Sibling rivalry? Higher birthweight after frozen embryo transfer compared with fresh sibling embryo transfers

Abstract

Frozen embryo transfers (ETs) have increased in the recent years, largely because of increased single ETs and thus higher numbers of supernumerary embryos available for cryopreservation, as well as an increased trend toward elective freezing of all embryos (with subsequent frozen ET). Further, increased laboratory proficiency and success of freezing and thawing of embryos have helped drive frozen ET success rates to be comparable to (and sometimes superior to) fresh ET. Existing literature has shown modest differences in live birth rates between these 2 cycle types in varying clinical scenarios. Birthweight is consistently different between fresh and frozen ETs, with frozen ETs generally being associated with a lower risk of low birthweight infants and higher risk of high birthweight infants. These are some outcomes examined (and confirmed) in the current study.The article by Raja et al. (1Raja E. Bhattacharya S. Masheswari A. McLernon D. Comparison of perinatal outcomes following frozen or fresh embryo transfer: separate analyses of singleton, twin and sibling live births from a linked national IVF registry.Fertil Steril. 2022; 118: 323-334Abstract Full Text Full Text PDF Scopus (1) Google Scholar) entitled “Comparison of perinatal outcomes following frozen or fresh embryo transfer: separate analyses of singleton, twin and sibling live births from a linked national IVF registry” confirms these findings in a unique analysis of the UK registry data, the Human Embryology and Fertilisation Authority, by comparing the perinatal outcomes of fresh vs. frozen cycles, including pairs of singleton siblings. The investigators queried 25 years of Human Embryology and Fertilisation Authority data from 1992–2017 and were able to link data for multiple live births from the same patient for the sibling analysis. One of the outcomes was a composite “healthy infant” outcome, which described infants born at ≥37 weeks with birthweight of 2,500–4,000 g and without congenital anomalies. The singleton live birth analysis included 132,679 live births (108,651 fresh and 24,028 frozen cycles). The risks of preterm (<37 weeks) and very preterm (<32 weeks) births were significantly lower in the frozen ET group than in the fresh ET group after controlling for age, parity, year, and number of embryos transferred. The risk of low birthweight (<2,500 g) was significantly lower in the frozen ET group than in the fresh ET group, even after excluding all preterm live births. Similarly, the risk of high birthweight infant (>4,000 g) was higher in the frozen ET group, with an adjusted relative risk (aRR) of 1.64. Slight differences were seen in the rates of congenital anomalies (slightly lower with frozen ET, aRR 0.85) and “healthy infant” composite outcome (slightly lower with frozen ET, aRR 0.96) in the singleton analysis.The twin live birth analysis included 29,742 and 3,956 sets of twins after fresh and frozen ETs, respectively. The investigators found overall similar results to the singleton analysis, with lower risk of very preterm birth and low birthweight after a frozen ET than after a fresh ET. As opposed to the singleton analysis, there was a slightly higher chance of having a healthy infant after frozen ET and no difference in the total preterm birth rates.The article’s most unique aspect was an analysis of sibling singleton pairs from the same patient, in which 1 sibling was born after a frozen ET and 1 was born after a fresh ET. Most sibling pairs evaluated (4,931 of 5,723) were pairs in which the first sibling was a result of a fresh ET and the second resulted from frozen ET; the birth order was controlled for. The sibling born after a frozen ET had a lower risk of preterm birth than their sibling born after a fresh ET, with an aRR of 0.81. The study found a higher incidence of high birthweight after frozen ET than after fresh ET (aRR 1.85), even when preterm births had been excluded. Similarly, there was a lower risk of having a small for gestational age infant and a higher risk of having a large for gestational age infant after frozen ET.This was an overall interesting, timely, and well-designed study that confirmed the findings of previous studies comparing frozen vs. fresh ETs; nevertheless, several limitations are unavoidable with large registry studies for which only certain data are collected. First, the twin analysis was unable to control for chorionicity, although it is known to impact the gestational age and other outcomes at delivery. Second, although the sibling analysis helps with controlling for the genetic contribution to birthweight, the investigators were unable to control for maternal body mass index, which has a known association with macrosomia and birth outcomes. However, this may have had little impact on their findings, given that a similar sibling study found that maternal body mass index did not significantly change between pregnancies (2Luke B. Brown M.B. Wantman E. Stern J.E. Toner J.P. Coddington III, C.C. 