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Article| Volume 43, ISSUE 4, P719-726, October 2021

Childhood growth of term singletons born after frozen compared with fresh embryo transfer

Open AccessPublished:August 09, 2021DOI:https://doi.org/10.1016/j.rbmo.2021.08.002

      Abstract

      Research question

      Is the growth of term singletons born after frozen embryo transfer (FET) comparable to those born after fresh embryo transfer and natural conception up to 5 years of age?

      Design

      Observational cohort study in an academic medical centre and municipal child health clinics with repeated measurements carried out by medical professionals. Term singletons born after FET (n = 110) and fresh embryo transfer (n = 181) and their matched natural conception controls (n = 543) born in Oulu, Northern Finland, were included. Mean weights, lengths, heights and head circumferences at the ages of 4, 8 and 18 months and 3 and 5 years were compared. At 3 and 5 years, body mass indices were compared.

      Results

      Childhood growth did not differ between term singletons born after FET, fresh embryo transfer and natural conception, correcting for exact age at measurement and adjusting for maternal body mass index and paternal height.

      Conclusions

      Similar growth between children born after FET, fresh embryo transfer and natural conception offers reassurance of the safety and feasibility of the steadily increasing use of embryo cryopreservation in assisted reproduction.

      KEYWORDS

      Introduction

      The health of children born after assisted reproductive technology (ART) has improved over the past few years, mainly because of a reduction in multiple gestations (
      • Henningsen A.A.
      • Gissler M.
      • Skjaerven R.
      • Bergh C.
      • Tiitinen A.
      • Romundstad L.B.
      • Wennerholm U.B.
      • Lidegaard O.
      • Nyboe Andersen A.
      • Forman J.L.
      Pinborg A. Trends in perinatal health after assisted reproduction: a Nordic study from the CoNARTaS group.
      ). In Finland, a policy of elective single embryo transfer (SET) was implemented in the late 1990s (
      • Martikainen H.
      • Orava M.
      • Lakkakorpi J.
      • Tuomivaara L.
      Day 2 elective single embryo transfer in clinical practice: better outcome in ICSI cycles.
      ;
      • Tiitinen A.
      • Gissler M.
      Effect of in vitro fertilization practices on multiple pregnancy rates in Finland.
      ), which was possible only when combined with extensive use of frozen embryo transfer (FET). Nowadays in Finland, more children are born after FET than after fresh embryo transfer (

      THL 2019a. THL (Finnish Institute for Health and Welfare) 2019. Hedelmöityshoidot 2017–2018 [Fertility treatments 2017–2018] (in Finnish).https://core.ac.uk/download/pdf/275589383.pdf. Accessed Dec 20, 2020.

      ) and, in Europe, the number of FET treatments has exceeded that of conventional IVF (
      • Wyns C.
      • Bergh C.
      • Calhaz-Jorge C.
      • De Geyter C.
      • Kupka M.S.
      • Motrenko T.
      • Rugescu I.
      • Smeenk J.
      • Tandler-Schneider A.
      • Vidakovic S.
      • Goossens V.
      European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE). ART in Europe, 2016: results generated from European registries by ESHRE.
      ). In the USA, FET was used in 32.7% of ART treatment cycles in

      CDC (Center for Disease Control and Prevention). 2016 Assisted Reproductive Technology National Summary Report.https://www.cdc.gov/art/pdf/2016-national-summary-slides/ART_2016_graphs_and_charts.pdf. Accessed Jan 24, 2021.

