Assisted Reproductive Technology and Newborn Size in Singletons Resulting from Fresh and Cryopreserved Embryos Transfer

RESEARCH ARTICLE Assisted Reproductive Technology and Newborn Size in Singletons Resulting from Fresh and Cryopreserved Embryos Transfer Galit Levi Dunietz1,2*, Claudia Holzman2, Yujia Zhang3, Nicole M. Talge2, Chenxi Li2, David Todem2, Sheree L. Boulet3, Patricia McKane4, Dmitry M. Kissin3, Glenn Copeland5, Dana Bernson6, Michael P. Diamond7 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Department of Neurology, University of Michigan, Ann Arbor, MI, United States of America, 2 Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, United States of America, 3 Division of Reproductive Health at the Centers for Disease Control and Prevention, Atlanta, GA, United States of America, 4 Michigan Department of Health and Human Services, Maternal and Child Health Epidemiology Section, Lansing, MI, United States of America, 5 Michigan Department of Health and Human Services, Division for Vital Records and Health Statistics, Lansing, MI, United States of America, 6 Massachusetts Department of Public Health, Boston, MA, United States of America, 7 Department of Obstetrics and Gynecology, Augusta University, Augusta, GA, United States of America * OPEN ACCESS Citation: Levi Dunietz G, Holzman C, Zhang Y, Talge NM, Li C, Todem D, et al. (2017) Assisted Reproductive Technology and Newborn Size in Singletons Resulting from Fresh and Cryopreserved Embryos Transfer. PLoS ONE 12 (1): e0169869. doi:10.1371/journal.pone.0169869 Editor: Joël R. Drevet, Universite Blaise Pascal, FRANCE Received: June 9, 2016 Accepted: December 22, 2016 Abstract Objectives and Study Design The aim of this study was two-fold: to investigate the association of Assisted Reproductive Technology (ART) and small newborn size, using standardized measures; and to examine within strata of fresh and cryopreserved embryos transfer, whether this association is influenced by parental infertility diagnoses. We used a population-based retrospective cohort from Michigan (2000–2009), Florida and Massachusetts (2000–2010). Our sample included 28,946 ART singletons conceived with non-donor oocytes and 4,263,846 non-ART singletons. Published: January 23, 2017 Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Data Availability Statement: The data were collected by a surveillance system of the centers for disease control and prevention (CDC). Data are stored at the CDC and are accessible to researchers who meet the criteria for access to confidential data. Sara Crawford from the Division of Reproductive health is the designated contact person. Her email is: Funding: GLD was partially supported by a T32 Grant from the Eunice Kennedy Shriver National Institute of Child Health & Human Development Methods Regression models were used to examine the association of ART and newborn size, measured as small for gestational age (SGA) and birth-weight-z-score, among four mutually exclusive infertility groups: female infertility only, male infertility only, combined female and male infertility, and unexplained infertility, stratified by fresh and cryopreserved embryos transfer. Results We found increased SGA odds among ART singletons from fresh embryos transfer compared with non-ART singletons, with little difference by infertility source [adjusted odds-ratio for SGA among female infertility only: 1.18 (95% CI 1.10, 1.26), male infertility only: 1.20 (95% CI 1.10, 1.32), male and female infertility: 1.18 (95% CI 1.06, 1.31) and unexplained infertility: 1.24 (95% CI 1.10, 1.38)]. Conversely, ART singletons, born following cryopreserved embryos transfer, had lower SGA odds compared with non-ART singletons, with PLOS ONE | DOI:10.1371/journal.pone.0169869 January 23, 2017 1 / 13 Assisted Reproductive Technology and Newborn Size (T32-HD046377). URL: www.nichd.nih.gov/Pages/ index.aspx. MPD is a stockholder in and on the board of directors of Advanced Reproductive Care, and has received a grant from the NIH/NICHD Cooperative Reproductive Medicine Network. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: MPD is a stockholder in and on the board of directors of Advanced Reproductive Care. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials. mild variation by infertility source [adjusted odds-ratio for SGA among female infertility only: 0.56 (95% CI 0.45, 0.71), male infertility only: 0.64 (95% CI 0.47, 0.86), male and female infertility: 0.52 (95% CI 0.36, 0.77) and unexplained infertility: 0.71 (95% CI 0.47, 1.06)]. Birth-weight-z-score was significantly lower for ART singletons born following fresh embryos transfer than non-ART singletons, regardless of infertility diagnoses. Introduction Assisted Reproductive Technology (ART) is an infertility therapy that involves the handling of both gametes in the laboratory to achieve pregnancy. ART-conceived singletons have an increased risk for low birth weight (LBW) compared with singletons in the general population. [1–9] LBW has long been used as an indicator for child health, however, its interpretation is unclear because LBW may be related to short gestation, small newborn size or their combination.[10–12] Therefore, indicators that distinguish LBW infants resulting from short gestation or small newborn size provide a more informative measure of risk by reducing this confounding. Two such indicators are small for gestational age (SGA) and birth-weight-z-score. The definition of SGA varies across studies and may include infants whose birth weight is below the 10th or 5th percentile (SGA/10th or SGA/5th) for gestational age or whose birth weight is 2 standard deviations below the mean birth weight for gestational age. Two recent studies did not detect an increased risk of SGA/10th for ART compared with non-ART singletons[13, 14], whereas, other studies reported a significantly increased risk of SGA/10th among ART singletons, with odds ratios ranging from 1.22–2.29.[8, 15–17] Using the 5th percentile, ART singletons were found to have a 40% higher odds for SGA birth compared with their non-ART counterparts.[18] These conflicting results may be attributed to the variety of SGA definitions, or to other sources of heterogeneity such as sample size and/or the approach to potential confounders e.g. plurality, social factors, ART and infertility characteristics. Birth-weight-z-score, constructed as a continuous measure, allows the comparison of newborn size across gestational ages, sexes and birth weights, representing the same relative birth weight for infants, rather than their absolute weight. Comp (...truncated)