No changes were found in ultrasound estimated fetal weight (EFW) centile between 20-22 and 32–34 weeks in in-vitro fertilisation (IVF) pregnancies compared to spontaneous conception (SC). Significant (P = 0.02) fastest fetal growth (mean increase in centile of 5 between 2nd to 3rd trimester) was observed in the frozen embryo transfer (FET) subgroup compared to SC, and IVF pregnancies resulting from fresh blastocyst transfer (FBT) and oocyte donation (OD). Low placentation was significantly (P < 0.001) more common in the IVF group than in the SC group but was not associated with a change in growth pattern suggesting that fetal growth in-utero is independent of placental location but may be influenced by embryo freezing

Jauniaux, Eric

Li, Xueyan

English

UCL Discovery

Placenta 145 (2024) 89–91Available online 1 December 20230143-4004/© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Antenatal fetal growth patterns in uncomplicated pregnancies according to mode of conception and placental location Xueyan Li, Eric Jauniaux * EGA Institute for Women’s Health, Faculty of Population Health Sciences, University College London (UCL), London, UK   A R T I C L E  I N F O   Keywords: Fetal growth In vitro fertilisation Placenta previa Embryo transfer A B S T R A C T   Newborns resulting from in-vitro fertilisation (IVF) had a significantly (P= 0.002) higher birthweight centile than those resulting from spontaneous conception (SC) but no significant changes were found in ultrasound estimated fetal weight (EFW) centile between 20-22 and 32–34 weeks between the IVF and SC groups. When stratified for the IVF methods used, significant (P = 0.02) fastest in-utero fetal growth (mean increase in centile of 5 between 2nd to 3rd trimester) was observed in the frozen embryo transfer (FET) subgroup compared to SC, and to IVF pregnancies resulting from fresh blastocyst transfer (FBT) or from oocyte donation (OD). Low placentation was significantly (P < 0.001) more common in the IVF group than in the SC group but was not associated with a change in growth pattern suggesting that fetal growth in-utero is independent of placental location but may be influenced by embryo freezing.   1. Introduction In-vitro fertilisation (IVF) has been associated with an increased incidence of small-for-gestational age (SGA) and low-birth weight (LBW) newborns [1,2]. Abnormally slow fetal growth has been reported to be more common in singleton compared to multiple IVF pregnancies [2]. Different IVF techniques have been shown to have a different impact on the risk of pregnancy complications and oocyte donation (OD) is associated with 4–5 times higher risk of pre-eclampsia than spontaneous conception (SC) [3,4]. Patients with a thinner endometrium are also more at risk of placental malperfusion resulting in fetal growth restric-tion (FGR) [5]. IVF is associated with a higher risk of low placentation i. e., low-lying/placenta previa [6] and placental development inside the low uterine segment (LUS) has been associated with a higher risk of SGA [7,8]. Prenatal fetal growth patterns and birthweight are influenced by many factors, however, most epidemiologic and cohort studies on the perinatal outcomes of IVF pregnancies do not adjust their data for confounding factors mainly maternal parity, exposure to tobacco smoke, body mass index (BMI) and ethnicity. In addition, most cohort studies provided little data on pre-existing maternal condition such as chronic hypertension glucose intolerance or thrombophilia, which are also, known factors affecting fetal growth and none provide longitudinal data on antenatal growth. The aim of the present study was to further eval-uate the possible impact of conception mode and placental location on fetal growth patterns during the second half of pregnancy. 2. Methods We conducted a single–centre, retrospective case control study of 203 uncomplicated singleton pregnancies that resulted in live births between 37 and 41 weeks of gestation over a 5 year-period ending in June 2022, at the Portland Hospital, London, UK. The study group included 116 couples with unexplained infertility with IVF pregnancies, resulting from autologous fresh emryo/blastoyst transfer (FBT) (n = 50), autologous frozen embryo transfer (FET) (n = 49) or (OD) (n = 17). All patients were managed using a standardised protocol which included, progesterone (400 mg pessary twice daily), low molecular weight hep-arin (20 mg SC daily) and aspirin (20 mg PO daily) supplements during the first trimester. The control group included 87 uncomplicated preg-nancies resulting from SC managed during the same period by the same obstetric team. Cases and controls were matched for parity and ethnicity. Exclusion criteria included multiple pregnancies, maternal exposure to active or passive smoking, preconception maternal medical conditions, medical complications during pregnancy, fetal congenital defect, and premature delivery. Ethical committee approval (HCA * Corresponding author. EGA Institute for Women’s Health, Faculty of Population Health Sciences, University College London (UCL), 84-86 Chenies Mews, London, WC1E 6HU, UK. E-mail address: e.jauniaux@ucl.ac.uk (E. Jauniaux).  