Excessive fetal growth in frozen embryo transfer: false alarm or clinical concern?

Excessive fetal growth in frozen embryo transfer: false alarm or clinical concern? Sir, Maheshwari et al. recently updated their previous meta-analysis on the impact of frozen embryo transfer on pregnancy outcome (Maheshwari et al., 2012, 2018). They confirmed, with more robust data and increased precision, the reduction in the risk of small for gestation age (SGA) newborns (RR = 0.62, 95%CI: 0.56–0.65) but also highlighted an increased risk of large for gestational age (LGA) (RR = 1.54, 95%CI: 1.48–1.61). These results (mainly obtained from observational studies) are in line with those emerging from two recent randomized control trials (excluded from the meta-analysis) on the effectiveness of the ‘freeze all’ strategy (Zhang et al., 2018; Shapiro et al., 2016). Interpretation of associations from observational studies is always challenging because of the risk of confounders (Grimes and Schulz, 2012). Nonetheless, some hypotheses can be formulated. In particular, Maheshwari et al. (2018) interpreted the reduction in SGA as a direct benefit of the frozen embryo transfer strategy on the endometrium. The hyperestrogenism associated with ovarian hyperstimulation could indeed cause ‘abnormal endometrial angiogenesis leading to (…) abnormal placentation’. On the other hand, they remained vague on the interpretation of the increased risk of LGA. They mentioned the hypothesis by Pinborg et al. (2014) who interpreted this effect as an overgrowth guided by epigenetic alterations at early embryonic stages. The freezing and thawing procedures could perturb the epigenetic processes causing overgrowth of the fetus. This view is also supported by the higher risk of LGA after frozen embryo transfer emerging from comparisons with the general population (Pinborg et al., 2014; Luke et al., 2017; Spijkers et al., 2017), an epidemiological comparison that is, however, exposed to relevant confounders, the most critical of which are the specific cause of infertility, socio-economic status and psychological conditions associated with infertility (Pandey et al., 2012; Siristatidis et al., 2013). Overall, the theory of an iatrogenic perturbation at the embryonic stages is plausible and fascinating, but inevitably fuels concerns and alarmism among physicians and patients. We suggest an alternative interpretation of the findings, namely a simple shift of the distribution curve of the newborns weights (Fig. 1). In other words, if frozen embryo replacement results in a more physiological placentation, one could expect a better fetal growth for all fetuses, not only for those who would have been SGA in fresh conditions. A significant proportion of embryos whose destiny was to be SGA if transferred in fresh conditions could be appropriate for gestational age (AGA) using the frozen approach and, similarly, a significant proportion of embryos whose destiny was to be AGA in fresh conditions could be LGA using the frozen approach. Of interest in this regard, in the study from Maheshwari et al., (2018), the magnitude of the reduction of the risk of SGA and the increase in the risk of LGA are specular and of very similar magnitude (−48% and +54%, respectively). If true, our interpretation would be extremely reassuring since it would support the view that frozen embryo transfer results in normalization of fetal growth, rather than causing overgrowth. Future well-designed observational studies comparing pregnancies from frozen embryo transfer and from natural conception may shed more light on this issue. An in-depth collection of patients’ characteristics is, however, warranted to allow for a reliable adjustment. Figure 1 View largeDownload slide Shifting of the curve of newborn weights from fresh embryo transfer (straight blue line) to frozen embryo transfer (dotted red line). The distribution is assumed to be normal just for clarity. Figure 1 View largeDownload slide Shifting of the curve of newborn weights from fresh embryo transfer (straight blue line) to frozen embryo transfer (dotted red line). The distribution is assumed to be normal just for clarity. Funding E.P. reports grants and non-financial support from Ferring, IBSA and Finox and grants, personal fees and non-financial support from MSD and Merck, outside the submitted work. E.S. reports personal fees from IBSA, grants from FERRING, grants from MERCK-SERONO, outside the submitted work. Conflicts of interest None declared. References Grimes DA , Schulz KF . False alarms and pseudo-epidemics: the limitations of observational epidemiology . Obstet Gynecol 2012 ; 120 : 920 – 927 . Google Scholar CrossRef Search ADS PubMed Luke B , Brown MB , Wantman E , Stern JE , Toner JP , Coddington CC 3rd . Increased risk of large-for-gestational age birthweight in singleton siblings conceived with in vitro fertilization in frozen versus fresh cycles . J Assist Reprod Genet 2017 ; 34 : 191 – 200 . Google Scholar CrossRef Search ADS PubMed Maheshwari A , Pandey S , Amalraj Raja E , Shetty A , Hamilton M , Bhattacharya S . Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer? . Hum Reprod Update 2018 ; 24 : 35 – 58 . Google Scholar CrossRef Search ADS PubMed Maheshwari A , Pandey S , Shetty A , Hamilton M , Bhattacharya S . Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of frozen thawed versus fresh embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis . Fertil Steril 2012 ; 98 : 368 – 377 . Google Scholar CrossRef Search ADS PubMed Pandey S , Shetty A , Hamilton M , Bhattacharya S , Maheshwari A . Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis . Hum Reprod Update 2012 ; 18 : 485 – 503 . Google Scholar CrossRef Search ADS PubMed Pinborg A , Henningsen AA , Loft A , Malchau SS , Forman J , Andersen AN. . Large baby syndrome in singletons born after frozen embryo transfer (FET): is it due to maternal factors or the cryotechnique? . Hum Reprod 2014 ; 29 : 618 – 627 . Google Scholar CrossRef Search ADS PubMed Shapiro BS , Daneshmand ST , Bedient CE , Garner FC . Comparison of birth weights in patients randomly assigned to fresh or frozen-thawed embryo transfer . Fertil Steril 2016 ; 106 : 317 – 321 . Google Scholar CrossRef Search ADS PubMed Siristatidis C , Sergentanis TN , Kanavidis P , Trivella M , Sotiraki M , Mavromatis I , Psaltopoulou T , Skalkidou A , Petridou ET . Controlled ovarian hyperstimulation for IVF: impact on ovarian, endometrial and cervical cancer—a systematic review and meta-analysis . Hum Reprod Update 2013 ; 19 : 105 – 123 . Google Scholar CrossRef Search ADS PubMed Spijkers S , Lens JW , Schats R , Lambalk CB . Fresh and frozen-thawed embryo transfer compared to natural conception: differences in perinatal outcome? Gynecol Obstet Invest 2017 ; 82 : 538 – 546 . Google Scholar CrossRef Search ADS PubMed Zhang B , Wei D , Legro RS , Shi Y , Li J , Zhang L , Hong Y , Sun G , Zhang T , Li W et al. . Obstetric complications after frozen versus fresh embryo transfer in women with polycystic ovary syndrome: results from a randomized trial . Fertil Steril 2018 ; 109 : 324 – 329 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Human Reproduction Update Oxford University Press

