Are Some Risks For Offspring of Assisted Reproductive Technologies?

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Patient Presentation
An 8-day-old female came to clinic for her health maintenance examination. The past medical history showed she was born by in vitro fertilization to a 34 year old G3 now P1 female at 36 2/7 weeks after preterm labor and mild maternal hypertension. The infant did not have any breathing problems but was quite slow to feed. She had had a murmur that was consistent with a patent ductus arteriosus that closed on repeated echocardiogram.

The pertinent physical exam showed a small for gestation age female with a birth weight = 2.163 kg (~10% for premature females), now 2.81 kg (down 4%), head circumference of 32 cm (10%), and length of 42 cm (~50%). The rest of her examination was normal.

The diagnosis of a healthy but small premature female was made. The pediatrician recommended to continue to use the higher calorie, premature infant formula that the baby was discharged with, and to return in 1 week for followup. The medical student asked the pediatrician if the prematurity and heart problems were because of the in vitro fertilization. The pediatrician said that he wasn’t entirely sure. “I know that there are lots of different technologies and the numbers are probably quite different for any of them. The one thing I personally have seen is a smaller number of multiple gestation pregnancies and those certainly have higher risks for the babies and the moms,” he noted.

Discussion
“ART [assisted reproductive technologies] includes all fertility treatments in which either eggs or embryos are handled. The main type of ART is in vitro fertilization (IVF). IVF involves extracting a woman’s eggs, fertilizing the eggs in the laboratory, and then transferring the resulting embryos into the woman’s uterus through the cervix.” In Europe 2-6% of all births are due to some type of ART and ART occurs in 2% of US births. In 2021 in the US, there were 91,906 live births and 97,128 live born infants due to ART. ART is an enabling medical treatment for subfertile or infertile patients. However with any medical treatment there are also potential risks which are outlined below.

The IVF technology and infertility itself appear to be separate risk factors for increased risks. Parental factors can include overall genetics and epigenetics factors, maternal environment (e.g. alcohol, drugs, tobacco use, weight, etc.), age, and reproductive disease (e.g. endometriosis, male fertility, etc). IVF factors can include many factors but especially specific technology type, (e.g. fresh versus frozen embryo transfer, number of embryos transferred, etc), and even culture media and culture time. The specific risks also vary depending on the control group used to study for possible risks (e.g. multiple versus singleton births, ART versus spontaneously conceived offspring, ART and spontaneously conceived offspring, IVF versus subfertile women, etc.). Some risk factors are possibly modifiable. For example, in the past multiple embryos were transferred. More recently fewer embryos are being transferred resulting in fewer multiple gestations and the risks associated with such pregnancies.

Learning Point
“Overall IVF is associated with an increased health risk for the offspring in the form of malformations, functional disorders and a poorer peripartum outcome.”
Potential risks after IVF by various meta-analyses studies shows:

  • General malformations – relative risk = 1.33 with confidence interval of 1.24-1.43
    • Cardiac malformation/defect – odds ratio = 1.45 with confidence interval of 1.20-1.76
    • Central nervous system malformation – odds ratio = 1.36 with confidence interval of 1.10-1.70
    • Musculoskeletal malformation – odds ratio = 1.35 with confidence interval of 1.12-1.64
    • Urogenital malformation – odds ratio = 1.58 with confidence interval of 1.28-1.94
  • Low birth weight (< 2500 grams) – odds ratio = 1.89 with confidence interval of 1.36-2.62
  • Macrosomia (> 4000 gram) – odds ratio = 1.85 with confidence interval of 1.46-2.33
  • Prematurity – odds ratio = 1.79 with confidence interval of 1.21-2.63

Summaries from other studies show that overall growth of ART offspring appears to be normal. There are conflicting results for neurodevelopmental outcomes, some of which is improved when adjusted for multiple births. Overall cancer risk is reported as “overall reassuring.” Data suggests there is also increased blood pressure and poorer metabolic profile with ART.

Questions for Further Discussion
1. What is the role of surfactant in bronchopulmonary dysplasia? A review can be found here
2. What are common epigenetic imprinting disorders? A review can be found here
3. How common is infertility?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Assisted Reproductive Technology and Infertility.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Berntsen S, Soderstrom-Anttila V, Wennerholm UB, et al. The health of children conceived by ART: ‘the chicken or the egg?’\’ Hum Reprod Update. 2019;25(2):137-158. doi:10.1093/humupd/dmz001

von Wolff M, Haaf T. In Vitro Fertilization Technology and Child Health. Dtsch Arztebl Int. 2020;117(3):23-30. doi:10.3238/arztebl.2020.0023

Hanevik HI, Hessen DO. IVF and human evolution. Hum Reprod Update. 2022;28(4):457-479. doi:10.1093/humupd/dmac014

ART Success Rates | CDC. Published August 2, 2023. Accessed September 12, 2023. https://www.cdc.gov/art/artdata/index.html

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

Published