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: 191-200Crossref PubMed Scopus (55) Google Scholar). Finally, the study’s definition of “healthy infant” is partially driven by the incidence of low and high birthweights, which may oversimplify the outcome by considering the extremes of birthweight to be similar in clinical impact. However, macrosomic infants on average have a lower risk of neonatal morbidity and mortality than their preterm and low birthweight counterparts. Thus, readers should be cautious when interpreting the results of the singleton analysis showing lower “healthy infant” rates after frozen ET, because this appears to be driven down by the higher incidence of high birthweight and may not truly indicate lower health in the infants conceived by frozen ET. Finally, large registry studies can often detect very small, and sometimes clinically insignificant, differences in outcomes; thus, findings which remained consistent between the 3 analyses (e.g., birthweight differences) should be preferentially emphasized.The strengths of this article are multiple. First, this study confirmed the findings of previous studies that showed a higher risk of high birthweight infants after frozen ET compared with fresh ET in a different population than the United States (2Luke B. Brown M.B. Wantman E. Stern J.E. Toner J.P. Coddington III, C.C. 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: 191-200Crossref PubMed Scopus (55) Google Scholar, 3Shapiro B.S. Daneshmand S.T. Bedient C.E. Garner F.C. Comparison of birth weights in patients randomly assigned to fresh or frozen-thawed embryo transfer.Fertil Steril. 2016; 106: 317-321Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 4Hwang S.S. Dukhovny D. Gopal D. Cabral H. Diop H. Coddington C.C. et al.Health outcomes for Massachusetts infants after fresh versus frozen embryo transfer.Fertil Steril. 2019; 112: 900-907Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar) and Norway (5Wennerholm U.B. Henningsen A.K. Romundstad L.B. Bergh C. Pinborg A. Skjaerven R. et al.Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group.Hum Reprod. 2013; 28: 2545-2553Crossref PubMed Scopus (260) Google Scholar). Importantly, this study also confirmed the previously reported findings that a live birth after frozen ET confers a lower risk of very preterm and preterm birth (5Wennerholm U.B. Henningsen A.K. Romundstad L.B. Bergh C. Pinborg A. Skjaerven R. et al.Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group.Hum Reprod. 2013; 28: 2545-2553Crossref PubMed Scopus (260) Google Scholar), which is known to significantly contribute to neonatal morbidity and mortality. The investigators employed thoughtful and rigorous exclusion criteria, excluding higher order multiple gestations, oocyte donor and gestational carrier cycles, preimplantation genetic testing, and cycles in which >3 embryos were transferred. Although these findings are not novel, they are important in confirming that frozen ET is associated with a higher risk of macrosomia and a lower risk of low birthweight. Now that these associations have been further validated, more research emphasis may be placed on elucidating the underlying biologic basis for these findings and exploring long-term neurodevelopmental and health outcomes for infants born after each transfer strategy. Frozen embryo transfers (ETs) have increased in the recent years, largely because of increased single ETs and thus higher numbers of supernumerary embryos available for cryopreservation, as well as an increased trend toward elective freezing of all embryos (with subsequent frozen ET). Further, increased laboratory proficiency and success of freezing and thawing of embryos have helped drive frozen ET success rates to be comparable to (and sometimes superior to) fresh ET. Existing literature has shown modest differences in live birth rates between these 2 cycle types in varying clinical scenarios. Birthweight is consistently different between fresh and frozen ETs, with frozen ETs generally being associated with a lower risk of low birthweight infants and higher risk of high birthweight infants. These are some outcomes examined (and confirmed) in the current study. The article by Raja et al. (1Raja E. Bhattacharya S. Masheswari A. McLernon D. Comparison of perinatal outcomes following frozen or fresh embryo transfer: separate analyses of singleton, twin and sibling live births from a linked national IVF registry.Fertil Steril. 2022; 118: 323-334Abstract Full Text Full Text PDF Scopus (1) Google Scholar) entitled “Comparison of perinatal outcomes following frozen or fresh embryo transfer: separate analyses of singleton, twin and sibling live births from a linked national IVF registry” confirms these findings in a unique analysis of the UK registry data, the Human Embryology and Fertilisation Authority, by comparing the perinatal outcomes of fresh vs. frozen cycles, including pairs of singleton siblings. The investigators queried 25 years of Human Embryology and Fertilisation Authority data from 1992–2017 and were able to link data for multiple live births from the same patient for the sibling analysis. One of the outcomes was a composite “healthy infant” outcome, which described infants born at ≥37 weeks with birthweight of 2,500–4,000 g and without congenital anomalies. The singleton live birth analysis included 132,679 live births (108,651 fresh and 24,028 frozen cycles). The risks of preterm (<37 weeks) and very preterm (<32 weeks) births were significantly lower in the frozen ET group than in the fresh ET group after controlling for age, parity, year, and number of embryos transferred. The risk of low birthweight (<2,500 g) was significantly lower in the frozen ET group than in the fresh ET group, even after excluding all preterm live births. Similarly, the risk of high birthweight infant (>4,000 g) was higher in the frozen ET group, with an adjusted relative risk (aRR) of 1.64. Slight differences were seen in the rates of congenital anomalies (slightly lower with frozen ET, aRR 0.85) and “healthy infant” composite outcome (slightly lower with frozen ET, aRR 0.96) in the singleton analysis. The twin live birth analysis included 29,742 and 3,956 sets of twins after fresh and frozen ETs, respectively. The investigators found overall similar results to the singleton