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Long-term health risk of offspring born from assisted reproductive technologies

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Abstract

Since the world’s first in vitro fertilization baby was born in 1978, there have been more than 8 million children conceived through assisted reproductive technologies (ART) worldwide, and a significant proportion of them have reached puberty or young adulthood. Many studies have found that ART increases the risk of adverse perinatal outcomes, including preterm birth, low birth weight, small size for gestational age, perinatal mortality, and congenital anomalies. However, data regarding the long-term outcomes of ART offspring are limited. According to the developmental origins of health and disease theory, adverse environments during early life stages may induce adaptive changes and subsequently result in an increased risk of diseases in later life. Increasing evidence also suggests that ART offspring are predisposed to an increased risk of non-communicable diseases, such as malignancies, asthma, obesity, metabolic syndrome, diabetes, cardiovascular diseases, and neurodevelopmental and psychiatric disorders. In this review, we summarize the risks for long-term health in ART offspring, discuss the underlying mechanisms, including underlying parental infertility, epigenetic alterations, non-physiological hormone levels, and placental dysfunction, and propose potential strategies to optimize the management of ART and health care of parents and children to eliminate the associated risks. Further ongoing follow-up and research are warranted to determine the effects of ART on the long-term health of ART offspring in later life.

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Data availability

Data sharing is not applicable to this manuscript, as no new datasets (human or animal) were generated or analyzed during the current study.

Abbreviations

ART:

Assisted reproductive technologies

IVF:

In vitro fertilization

ICSI:

Intracytoplasmic sperm injection

PGT:

Preimplantation genetic testing

SC:

Spontaneously conceived

IUGR:

Intrauterine growth restriction

ALL:

Acute lymphoid leukemia

FET:

Frozen embryo transfer

BMI:

Body mass index

HFD:

High-fat diet

TSH:

Thyroid-stimulating hormone

TRH:

Thyrotropin-releasing hormone

E2:

Estradiol

ET:

Embryo transplantation

T4:

Thyroxine

FT4:

Free thyroxine

ASD:

Autism spectrum disorder

PCOS:

Polycystic ovarian syndrome

ADHD:

Attention deficit and hyperactivity disorder

ID:

Intellectual disability

OHSS:

Ovarian hyperstimulation syndrome

CP:

Cerebral palsy

OS:

Ovulation stimulation

IGF2:

Insulin-like growth factor 2

COH:

Controlled ovarian hyperstimulation

OCP:

Oral contraceptive pill

SET:

Single-embryo transfer

NCD:

Non-communicable diseases

DOHaD:

Developmental origins of health and disease

HR:

Hazard ratio

OR:

Odd ratio

CI:

Confidence interval

SFA:

Saturated fatty acid

HOMA-IR:

Homeostasis model assessment-insulin resistance

SBP:

Systolic blood pressure

DBP:

Diastolic blood pressure

RR:

Relative risk

PGD:

Preimplantation genetic diagnosis

DHEAS:

Dehydroepiandrosterone sulfate

LH:

Luteinizing hormone

DNA:

Deoxyribonucleic acid

EEC:

Endometrial epithelial cell

YCM:

Y-chromosome microdeletion

RNA:

Ribonucleic acid

MII:

Meiosis II

TFG:

Trafficking from ER to golgi regulator

MAPK:

Mitogen-activated protein kinase

AKT:

Protein kinase B

FSH:

Follicle-stimulating hormone

LBW:

Low birth weight

SGA:

Small for gestational age

LGA:

Large for gestational age

hCG:

Human chorionic gonadotrophin

OB/GYN:

Obstetrics and gynecology

IQ:

Intelligence quotient

niPGT:

Noninvasive PGT

NO:

Nitrogen monoxide

GnRH‑a:

Gonadotropin-releasing hormone analogue

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Acknowledgements

We are grateful to Li Jin, Xianhua Lin, and Chenming Xu for participating in the discussion of this article.

Funding

This work was supported by the National Key Research and Development Program of China (2021YFC2700701, 2022YFC2703505), the National Natural Science Foundation of China (8211101588, 82088102, 82171686), the Program of Shanghai Academic Research Leader (20XD1424100), the Natural Science Foundation of Shanghai (20ZR1463100), the Clinical research program of Shanghai Municipal Health Commission (202340222), the Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01), the Clinical Research Plan of Shanghai Shenkang Hospital Development Center (SHDC2023CRD001, SHDC2020CR1008A), the Outstanding Youth Medical Talents of Shanghai Rising Stars of Medical Talent Youth Development Program, the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-064), the Shanghai Clinical Research Center for Gynecological Diseases (22MC1940200), the Shanghai Urogenital System Diseases Research Center (2022ZZ01012), the Key Discipline Construction Project（2023-2025）of Three-Year Initiative Plan for Strengthening Public Health System Construction in Shanghai (GWVI-11.1-35) and Shanghai Frontiers Science Research Base of Reproduction and Development.

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Author notes

  1. Siwei Zhang and Qinyu Luo contributed equally.

Authors and Affiliations

  1. Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, No. 419, Fangxie Rd, Shanghai, 200011, China

    Siwei Zhang, Renyu Meng, Jing Yan, Yanting Wu & Hefeng Huang

  2. Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University School of Medicine, Hangzhou, China

    Qinyu Luo & Hefeng Huang

  3. Research Unit of Embryo Original Diseases (No. 2019RU056), Chinese Academy of Medical Sciences, Shanghai, China

    Yanting Wu & Hefeng Huang

Authors
  1. Siwei Zhang
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  2. Qinyu Luo
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  3. Renyu Meng
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  4. Jing Yan
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  5. Yanting Wu
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  6. Hefeng Huang
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Contributions

Y.T.W. and H.F.H. conceived the review design and revised the drafts. Y.T.W., S.W.Z., Q.Y.L, R.Y.M., and J.Y., analyzed and interpreted the literature and drafted the manuscript. Y.T.W. and H.F.H. coordinated the study and critically revised the manuscript for important intellectual content to its final version. All authors commented on the drafts and approved the final draft.

Corresponding authors

Correspondence to Yanting Wu or Hefeng Huang.

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Zhang, S., Luo, Q., Meng, R. et al. Long-term health risk of offspring born from assisted reproductive technologies. J Assist Reprod Genet 41, 527–550 (2024). https://doi.org/10.1007/s10815-023-02988-5

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