Assisted Reproduction · Safety and Risks

Health of singletons born after frozen embryo transfer until early adulthood: a Finnish register study

Terho AM, Tiitinen A, Martikainen H, Gissler M, Pelkonen S

Published November 24, 2022 Human reproduction (Oxford, England)
DOI 10.1093/humrep/deac211 PMID 36166701 PMC PMC9712944

RRM Academy Synopsis

Frozen transfer children had slightly more hospital care than controls

Frozen embryo transfer children had modestly more hospital care than naturally conceived children. A Finnish register cohort followed all three groups for 18 to 20 years on average. Admissions occurred in 48 out of 100 after frozen transfer and 46.5 out of 100 after natural conception. Frozen and fresh transfer groups did not differ significantly in diagnoses or hospital care.

Key Findings

  • No significant differences appeared between the frozen and fresh embryo transfer groups in the frequency of diagnoses in any ICD-10 chapter or in the need for hospital care.
  • Outpatient hospital visits were recorded for 93.5% of the frozen transfer group and 92.2% of the natural conception group (adjusted hazard ratio, aHR, 1.23; 95% CI 1.17, 1.30).
  • Hospital admissions were recorded for 48% of the frozen transfer group and 46.5% of the natural conception group (aHR 1.28; 95% CI 1.19, 1.37).
  • Compared with natural conception, the frozen transfer group had higher adjusted risks of diagnoses in several ICD-10 chapters. Birth defects and chromosome conditions had an aHR of 1.31 (95% CI 1.14, 1.50).
  • The neoplasm aHR against natural conception was 1.68 (95% CI 1.48, 1.91); malignant neoplasms occurred in 7 (0.4%), 8 (0.3%) and 118 (0.4%) of the frozen, fresh and natural groups.

Interpretation

The study is a retrospective register cohort of 1825 frozen transfer, 2933 fresh transfer and 31 136 naturally conceived singletons. Results were adjusted for preterm birth, maternal age, parity, socioeconomic status and sex. Cohort designs show associations, and the authors note that residual confounding may remain. The register covers hospital care only, so milder illness treated elsewhere is missing. The authors could not separate assisted reproduction from parents' reduced fertility. Only slow freezing was used in Finland when these children were born, so the findings may not apply to vitrification. The authors state that larger cohorts would be needed to study rare outcomes such as cancer.

RRM Context

Embryo transfer, fresh or frozen, bypasses the reason a couple is not conceiving. That reason stays unresolved. The authors note that parents' reduced fertility is also associated with poorer asthma and infection outcomes in children. The mechanisms remain partly unclear. Restorative reproductive medicine evaluates both partners to find and treat the cause of reduced fertility.

Abstract

Is the health of singletons born after frozen embryo transfer (FET) comparable to that of singletons born after fresh embryo transfer (ET) until early adulthood? The health of singletons born after FET does not differ from that of singletons born after fresh ET. The differences in perinatal outcomes of children born after FET and fresh ET are well known. FET is associated with an increased risk of large-for-gestational-age but diminished risks of preterm birth (PTB), small-for-gestational-age and decreased perinatal mortality compared to fresh ET. However, knowledge on the long-term health after FET is scarce. This retrospective register-based cohort study compares singletons born after FET (n = 1825) between the years 1995 and 2006 to those born after fresh ET (n = 2933) and natural conception (NC, n = 31 136) with a mean follow-up time of 18-20 years. Singletons born after FET were compared to those born after fresh ET and NC regarding the frequencies of diagnoses in the main ICD-10 chapters (International Statistical Classification of Diseases and Related Health Problems, 10th revision), the number of outpatient visits and hospital admissions, and mortality. Adjustments were made for PTB, maternal age, parity, socioeconomic status based on mother's occupation and offspring sex. The study combines data from the Finnish Medical Birth Register, the Finnish Care Register for Health Care (CRHC) and the Cause-of-Death Register at Statistics Finland. The Student's T-test was used for continuous variables, and the Chi-square test was used for categorical variables. Cox regression was used to estimate crude and adjusted hazard ratios (HRs and aHRs, respectively). A general linear model was used to compare the means of outpatient visits, hospital admissions and lengths of hospital stays per person. No significant differences between the FET and fresh ET groups were found in the frequency of diagnoses in any of the ICD-10 chapters or in the parameters describing the need for hospital care. However, compared to the NC group, higher proportions in the FET group had outpatient visits in the hospital (93.5% vs 92.2%, aHR 1.23, 95% CI 1.17, 1.30) or hospital admissions (48% vs 46.5%, aHR 1.28, 95% CI 1.19, 1.37). Compared to the NC group, the FET group had elevated adjusted risks of diagnoses of infectious and parasitic diseases (aHR 1.24; 95% CI 1.11, 1.38), neoplasms (aHR 1.68; 95% CI 1.48, 1.91), diseases of the eye and adnexa, the ear or mastoid process (aHR 1.11; 95% CI 1.01, 1.21), the respiratory system (aHR 1.15; 95% CI 1.06, 1.23), the digestive system (aHR 1.17; 95% CI 1.05, 1.32), the skin or subcutaneous tissue (aHR 1.28; 95% CI 1.14, 1.43) and the genitourinary system (aHR 1.27; 95% CI 1.11, 1.45), as well as congenital malformations or chromosomal abnormalities (aHR 1.31; 95% CI 1.14, 1.50) and symptoms, signs or abnormal clinical or laboratory findings (aHR 1.25, 95% CI 1.16, 1.34). Only hospital-based inpatient and outpatient care is covered by the CRHC register, excluding milder cases diagnosed elsewhere. We were not able to study the effect of ART treatments and subfertility separately in our setting. In addition, although our cohort is reasonably sized, even larger cohorts would be needed to reliably study rare outcomes, such as cancer. For many ICD-10 chapters, we present the first published data on the long-term outcome of singletons born after FET. The results on FET versus fresh ET are reassuring, whereas the results on FET versus NC warrant further investigation. Finnish government research funding was obtained for this study. Funding was also obtained from the Finnish Medical Society Duodecim, the Päivikki and Sakari Sohlberg Foundation, Orion Research Foundation, Finnish Society of Obstetrics and Gynaecology (research grants to A.M.T.) and Finnish government research funding. The funding sources were not involved in the planning or execution of the study. The authors have no competing interests to declare. N/A.

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Assisted Reproduction › Safety and Risks › Long Term Child Outcomes
Hannu Martikainen
H Martikainen
PMID 36166701 36166701 DOI 10.1093/humrep/deac211 10.1093/humrep/deac211 Terho et al. 2022, Terho 2022