analysis, with lower risk of very preterm birth and low birthweight after a frozen ET than after a fresh ET. As opposed to the singleton analysis, there was a slightly higher chance of having a healthy infant after frozen ET and no difference in the total preterm birth rates. The article’s most unique aspect was an analysis of sibling singleton pairs from the same patient, in which 1 sibling was born after a frozen ET and 1 was born after a fresh ET. Most sibling pairs evaluated (4,931 of 5,723) were pairs in which the first sibling was a result of a fresh ET and the second resulted from frozen ET; the birth order was controlled for. The sibling born after a frozen ET had a lower risk of preterm birth than their sibling born after a fresh ET, with an aRR of 0.81. The study found a higher incidence of high birthweight after frozen ET than after fresh ET (aRR 1.85), even when preterm births had been excluded. Similarly, there was a lower risk of having a small for gestational age infant and a higher risk of having a large for gestational age infant after frozen ET. This was an overall interesting, timely, and well-designed study that confirmed the findings of previous studies comparing frozen vs. fresh ETs; nevertheless, several limitations are unavoidable with large registry studies for which only certain data are collected. First, the twin analysis was unable to control for chorionicity, although it is known to impact the gestational age and other outcomes at delivery. Second, although the sibling analysis helps with controlling for the genetic contribution to birthweight, the investigators were unable to control for maternal body mass index, which has a known association with macrosomia and birth outcomes. However, this may have had little impact on their findings, given that a similar sibling study found that maternal body mass index did not significantly change between pregnancies (2Luke B. Brown M.B. Wantman E. Stern J.E. Toner J.P. Coddington III, C.C. 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: 191-200Crossref PubMed Scopus (55) Google Scholar). Finally, the study’s definition of “healthy infant” is partially driven by the incidence of low and high birthweights, which may oversimplify the outcome by considering the extremes of birthweight to be similar in clinical impact. However, macrosomic infants on average have a lower risk of neonatal morbidity and mortality than their preterm and low birthweight counterparts. Thus, readers should be cautious when interpreting the results of the singleton analysis showing lower “healthy infant” rates after frozen ET, because this appears to be driven down by the higher incidence of high birthweight and may not truly indicate lower health in the infants conceived by frozen ET. Finally, large registry studies can often detect very small, and sometimes clinically insignificant, differences in outcomes; thus, findings which remained consistent between the 3 analyses (e.g., birthweight differences) should be preferentially emphasized. The strengths of this article are multiple. First, this study confirmed the findings of previous studies that showed a higher risk of high birthweight infants after frozen ET compared with fresh ET in a different population than the United States (2Luke B. Brown M.B. Wantman E. Stern J.E. Toner J.P. Coddington III, C.C. 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: 191-200Crossref PubMed Scopus (55) Google Scholar, 3Shapiro B.S. Daneshmand S.T. Bedient C.E. Garner F.C. Comparison of birth weights in patients randomly assigned to fresh or frozen-thawed embryo transfer.Fertil Steril. 2016; 106: 317-321Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 4Hwang S.S. Dukhovny D. Gopal D. Cabral H. Diop H. Coddington C.C. et al.Health outcomes for Massachusetts infants after fresh versus frozen embryo transfer.Fertil Steril. 2019; 112: 900-907Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar) and Norway (5Wennerholm U.B. Henningsen A.K. Romundstad L.B. Bergh C. Pinborg A. Skjaerven R. et al.Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group.Hum Reprod. 2013; 28: 2545-2553Crossref PubMed Scopus (260) Google Scholar). Importantly, this study also confirmed the previously reported findings that a live birth after frozen ET confers a lower risk of very preterm and preterm birth (5Wennerholm U.B. Henningsen A.K. Romundstad L.B. Bergh C. Pinborg A. Skjaerven R. et al.Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group.Hum Reprod. 2013; 28: 2545-2553Crossref PubMed Scopus (260) Google Scholar), which is known to significantly contribute to neonatal morbidity and mortality. The investigators employed thoughtful and rigorous exclusion criteria, excluding higher order multiple gestations, oocyte donor and gestational carrier cycles, preimplantation genetic testing, and cycles in which >3 embryos were transferred. Although these findings are not novel, they are important in confirming that frozen ET is associated with a higher risk of macrosomia and a lower risk of low birthweight. Now that these associations have been further validated, more research emphasis may be placed on elucidating the underlying biologic basis for these findings and exploring long-term neurodevelopmental and health outcomes for infants born after each transfer strategy. Comparison of perinatal outcomes after frozen or fresh embryo transfer: separate analyses of singleton, twin, and sibling live births from a linked national in vitro fertilization registryFertility and SterilityVol. 118Issue 2PreviewTo determine whether perinatal outcomes following frozen vs. fresh embryo transfer (ET) differ within singletons, within sets of twins, and between siblings. Full-Text PDF Open Access