Excessive fetal growth in frozen embryo transfer: false alarm or clinical concern?

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Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
ISSN
1355-4786
eISSN
1460-2369
D.O.I.
10.1093/humupd/dmy010
Publisher site
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Abstract

Sir, Maheshwari et al. recently updated their previous meta-analysis on the impact of frozen embryo transfer on pregnancy outcome (Maheshwari et al., 2012, 2018). They confirmed, with more robust data and increased precision, the reduction in the risk of small for gestation age (SGA) newborns (RR = 0.62, 95%CI: 0.56–0.65) but also highlighted an increased risk of large for gestational age (LGA) (RR = 1.54, 95%CI: 1.48–1.61). These results (mainly obtained from observational studies) are in line with those emerging from two recent randomized control trials (excluded from the meta-analysis) on the effectiveness of the ‘freeze all’ strategy (Zhang et al., 2018; Shapiro et al., 2016). Interpretation of associations from observational studies is always challenging because of the risk of confounders (Grimes and Schulz, 2012). Nonetheless, some hypotheses can be formulated. In particular, Maheshwari et al. (2018) interpreted the reduction in SGA as a direct benefit of the frozen embryo transfer strategy on the endometrium. The hyperestrogenism associated with ovarian hyperstimulation could indeed cause ‘abnormal endometrial angiogenesis leading to (…) abnormal placentation’. On the other hand, they remained vague on the interpretation of the increased risk of LGA. They mentioned the hypothesis by Pinborg et al. (2014) who interpreted this effect as an overgrowth guided by epigenetic alterations at early embryonic stages. The freezing and thawing procedures could perturb the epigenetic processes causing overgrowth of the fetus. This view is also supported by the higher risk of LGA after frozen embryo transfer emerging from comparisons with the general population (Pinborg et al., 2014; Luke et al., 2017; Spijkers et al., 2017), an epidemiological comparison that is, however, exposed to relevant confounders, the most critical of which are the specific cause of infertility, socio-economic status and psychological conditions associated with infertility (Pandey et al., 2012; Siristatidis et al., 2013). Overall, the theory of an iatrogenic perturbation at the embryonic stages is plausible and fascinating, but inevitably fuels concerns and alarmism among physicians and patients. We suggest an alternative interpretation of the findings, namely a simple shift of the distribution curve of the newborns weights (Fig. 1). In other words, if frozen embryo replacement results in a more physiological placentation, one could expect a better fetal growth for all fetuses, not only for those who would have been SGA in fresh conditions. A significant proportion of embryos whose destiny was to be SGA if transferred in fresh conditions could be appropriate for gestational age (AGA) using the frozen approach and, similarly, a significant proportion of embryos whose destiny was to be AGA in fresh conditions could be LGA using the frozen approach. Of interest in this regard, in the study from Maheshwari et al., (2018), the magnitude of the reduction of the risk of SGA and the increase in the risk of LGA are specular and of very similar magnitude (−48% and +54%, respectively). If true, our interpretation would be extremely reassuring since it would support the view that frozen embryo transfer results in normalization of fetal growth, rather than causing overgrowth. Future well-designed observational studies comparing pregnancies from frozen embryo transfer and from natural conception