      .
      Knowledge of the early growth and development of children born after FET is still limited. In a register-based cohort study of the morbidity of children born after FET, no difference was found in the somatic health between children born after FET compared with those born after fresh embryo transfer up to the age of 3 years (
      • Pelkonen S.
      • Gissler M.
      • Koivurova S.
      • Lehtinen S.
      • Martikainen H.
      • Hartikainen A.L.
      • Tiitinen A.
      Physical health of singleton children born after frozen embryo transfer using slow freezing: a 3-year follow-up study.
      ). Some differences, however, were observed in pregnancy-related complications and adverse perinatal outcomes of pregnancies conceived after FET compared with fresh embryo transfer (
      • 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?.
      ;
      • Sha T.
      • Yin X.
      • Cheng W.
      • Massey I.Y.
      Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis.
      ). Furthermore, singletons born after FET have higher mean birth weight and a higher risk of being large-for-gestational-age (LGA) than fresh embryo transfer singletons (
      • Pelkonen S.
      • Koivunen R.
      • Gissler M.
      • Nuojua-Huttunen S.
      • Suikkari A.M.
      • Hydén-Granskog C.
      • Martikainen H.
      • Tiitinen A.
      • Hartikainen A.-L.
      Perinatal outcome of children born after frozen and fresh embryo transfer: the Finnish cohort study 1995–2006.
      ;
      • Sazonova A.
      • Källen K.
      • Thurin-Kjellberg A.
      • Wennerholm U.B.
      • Bergh C.
      Obstetric outcome in singletons after in vitro fertilization with cryopreserved/thawed embryos.
      ;
      • Wennerholm U.B.
      • Henningsen A.K.
      • Romundstad L.B.
      • Bergh C.
      • Pinborg A.
      • Skjaerven R.
      • Forman J.
      • Gissler M.
      • Nygren K.G.
      • Tiitinen A.
      Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group.
      ;
      • Pinborg A.
      • Henningsen A.A.
      • Loft A.
      • Malchau S.S.
      • Forman J.
      • Andersen A.N.
      Large baby syndrome in singletons born after frozen embryo transfer (FET): is it due to maternal factors or the cryotechnique?.
      ;
      • 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?.
      ;
      • Sha T.
      • Yin X.
      • Cheng W.
      • Massey I.Y.
      Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis.
      ;
      • Terho A,
      • Pelkonen S,
      • Opdahl S,
      • Romundstad L,B,
      • Bergh C,
      • Wennerholm U,B,
      • Henningsen A.A.
      • Pinborg A.
      • Gissler M.
      • Tiitinen A.
      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 clinical significance of this intrauterine growth difference remains unclear. A few studies have described the growth of children born after FET, fresh embryo transfer and natural conception, and the evidence has been mostly reassuring. Some contradictory findings, however, with unclear clinical significance, have been reported (
      • Wennerholm U.B.
      • Albertsson-Wikland K.
      • Bergh C.
      • Hamberger L.
      • Niklasson A.
      • Nilsson L.
      • Thiringer K.
      • Wennergren M.
      • Wikland M.
      • Borres M.P.
      Postnatal growth and health in children born after cryopreservation as embryos.
      ;
      • Green M.P.
      • Mouat F.
      • Miles H.L.
      • Hopkins S.A.
      • Derraik J.G.
      • Hofman P.L.
      • Peek J.C.
      • Cutfield W.S.
      Phenotypic differences in children conceived from fresh and thawed embryos in in vitro fertilization compared with naturally conceived children.
      ;
      • Hann M.
      • Roberts S.A.
      • D'Souza S.W.
      • Clayton P.
      • Macklon N.
      • Brison D.R.
      The growth of assisted reproductive treatment-conceived children from birth to 5 years: a national cohort study.
      ;
      • Ainsworth A.J.
      • Wyatt M.A.
      • Shenoy C.C.
      • Hathcock M.
      • Coddington C.C.
      Fresh versus frozen embryo transfer has no effect on childhood weight.
      ;
      • Turner S.
      • Maclean E.
      • Dick S.
      • Aucott L.
      • Maheshwari A.
      Is conception by in vitro fertilization associated with altered antenatal and postnatal growth trajectories?.
      ;
      • Magnus M.C.
      • Wilcox A.J.
      • Fadum E.A.
      • Gjessing H.K.
      • Opdahl S.
      • Juliusson P.B.
      • Romundstad L.B.
      • Håberg S.E.
      Growth in children conceived by ART.
      ).
      In Finland, 98% of all children attend scheduled, standardized check-ups in municipal child health clinics, which are free of charge for the purpose of screening for growth and developmental abnormalities (

      THL 2019b. THL (Finnish Institute for Health and Welfare) 2019. Terveystarkastusten ja muiden käyntien toteumat äitiys- ja lastenneuvolassa 2018 sekä kouluterveydenhuollossa lukuvuonna 2018-19 [Health examinations and other visits in maternity and child health clinics in 2018 and in school health care in the academic year 2018-19] (in Finnish).https://www.julkari.fi/bitstream/handle/10024/138990/Tr_46_2019.pdf?sequence=5&isAllowed=y. Accessed Dec 20, 2020.

