Differential gene expression during placentation in pregnancies conceived with different fertility treatments compared with spontaneous pregnancies

Lee, Bora; Koeppel, Alexander F.; Wang, Erica T.; Gonzalez, Tania L.; Sun, Tianyanxin; Kroener, Lindsay; Lin, Yayu; Joshi, Nikhil; Ghadiali, Tejal; Turner, Stephen D.; Rich, Stephen S.; Farber, Charles R.; Rotter, Jerome I.; Chen, Yii‐Der Ida; Goodarzi, Mark O.; Guller, Seth; Harwood, Bryna; Serna, Tania Basu; Williams, John; Pisarska, Margareta D.

doi:10.1016/j.fertnstert.2018.11.005

Cited by 13 publications

(6 citation statements)

References 88 publications

(86 reference statements)

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“…Placentation may be altered due to the supraphysiological blood concentrations of oestradiol and progesterone following ovarian stimulation and fresh ET, lasting at least through the first trimester (Järvelä et al, 2014) and possibly causing increased risk of low birth weight (Pereira et al, 2017). Varying epigenetic changes and differences in gene expression in placentas and children from pregnancies originating after FET, fresh ET and NC have been discovered (Estill et al, 2016;Choux et al, 2018;Lee et al, 2019). It has also been suggested that the effect of ART on DNA methylation in placenta is genotype specific (Marjonen et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

High birth weight and large-for-gestational-age in singletons born after frozen compared to fresh embryo transfer, by gestational week: a Nordic register study from the CoNARTaS group

et al. 2021

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STUDY QUESTION When do the differences in birth weights become apparent between singletons born after frozen embryo transfer (FET) and fresh embryo transfer (fresh ET)? SUMMARY ANSWER Mean birth weights after FET become significantly higher starting from gestational week (GW) 33 among boys and from GW 34 among girls. WHAT IS KNOWN ALREADY In recent years, there has been a steep rise in recorded FET treatments, enabling widespread use of elective single embryo transfer, thus reducing the risks associated with multiple gestations. However, singletons born after FET are heavier and there is a higher risk of large-for-gestational-age (LGA) (birth weight > 90 percentiles) compared to fresh ET. In contrast, risk of small-for-gestational-age (SGA, birth weight < 10 percentiles) is lower in singletons born after FET compared to fresh ET. The reasons, timing and consequences of these differences remain largely unclear. There is limited evidence about whether this difference in growth develops before the last trimester of pregnancy. STUDY DESIGN, SIZE, DURATION This retrospective Nordic register-based cohort study compared singletons born after FET (n = 17 500) to singletons born after fresh ET (n = 69 510) and natural conception (NC, n = 3 311 588). All live born singletons born between the years 2000 and 2015 in Denmark, Norway and Sweden at gestational age ≥22 weeks were included from the population-based Committee of Nordic ART and Safety (CoNARTaS) study population. PARTICIPANTS/MATERIALS, SETTING, METHODS Children born after FET were compared to those born after fresh ET and NC for mean birth weight and proportion of LGA and SGA for each GW at