Contents lists available at ScienceDirect Placenta journal homepage: www.elsevier.com/locate/placenta https://doi.org/10.1016/j.placenta.2023.11.016 Received 7 April 2023; Received in revised form 20 October 2023; Accepted 25 November 2023   Placenta 145 (2024) 89–9190Healthcare UK R&D/22/008) was obtained prior to the start of this study. Pregnancies were dated according to the last menstrual period (LMP) and confirmed by the fetal crown-rump length (CRL) at 11–14 weeks. Standardised ultrasound fetal biometry measurements were obtained at 20–22 and 32–34 weeks. The estimated fetal weight (EFW) and the corresponding percentiles and birthweight (BW) percentiles were calculated using the growth curves of the Fetal Medicine Foundation (https://fetalmedicine.org/). The placental location was recorded as anterior, posterior, or fundal when in the upper segment of the uterus, or as low-lying (when the placental edge was 0.5–2 cm from the internal os) or previa (when the placenta was < 0.5 cm from the internal os or covering it) at any gestational age after 16 weeks [9]. All examination were performed by the same operator (EJ) using a GE Voluson E10, GE Medical System, Zipf, Austria. Stata/IC version 15.0 (StataCorp LLC, TX, USA) was used for anal-ysis. Categorical variables were compared using the Pearson’s chi- square test and continuous variables using a t-test. Changes in fetal weight centile between the second and third trimester were analysed using Analysis of Covariance (ANCOVA). A P value < 0.05 was consid-ered significant. 3. Results Patients in the IVF group were significantly older (35.8 (SD 4.2) vs 34.3 (SD 3.9) years of age, P = 0.03) and the corresponding newborns had a significantly higher BW centile (56.0 (22.9) vs 48.9 (23.2), P =0.002) than those in the SC group. There was no significant difference for the other parameters (BMI, maternal age and fetal gender) between the groups. There was no significant difference between the IVF group as a whole and the SC control group in terms of changes in EFW centile from 2nd to 3rd trimester (Table 1). FET was associated with the fastest in-utero fetal growth (Fig. 1), with a mean increase in centile of 5, compared to controls and to FBT and OD (P = 0.02). There was no difference in growth patterns between fetuses conceived by FBT or OD. IVF was associated with a significantly (P < 0.001) higher incidence of low placentation compared to SC (42.2% vs 11.49%). No difference in changes in fetal growth pattern was found according to the placental location (IVF vs. controls, P = 0.82; IVF subgroups P = 0.95). 4. Discussion Systematic reviews have reported a higher incidence SGA, preterm birth, congenital malformation and perinatal mortality in IVF preg-nancies compared to SC controls [1] but the authors did not stratify the data for placental-related pregnancy complications nor for other con-founding factors that can influence fetal growth. Similarly, studies on fetal growth and placental location did not exclude patients with pre-existing medical disorders such as thrombophilia and those who were active smokers [7,8]. A recent study using a novel unified prenatal-postnatal modelling in IVF pregnancies found a higher EFW and birthweight Z-scores in FET than in FBT [10]. The data of our study, confirm the lower risks of SGA at birth in FET pregnancies compared to other IVF methods [10–12] and shows for the first time that the faster fetal growth in FET pregnancies starts from mid-gestation. The trophoblastic cells in IVF-FET present a different expression in imprinted genes PEG10 mRNA and protein compared to IVF-ET controls [13] suggesting that the effect of embryo freezing on fetal growth may be due to difference in placental development. The main strength of the present study is the homogeneity of our cohort of uncomplicated IVF pregnancies, stratified for different IVF techniques and to include the main factors influencing fetal growth in the analysis. The primary limitation of our cohort study is its retro-spective design. However, all ultrasound measurements were performed by the same operator using the same ultrasound equipment and a standardised protocol limiting the ascertainment bias of larger cohorts and epidemiologic studies. Funding No funding was obtained for this study. Declaration of competing interest The authors report no conflict of interest. Table 1 Comparison of birthweight centile between study groups for change from 2nd to 3rd trimester.  