may shed more light on this issue. An in-depth collection of patients’ characteristics is, however, warranted to allow for a reliable adjustment. Figure 1 View largeDownload slide Shifting of the curve of newborn weights from fresh embryo transfer (straight blue line) to frozen embryo transfer (dotted red line). The distribution is assumed to be normal just for clarity. Figure 1 View largeDownload slide Shifting of the curve of newborn weights from fresh embryo transfer (straight blue line) to frozen embryo transfer (dotted red line). The distribution is assumed to be normal just for clarity. Funding E.P. reports grants and non-financial support from Ferring, IBSA and Finox and grants, personal fees and non-financial support from MSD and Merck, outside the submitted work. E.S. reports personal fees from IBSA, grants from FERRING, grants from MERCK-SERONO, outside the submitted work. Conflicts of interest None declared. References Grimes DA , Schulz KF . False alarms and pseudo-epidemics: the limitations of observational epidemiology . Obstet Gynecol 2012 ; 120 : 920 – 927 . Google Scholar CrossRef Search ADS PubMed Luke B , Brown MB , Wantman E , Stern JE , Toner JP , Coddington CC 3rd . Increased risk of large-for-gestational age birthweight in singleton siblings conceived with in vitro fertilization in frozen versus fresh cycles . J Assist Reprod Genet 2017 ; 34 : 191 – 200 . Google Scholar CrossRef Search ADS PubMed Maheshwari A , Pandey S , Amalraj Raja E , Shetty A , Hamilton M , Bhattacharya S . Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer? . Hum Reprod Update 2018 ; 24 : 35 – 58 . Google Scholar CrossRef Search ADS PubMed Maheshwari A , Pandey S , Shetty A , Hamilton M , Bhattacharya S . Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of frozen thawed versus fresh embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis . Fertil Steril 2012 ; 98 : 368 – 377 . Google Scholar CrossRef Search ADS PubMed Pandey S , Shetty A , Hamilton M , Bhattacharya S , Maheshwari A . Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis . Hum Reprod Update 2012 ; 18 : 485 – 503 . Google Scholar CrossRef Search ADS PubMed Pinborg A , Henningsen AA , Loft A , Malchau SS , Forman J , Andersen AN. . Large baby syndrome in singletons born after frozen embryo transfer (FET): is it due to maternal factors or the cryotechnique? . Hum Reprod 2014 ; 29 : 618 – 627 . Google Scholar CrossRef Search ADS PubMed Shapiro BS , Daneshmand ST , Bedient CE , Garner FC . Comparison of birth weights in patients randomly assigned to fresh or frozen-thawed embryo transfer . Fertil Steril 2016 ; 106 : 317 – 321 . Google Scholar CrossRef Search ADS PubMed Siristatidis C , Sergentanis TN , Kanavidis P , Trivella M , Sotiraki M , Mavromatis I , Psaltopoulou T , Skalkidou A , Petridou ET . Controlled ovarian hyperstimulation for IVF: impact on ovarian, endometrial and cervical cancer—a systematic review and meta-analysis . Hum Reprod Update 2013 ; 19 : 105 – 123 . Google Scholar CrossRef Search ADS PubMed Spijkers S , Lens JW , Schats R , Lambalk CB . Fresh and frozen-thawed embryo transfer compared to natural conception: differences in perinatal outcome? Gynecol Obstet Invest 2017 ; 82 : 538 – 546 . Google Scholar CrossRef Search ADS PubMed Zhang B , Wei D , Legro RS , Shi Y , Li J , Zhang L , Hong Y , Sun G , Zhang T , Li W et al. . Obstetric complications after frozen versus fresh embryo transfer in women with polycystic ovary syndrome: results from a randomized trial . Fertil Steril 2018 ; 109 : 324 – 329 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Human Reproduction UpdateOxford University Press

Published: Apr 18, 2018

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