birth. Chi-square test and tests for relative proportions were used to compare categorical variables and Student’s t-test was used to compare continuous variables. Adjusted odds ratios (aORs) for LGA and SGA were calculated using logistic regressions, adjusting for year of birth, maternal age, parity, BMI, chronic hypertension, diabetes, smoking and offspring sex. MAIN RESULTS AND THE ROLE OF CHANCE Mean birth weights were significantly higher after FET compared to fresh ET starting from GW 33 (range from 75 g to 228 g by week) for boys and starting from GW 34 (range from 90 g to 236 g by week) for girls. Boys born after FET had a significantly higher proportion of LGA (11.0–15.1%) at birth between GW 36 and 42, compared to those born after fresh ET (7.1–9.4%) (range from P < 0.001 to P = 0.048 by week). For girls born after FET, the difference was seen between GW 37 and 42 (10.6–13.4%) compared to those born after fresh ET (6.6–8.0%) (range from P < 0.001 to P = 0.009 by week). The proportion of SGA was significantly lower among boys born after FET (7.6–8.7%) compared to fresh ET (11.9–13.6%) between GW 36 and 42 (range from P < 0.001 to P = 0.016 by week). For girls born after FET, the difference was seen between GW 38 and 42 (7.0–9.3%) compared to those born after fresh ET (13.0–14.6%) (P < 0.001). The proportion of LGA (12.3–15.1%) was significantly higher for boys born after FET between GW 38 and 41 (P < 0.001) and for girls born after FET (12.6–13.4%) between GW 37 and 40 (range from P < 0.001 to P = 0.018 by week), compared to naturally conceived boys (9.7–9.9%) and girls (9.0–10.0%). All singletons born after FET had a higher risk of LGA compared to singletons born after fresh ET (aOR 1.87, 95% CI 1.76–1.98) and singletons born after NC (aOR 1.28, 95% CI 1.22–1.35). LIMITATIONS, REASONS FOR CAUTION There may be residual confounding factors that we were not able to control for, most importantly the causes of preterm birth, which may also influence foetal growth. A further limitation is that we have no knowledge on growth patterns between implantation and GW 22. Finally, the number of children born extremely preterm or post-term was limited even in this large study population. WIDER IMPLICATIONS OF THE FINDINGS This is, to date, the largest study on birth weights among preterm and term ART singletons with a population-based design and NC control group. The results suggest that the freeze–thaw process is associated with higher birthweights and greater risk of LGA at least in the last trimester of pregnancy. This is an important aspect of the safety profile of ART. More research is needed on the long-term outcome of these children. STUDY FUNDING/COMPETING INTEREST(S) The CoNARTaS collaboration has received the following funding: the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk [71450], the Central Norway Regional Health Authorities [46045000], the Norwegian Cancer Society [182356-2016], the Nordic Federation of Obstetrics and Gynaecology [NF13041, NF15058, NF16026 and NF17043], the Interreg Öresund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project) and the Research Council of Norway’s Centre of Excellence funding scheme [262700]. None of the authors have any competing interests to declare. TRIAL REGISTRATION NUMBER ISRCTN11780826.