Comparison/group n 2nd trimester Mean (SD) 3rd trimester Mean (SD) Change Mean (SD) P-value (*) All IVF vs. control     0.85 Control 87 52 (17) 53 (20) 0 (22)  All IVF 116 56 (16) 56 (18) 0 (19)   IVF subgroups     0.07 (#) FBT 50 53 (13) 49 (16) − 4 (14)  FET 49 59 (18) 64 (18) 5 (24)  OD 17 56 (14) 53 (17) − 3 (16)   IVF subgroups vs. control      Control 87 52 (17) 53 (20) 0 (22)  FBT 50 53 (13) 49 (16) − 4 (14) 0.62 (+) FET 49 59 (18) 64 (18) 5 (24) 0.02 (+) OD 17 56 (14) 53 (17) − 3 (16) 1.00 (+) (*) P-values for change in fetal weight between 2nd and 3rd trimester between groups. Differences adjusted for weight at 2nd trimester. (#) P-value for overall comparison between three IVF subgroups. (+) P-values given a Bonferroni adjustment to allow for multiple comparisons to the control group. FBT = fresh blastocyst transfer; FET = frozen embryo transfer; OD = oocyte donation. Fig. 1. Box of changes in EFW centile between 2nd and 3rd trimester in the control group vs fresh blastocyst transfer (FBT), frozen embryo transfer (FET) and oocyte donation (OD). X. Li and E. Jauniaux                                                                                                                                                                                                                         Placenta 145 (2024) 89–9191Acknowledgement The authors are grateful to the staff of the Portland hospital, Hospital Corporation of America (HCA) healthcare, for their continuous support during this study and to Mr Paul Bassett, M.Sc. (Stats consultancy Ltd, Bucks, UK) for his help with the statistical analysis. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.placenta.2023.11.016. References [1] J. Qin, X. Liu, X. Sheng, H. Wang, S. Gao, Assisted reproductive technology and the risk of pregnancy-related complications and adverse pregnancy outcomes in singleton pregnancies: a meta-analysis of cohort studies, Fertil. Steril. 105 (2016), 73-85. e6. [2] J. Qin, X. Liu, X. Sheng, H. Wu, S. Gao, Y. You, T. Yang, H. Wang, Wolrdwide prevalence of adverse pregnancy outcomes among singleton pregnancies after in vitro fertilization/intracytoplasmic sperm injection: a meta-analysis of cohort studies, Arch. Gynecol. Obstet. 295 (2017) 285–301. [3] A. Blázquez, D. García, A. Rodríguez, R. Vassena, F. Figueras, V. Vernaeve, Is oocyte donation a risk factor for preeclampsia? A systematic review and meta- analysis, J. Assist. Reprod. Genet. 33 (2016) 855–863. [4] A. Keukens, M. van Wely, C. van der Meulen, M.H. Mochtar, Pre-eclampsia in pregnancies resulting from oocyte donation, natural conception or IVF: a systematic review and meta-analysis, Hum. Reprod. 37 (2022) 586–599. [5] H. Ganer Herman, A. Volodarsky-Perel, T.N. Ton Nu, A. Machado-Gedeon, Y. Cui, J. Shaul, M.H. Dahan, Pregnancy complications and placental histology following embryo transfer with a thinner endometrium, Hum. Reprod. 37 (2022) 1739–1745. [6] E. Jauniaux, A. Moffett, G.J. Burton, Placental implantation disorders, Obstet. Gynecol. Clin. N. Am. 47 (2020) 117–132. [7] E. Weiner, H. Miremberg, E. Grinstein, Y. Mizrachi, L. Schreiber, J. Bar, The effect of placenta previa on fetal growth and pregnancy outcome, in correlation with placental pathology, J. Perinatol. 36 (2016) 1073–1078. [8] E. Weiner, H. Miremberg, E. Grinstein, L. Schreiber, S. Ginath, J. Bar, M. Kovo, Placental histopathology lesions and pregnancy outcome in pregnancies complicated with symptomatic vs. non-symptomatic placenta previa, Early Hum. Dev. 101 (2016) 85–89. [9] U.M. Reddy, A.Z. Abuhamad, D. Levine, G.R. Saade, Fetal imaging workshop invited participants. Fetal imaging: executive summary of a joint Eunice Kennedy Shriver national institute of child Health and human development, society for maternal-fetal medicine, American institute of ultrasound in medicine, American College of obstetricians and gynecologists, American College of radiology, society for pediatric radiology, and society of radiologists in ultrasound fetal imaging workshop, J. Ultrasound Med. 33 (2014) 745–757. [10] P.I. Cavoretto, A. Farina, G. Gaeta, A. Seidenari, M. Pozzoni, S. Spinillo, D. Morano, A. Alteri, P. Viganò, M. Candiani, Greater estimated fetal weight and birth weight in IVF/ICSI pregnancy after frozen-thawed vs fresh blastocyst transfer: prospective cohort study with novel unified modeling methodology, Ultrasound Obstet. Gynecol. 60 (2022) 76–85. [11] A. Pinborg, A.A. Henningsen, A. Loft, S.S. Malchau, J. Forman, A.N. Andersen, Large baby syndrome in singletons born after frozen embryo transfer (FET): is it due to maternal factors or cryotechnique? Hum. Reprod. 29 (2014) 618–627. [12] A. Maheshwari, S. Pandey, E. Amalraj Raja, A. Shetty, S. Bhattacherya, Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer? Hum. Reprod. Update 24 (2018) 35–38. [13] L. Yang, Z. Li, Y. Liu, J.W. Zhang, Y.X. Wang, J.J. Hu, Y.C. Guan, L.J. Sun, Influences of fresh and frozen embryo transfer on neonatal birthweight and the expression of imprinted genes PEG10/L3MBTL1 in placenta, Reprod. Biol. 22 (2022), 100665. X. Li and E. Jauniaux                                                                                                                                                                                                                         

Antenatal fetal growth patterns in uncomplicated pregnancies according to mode of conception and placental location

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Antenatal fetal growth patterns in uncomplicated pregnancies according to mode of conception and placental location

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