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      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus

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          ABSTRACT

          STUDY QUESTION

          What were the risks with regard to the pregnancy outcomes of patients who conceived by frozen-thawed embryo transfer (FET) during a hormone replacement cycle (HRC-FET)?

          SUMMARY ANSWER

          The patients who conceived by HRC-FET had increased risks of hypertensive disorders of pregnancy (HDP) and placenta accreta and a reduced risk of gestational diabetes mellitus (GDM) in comparison to those who conceived by FET during a natural ovulatory cycle (NC-FET).

          WHAT IS KNOWN ALREADY

          Previous studies have shown that pregnancy and live-birth rates after HRC-FET and NC-FET are comparable. Little has been clarified regarding the association between endometrium preparation and other pregnancy outcomes.

          STUDY DESIGN, SIZE, DURATION

          A retrospective cohort study of patients who conceived after HRC-FET and those who conceived after NC-FET was performed based on the Japanese assisted reproductive technology registry in 2014.

          PARTICIPANTS/MATERIALS, SETTING, METHODS

          The pregnancy outcomes were compared between NC-FET (n = 29 760) and HRC-FET (n = 75 474) cycles. Multiple logistic regression analyses were performed to investigate the potential confounding factors.

          MAIN RESULTS AND THE ROLE OF CHANCE

          The pregnancy rate (32.1% vs 36.1%) and the live birth rate among pregnancies (67.1% vs 71.9%) in HRC-FET cycles were significantly lower than those in NC-FET cycles. A multiple logistic regression analysis showed that pregnancies after HRC-FET had increased odds of HDPs [adjusted odds ratio, 1.43; 95% confidence interval (CI), 1.14–1.80] and placenta accreta (adjusted odds ratio, 6.91; 95% CI, 2.87–16.66) and decreased odds for GDM (adjusted odds ratio, 0.52; 95% CI, 0.40–0.68) in comparison to pregnancies after NC-FET.

          LIMITATIONS, REASONS FOR CAUTION

          Our study was retrospective in nature, and some cases were excluded due to missing data. The implication of bias and residual confounding factors such as body mass index, alcohol consumption, and smoking habits should be considered in other observational studies.

          WIDER IMPLICATIONS OF THE FINDINGS

          Pregnancies following HRC-FET are associated with higher risks of HDPs and placenta accreta and a lower risk of GDM. The association between the endometrium preparation method and obstetrical complication merits further attention.

          STUDY FUNDING/COMPETING INTEREST(S)

          No funding was obtained for this work. The authors declare no conflicts of interest in association with the present study.

          TRIAL REGISTRATION NUMBER

          Not applicable.

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          Most cited references16

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          Placenta accreta: pathogenesis of a 20th century iatrogenic uterine disease.

          Placenta accreta refers to different grades of abnormal placental attachment to the uterine wall, which are characterised by invasion of trophoblast into the myometrium. Placenta accreta has only been described and studied by pathologists for less than a century. The fact that the first detailed description of a placenta accreta happened within a couple of decades of major changes in the caesarean surgical techniques is highly suggestive of a direct relationship between prior uterine surgery and abnormal placenta adherence. Several concepts have been proposed to explain the abnormal placentation in placenta accreta including a primary defect of the trophoblast function, a secondary basalis defect due to a failure of normal decidualization and more recently an abnormal vascularisation and tissue oxygenation of the scar area. The vast majority of placenta accreta are found in women presenting with a previous history of caesarean section and a placenta praevia. Recent epidemiological studies have also found that the strongest risk factor for placenta praevia is a prior caesarean section suggesting that a failure of decidualization in the area of a previous uterine scar can have an impact on both implantation and placentation. Ultrasound studies of uterine caesarean section scar have shown that large and deep myometrial defects are often associated with absence of re-epithelialisation of the scar area. These findings support the concept of a primary deciduo-myometrium defect in placenta accreta, exposing the myometrium and its vasculature below the junctional zone to the migrating trophoblast. The loss of this normal plane of cleavage and the excessive vascular remodelling of the radial and arcuate arteries can explain the in-vivo findings and the clinical consequence of placenta accreta. Overall these data support the concept that abnormal decidualization and trophoblastic changes of the placental bed in placenta accreta are secondary to the uterine scar and thus entirely iatrogenic.
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            Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group.

