A Zhejiang University-led study in China has compared the cognitive outcomes of children conceived through frozen embryo transfer using hormone replacement therapy with those conceived via natural cycle protocols. The retrospective cohort, drawn from a reproductive centre, followed 1,538 families and 790 singletons born between 2004 and 2017. It found no meaningful difference in early childhood IQ between the two uterine-preparation methods, but noted higher rates of unusually large babies and admissions to newborn care units in the hormone replacement therapy group.
Researchers distinguished two ways of preparing the uterus for embryo transfer. The natural cycle method relies on the mother’s own hormonal rhythm to thicken the uterine lining, with monitoring and sometimes an injection to trigger ovulation, plus progesterone support in early pregnancy. By contrast, hormone replacement therapy uses externally supplied estrogen and progesterone to artificially build up the lining, without triggering ovulation.
The team drew on medical records and follow-up cognitive assessments from a reproductive centre in China. They excluded blastocyst transfers and included singletons only. Of the 790 eligible children, 434 were conceived with the natural cycle approach and 356 with hormone replacement therapy. The assessments were conducted when the children were between three and six years old, using a standardised intelligence test adapted for Chinese children. Verbal and performance IQ tasks were combined into a full-scale IQ, with assessors blinded to the embryo transfer method.
After adjusting for factors such as transfer year, parental ages and body mass index, fertilisation method (IVF or ICSI), duration of embryo freezing, endometrial thickness, maternal estrogen level, length of pregnancy, and newborn unit admissions, the study found no statistically significant differences in verbal, performance, or full-scale IQ between the two groups. The hormone group’s full-scale IQ averaged about two points lower after adjustment, a difference that did not reach conventional levels of statistical significance.
Rates of intellectual disability, defined as an IQ below 80, were similar across groups. A secondary finding showed the hormone group scoring slightly higher on the vocabulary subtest, but the authors caution that this result was exploratory and not corrected for multiple comparisons.
The researchers also performed subgroup analyses by child sex and by fertilisation method (standard IVF vs intracytoplasmic sperm injection). Across all subgroups, no statistically significant IQ differences emerged between hormone replacement therapy and natural cycle protocols.
In discussing potential mechanisms, the authors note that maternal estrogen levels in the hormone therapy group were, on average, about a third higher than in the natural cycle group, though with wide variation and about a quarter of hormone-treated mothers experiencing levels more than four times higher than typical natural-cycle levels. The study did not test estrogen levels directly for cognitive outcomes, but the authors suggest this difference could be relevant to prior research linking high estrogen exposure to neurodevelopmental outcomes.
Birth outcomes differed between groups. Babies conceived after hormone therapy were more likely to be large for gestational age—22.2% versus 15.2% in the natural cycle group—and to require newborn care unit admission—14.6% versus 9.0%. Jaundice, respiratory diseases, and preterm birth were among the major reasons cited for admissions.
As with all retrospective analyses, the authors emphasise limitations. The non-randomised design means unmeasured factors such as parental lifestyle or socioeconomic status could influence results, and the treatment period spanned years during which clinical practices evolved. They caution against over-adjustment in the statistical model, and note that findings may not apply to blastocyst transfers or to women who do not ovulate regularly. The children were followed only up to age six, so longer-term effects remain unknown.
The study, titled Cognitive function in offspring born after frozen embryo transfer following hormone replacement therapy cycles versus natural cycles: a retrospective cohort study, was authored by Xiaomeng Shi, Xiaojing Wu, Aqiong Xie, Shuangying Liu, Xiaoqian Zhou, Yingzhi Yang, Minyue Tang and Yimin Zhu of Zhejiang University.