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Section: Discussionmentioning

confidence: 99%

High birth weight and large-for-gestational-age in singletons born after frozen compared to fresh embryo transfer, by gestational week: a Nordic register study from the CoNARTaS group

et al. 2021

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“…A second study investigated first-trimester samples from chorionic villus sampling and included a non-IVF fertility treatment group in addition to the IVF and SC groups. Herein the authors reported modest differences in the transcriptome and suggested that underlying infertility, in addition to treatment-related factors, might be key contributors to the observed gene expression abnormalities in the IVF group ( Lee et al, 2019 ). Similarly, a recent study that compared first-trimester maternal plasma metabolomic profiles in women undergoing IVF, non-IVF fertility treatment, and SC ( Sun et al, 2019 ) found elevated circulating levels of several lipid and lipid-related components (e.g., steroid metabolites, and lipids with docosahexaenoyl acyl chains, and acylcholines) in the infertile groups of women, especially when IVF was performed.…”

Section: Intrauterine Mechanisms–placental Programming In Artmentioning

confidence: 90%

The Consequences of Assisted Reproduction Technologies on the Offspring Health Throughout Life: A Placental Contribution

Schroêder

Badini

Sferruzzi‐Perri

et al. 2022

Front. Cell Dev. Biol.

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The use of assisted reproductive technologies (ART) worldwide has led to the conception and birth of over eight million babies since being implemented in 1978. ART use is currently on the rise, given growing infertility and the increase in conception age among men and women in industrialized countries. Though obstetric and perinatal outcomes have improved over the years, pregnancies achieved by ART still bear increased risks for the mother and the unborn child. Moreover, given that the first generation of ART offspring is now only reaching their forties, the long-term effects of ART are currently unknown. This is important, as there is a wealth of data showing that life-long health can be predetermined by poor conditions during intrauterine development, including irregularities in the structure and functioning of the placenta. In the current review, we aim to summarize the latest available findings examining the effects of ART on the cardiometabolic, cognitive/neurodevelopmental, and behavioral outcomes in the perinatal period, childhood and adolescence/adulthood; and to examine placental intrinsic factors that may contribute to the developmental outcomes of ART offspring. Altogether, the latest knowledge about life outcomes beyond adolescence for those conceived by ART appears to suggest a better long-term outcome than previously predicted. There are also changes in placenta structure and functional capacity with ART. However, more work in this area is critically required, since the potential consequences of ART may still emerge as the offspring gets older. In addition, knowledge of the placenta may help to foresee and mitigate any adverse outcomes in the offspring.

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“…However, several studies (34)(35)(36) supported that the alternation of epigenetics in the process of FET was linked with abnormal placentation and fetal growth. In addition, differences in gene expression were detected in placentas and fetuses from FET cycles (37). Owing to the limited sample size and multiple potential factors during pregnancy, further researches are needed to address these changes.…”

Section: Comparison With Other Studiesmentioning

confidence: 99%

The Impact of Embryo Storage Time on Pregnancy and Perinatal Outcomes and the Time Limit of Vitrification: A Retrospective Cohort Study

et al. 2021

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BackgroundThe technique of embryo cryopreservation has been increasingly applied in clinical settings. However, there has been a concern about the safety and efficacy of long-term freezing of embryos. Therefore, the aim of this study was to evaluate whether storage time of vitrification had any effects on pregnancy as well as perinatal outcomes, further, to explore the appropriate time limit of vitrification.MethodsThe study included women who underwent at least one frozen-thawed cycle with single embryo transfer between January 1st, 2016 and September 30th, 2019. Patients were assigned into 3 groups according to the storage time (<3 months, 3-12 months and >12 months) to evaluate the impact of embryo storage time on pregnancy and perinatal outcomes. To further investigate the time limit of vitrification, propensity score matching was used to compare the primary outcomes of patients with storage time of 1-3 years, 3-5 years, and >5 years to those stored for ≤1 year.ResultsA total of 9806 frozen-thawed embryo transfer cycles were included in our study. After adjustment for confounding variables, no significant differences were found in pregnancy outcomes among groups. However, postponement of transfer increased the risks of large for gestational age and placenta previa. In addition, after propensity score matching, 171 cycles with storage time >5 years were matched with those ≤1 year, both the clinical pregnancy rate and live birth rate decreased significantly when the storage time exceeded 5 years.ConclusionsThe duration of vitrification did not significantly affect the pregnancy outcomes within 5 years period. However, the clinical pregnancy rate and live birth rate both decreased significantly when the duration of vitrification exceeded 5 years. It is worth noting that the conclusion was drawn from a small sample study after propensity score matching and should be treated with caution. In addition, the cycles were from different time periods, which could have an impact on the results.

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Differential gene expression during placentation in pregnancies conceived with different fertility treatments compared with spontaneous pregnancies

Abstract: Objective: To identify differences in the transcriptomic profiles during placentation from pregnancies conceived spontaneously to those with infertility, using non-in vitro fertilization (NIFT) or in vitro fertilization (IVF).

Cited by 13 publications

References 88 publications

High birth weight and large-for-gestational-age in singletons born after frozen compared to fresh embryo transfer, by gestational week: a Nordic register study from the CoNARTaS group

High birth weight and large-for-gestational-age in singletons born after frozen compared to fresh embryo transfer, by gestational week: a Nordic register study from the CoNARTaS group

The Consequences of Assisted Reproduction Technologies on the Offspring Health Throughout Life: A Placental Contribution

The Impact of Embryo Storage Time on Pregnancy and Perinatal Outcomes and the Time Limit of Vitrification: A Retrospective Cohort Study

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