            What are the risks of adverse outcomes in singletons born after frozen-thawed embryo transfer (FET)? Singletons born after FET have a better perinatal outcome compared with singletons born after fresh IVF and ICSI as regards low birthweight (LBW) and preterm birth (PTB), but a worse perinatal outcome compared with singletons born after spontaneous conception. Previous studies have shown a worse perinatal outcome in children born after IVF in general compared with children born after spontaneous conception. In singletons born after FET, a lower rate of PTB and LBW and a higher rate of large for gestational age (LGA) compared with singletons born after fresh IVF have been shown. A retrospective Nordic population-based cohort study of all singletons conceived after FET in Denmark, Norway and Sweden until December 2007 was performed. Singletons born after FET (n = 6647) were compared with a control group of singletons born after fresh IVF and ICSI (n = 42 242) and singletons born after spontaneous conception (n = 288 542). Data on perinatal outcomes were obtained by linkage to the national Medical Birth Registries. Odds ratios were calculated for several perinatal outcomes and adjustments were made for maternal age, parity, year of birth, offspring sex and country of origin. Singletons born after FET had a lower risk of LBW (adjusted odds ratio (aOR) 0.81, 95% confidence interval (CI) 0.71-0.91), PTB (aOR 0.84, 95% CI 0.76-0.92), very PTB (VPTB; aOR 0.79, 95% CI 0.66-0.95) and small for gestational age (SGA; aOR 0.72, 95% CI 0.62-0.83), but a higher risk of post-term birth (aOR 1.40, 95% CI 1.27-1.55), LGA (aOR 1.45, 95% CI 1.27-1.64), macrosomia (aOR 1.58, 95% CI 1.39-1.80) and perinatal mortality (aOR 1.49, 95% CI 1.07-2.07) compared with singletons born after fresh IVF and ICSI. Compared with children conceived after spontaneous conception, singletons born after FET had a higher risk of LBW (aOR 1.27, 95% CI 1.13-1.43), very LBW (aOR 1.69, 95% CI 1.33-2.15), PTB (aOR 1.49, 95% CI 1.35-1.63), VPTB (aOR 2.68, 95% CI 2.24-3.22), SGA (aOR 1.18, 95% CI 1.03-1.35), LGA (aOR 1.29, 95% CI 1.15-1.45), macrosomia (aOR 1.29, 95% CI 1.15-1.45) and perinatal (aOR 1.39, 95% CI 1.03-1.87) neonatal (aOR 1.87, 95% CI 1.23-2.84) and infant mortality (aOR 1.92, 95% CI 1.36-2.72). When analyzing trends over time, the risk of being born LGA increased over time for singletons born after FET compared with singletons born after fresh IVF and ICSI (P = 0.04). As in all observational studies, the possible role of residual confounding factors and bias should be considered. In this study, we were not able to control for confounding factors, such as BMI, smoking and reason for, or length of, infertility. Perinatal outcomes in this large population-based cohort of children born after FET from three Nordic countries compared with fresh IVF and ICSI and spontaneous conception were in agreement with the literature.
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              Fresh versus frozen embryo transfer: backing clinical decisions with scientific and clinical evidence.

              Improvements in vitrification now make frozen embryo transfers (FETs) a viable alternative to fresh embryo transfer, with reports from observational studies and randomized controlled trials suggesting that: (i) the endometrium in stimulated cycles is not optimally prepared for implantation; (ii) pregnancy rates are increased following FET and (iii) perinatal outcomes are less affected after FET.
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                Author and article information

                Journal
                Human Reproduction
                Oxford University Press (OUP)
                0268-1161
                1460-2350
                August 2019
                August 01 2019
                July 12 2019
                August 2019
                August 01 2019
                July 12 2019
                : 34
                : 8
                : 1567-1575
                Affiliations
                [1 ]Department of Perinatal Medicine and Maternal Care, National Center for Child Health and Development, Tokyo 157-8535, Japan
                [2 ]Department of Comprehensive Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
                [3 ]Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan
                [4 ]Department of Obstetrics and Gynecology, The University of Tokushima Graduate School, Institute of Health Biosciences, Tokushima 770-8503, Japan
                [5 ]Department of Social Medicine, National Center for Child Health and Development, Tokyo 157-8535, Japan
                [6 ]Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan
                [7 ]Department of Obstetrics and Gynecology, Saitama Medical University, Saitama 350-0495, Japan
                Article
                10.1093/humrep/dez079
                31299081
                9bf60098-9edb-4dff-b0aa-7a3369827190
                © 2019

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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