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Association of transfer of frozen embryos in the programmed cycle with hypertensive disorders of pregnancy

Published:February 12, 2022DOI:https://doi.org/10.1016/j.ajog.2022.02.009

      Objective

      Ovulatory women with cryopreserved embryos have the option to conceive via a programmed cycle, in which the menstrual cycle is artificially created through medications, or via a natural cycle, in which the physiological menstrual cycle is simply monitored to appropriately time the transfer of an embryo in relationship to ovulation. Thus, the hallmark of a natural cycle is the presence of a corpus luteum.
      • Ghobara T.
      • Gelbaya T.A.
      • Ayeleke R.O.
      Cycle regimens for frozen-thawed embryo transfer.
      The contribution of the corpus luteum to early placental development, a critical component to optimizing many pregnancy outcomes, has been increasingly recognized.
      • Conrad K.P.
      • von Versen-Höynck F.
      • Baker V.L.
      Potential role of the corpus luteum in maternal cardiovascular adaptation to pregnancy and preeclampsia risk.
      As patients conceiving via assisted reproductive technology are at higher risk of adverse pregnancy outcomes, risk reduction strategies that do not compromise live birth rates are crucial.
      • Zhu L.
      • Zhang Y.
      • Liu Y.
      • et al.
      Maternal and live-birth outcomes of pregnancies following assisted reproductive technology: a retrospective cohort study.
      We sought to determine whether frozen embryo transfer (FET) in the programmed cycle vs natural cycle was associated with increased risks of hypertensive disorders of pregnancy (HDP) in ovulatory women.

      Study Design

      We conducted a secondary analysis of a retrospective cohort study on the association of fetal fraction with HDP in in vitro fertilization–conceived singleton pregnancies.
      • Cagino K.
      • Bortoletto P.
      • McCarter K.
      • et al.
      Association between low fetal fraction and hypertensive disorders of pregnancy in in vitro fertilization-conceived pregnancies.
      Here, we restricted the analysis to ovulatory women who underwent FET in the natural or programmed cycle and had a live birth at >20 weeks of gestation at a single academic center from 2013 to 2019. The primary outcome was a diagnosis of HDP during the delivery hospitalization. HDP was defined as worsening chronic hypertension, a new diagnosis of gestational hypertension, superimposed preeclampsia, or preeclampsia with or without severe features. The secondary outcome was small for gestational age (SGA), defined as a birthweight of <10th percentile by fetal sex and gestational age. We performed multivariable logistic regression analyses to determine whether frozen transfer cycle type was associated with (1) HDP and (2) SGA, controlling for maternal age at time of transfer, prepregnancy body mass index, maternal comorbidities (diabetes mellitus, hypertension, antiphospholipid antibody syndrome, or lupus), and antenatal aspirin use in both regression models.

      Results

      We included 299 women (78.3%) who underwent natural FET and 109 women (26.7%) who underwent programmed FET. Demographic characteristics were similar between groups. The adjusted prevalence rates of HDP were 22.1% in natural FET and 32.4% in programmed FET. The most common type of HDP diagnosed was gestational hypertension (74.7%), followed by preeclampsia with severe features (10.5%) and without severe features (8.4%). Transfer in the programmed cycles was associated with higher odds of HDP than transfer in the natural cycles (adjusted odds ratio [aOR], 1.65; 95% confidence interval [CI], 1.01–2.72; P=.048). The adjusted prevalence rates of SGA were 10.4% in natural FET and 7.4% in programmed FET. Transfer cycle type was not associated with a diagnosis of SGA (aOR, 0.72; 95% CI, 0.32–1.65; P=.443) (Table) .
      TableMultivariable regression for hypertensive disorder of pregnancy and small for gestational age outcomes
      VariableHDPSGA
      aOR95% CIP valueaOR95% CIP value
      Transfer cycle type
       NaturalRefRefRefRefRefRef
       Programmed1.651.01–2.72.0480.720.32–1.65.443
      BMI1.071.00–1.13.0450.900.80–1.01.074
      Maternal age1.010.95–1.08.7111.050.95–1.16.307
      Maternal comorbidities1.510.62–3.66.3661.950.51–7.52.333
      Aspirin use in pregnancy1.710.78–3.73.1790.770.21–2.88.703
      aOR, adjusted odds ratio; BMI, body mass index; CI, confidence interval; HDP, hypertensive disorders of pregnancy; Ref, referent; SGA, small for gestational age.
      Bortoletto. Frozen embryo transfer cycle type and hypertensive disorders of pregnancy. Am J Obstet Gynecol 2022.

      Conclusion

      In ovulatory women conceiving via FET, transfer in the programmed cycles, where a corpus luteum is not present, was associated with higher odds of HDP than transfer in the natural FET cycles. Prioritizing the use of natural FET cycles may represent an opportunity for risk reduction for ovulatory women undergoing FET cycles who would otherwise be counseled toward programmed FET.

      References

        • Ghobara T.
        • Gelbaya T.A.
        • Ayeleke R.O.
        Cycle regimens for frozen-thawed embryo transfer.
        Cochrane Database Syst Rev. 2017; 7: CD003414
        • Conrad K.P.
        • von Versen-Höynck F.
        • Baker V.L.
        Potential role of the corpus luteum in maternal cardiovascular adaptation to pregnancy and preeclampsia risk.
        Am J Obstet Gynecol. 2021; ([Epub ahead of print])
        • Zhu L.
        • Zhang Y.
        • Liu Y.
        • et al.
        Maternal and live-birth outcomes of pregnancies following assisted reproductive technology: a retrospective cohort study.
        Sci Rep. 2016; 6: 35141
        • Cagino K.
        • Bortoletto P.
        • McCarter K.
        • et al.
        Association between low fetal fraction and hypertensive disorders of pregnancy in in vitro fertilization-conceived pregnancies.
        Am J Obstet Gynecol MFM. 2021; 3: 100463