      ). This makes meticulous, prospectively collected child growth data available. The main goal of an ART treatment is a healthy child. Therefore, reliable data on the growth patterns of children born after ART are needed to provide patients with exact and up-to-date information on their treatment choices. The aim of the present study was to investigate the childhood growth of children born after FET compared with fresh embryo transfer and natural conception derived from high-coverage municipal follow-up data from child health clinics in Finland.

      Materials and methods

      Study population

      This study is an observational cohort of all term (gestational weeks 37–42) singletons born after FET and fresh embryo transfer in Oulu University Hospital between 2006 and 2011 and residing in the Oulu city area in Northern Finland. For each child in the study, two controls who had a natural conception from the same geographical area were obtained from the Finnish Medical Birth Register. The controls were matched for sex, birth year, maternal age (+/– 1 year) and parity. All data were prospectively collected by the infertility clinics, Oulu University Hospital and the municipal child health clinics, and then retrospectively linked by the study group.
      The data on the fertility treatments were obtained from the two infertility clinics operating in the area: Oulu University Hospital Infertility Clinic and Family Federation of Finland, Oulu. Fresh and frozen embryo transfers were carried out on day 2–3, and, at the time, in all FET treatments, slow freezing was used. Of the FET treatments, 90.8% were carried out in a natural cycle, and luteal (progesterone) support was routinely used. The mothers’ unique personal identifier codes were used to link the data to the pregnancy, delivery and perinatal health information from the medical records at the Oulu University Hospital. These records consist of the clinical notes made by the treating physicians and midwives, and they are recorded in a structured manner. For controls who had a natural conception, pregnancy and perinatal health data were obtained from the Finnish Medical Birth Register, which includes nationwide data on all births of fetuses with a birth weight of at least 500 g or with a gestational age of at least 22 weeks, as well as data on their mothers based on medical records from primary care and birth hospital (
      THL
      THL (Finnish Institute for Health and Welfare) 2021.
      ). Child growth data were then obtained from municipal child health clinics using the children's unique personal identifier codes. The study population is presented in Figure 1.
      Figure 1
      Figure 1The study population. ET, embryo transfer; FET, frozen embryo transfer; NC, natural conception.

      Study approval

      Study permission was granted on 6 October 2017 by the Finnish Institute for Health and Welfare, THL (THL/540/5.05.00/2017). In Finland, separate ethical approval is not required in scientific projects based on data from registers and medical records, as no registered person is contacted.

      Outcomes and statistical analyses

      Mean weights, lengths, heights and head circumferences were compared between the groups at birth, at 4, 8 and 18 months and at 3 and 5 years of age. At 3 and 5 years of age, the mean body mass indices were also compared. All analyses were carried out for the entire population and further stratified by the sex of the child. Some measurement values were missing because not all children attended every scheduled child health clinic appointment. Over 80% of the included children for each study group, however, were measured at each point. At the age of 5 years, data on weight were available for 96 children (87.3%) in the FET, 165 children (91.2%) in the fresh embryo transfer and 531 children (97.8%) in the natural conception group.
      Chi-squared test was used to compare categorical variables and, where significant differences were found, standard normal deviation test was used to compare percentages between any two groups. One-way analysis of variance was used to compare continuous variables with post-hoc Tukey's honest significance test correction for multiple comparisons. Growth measurement values were compared using linear mixed model corrected for exact age at measurement and adjusted for maternal body mass index (BMI) and paternal height. For all statistical analyses, IBM SPSS Statistical Software (IBM Statistics for Windows, Version 25, IBM Corp, Armonk, NY, USA) was used. For figures, draw.io and GraphPad Prism 8.0.1 softwares were used.

      Results

      Background characteristics

      A description of the study population is presented in Table 1. Fewer SET took place in the FET group compared with fresh embryo transfer group (52.7% versus 64.6%; P = 0.038). No other significant differences between FET and fresh embryo transfer were found. Compared with natural conception, gestational age at birth was shorter (277 versus 280 days; P = 0.001) and the incidence of blood pressure disorders was higher (13.6 versus 6.3%; P = 0.010) in the FET group. For fresh embryo transfer, the incidence of blood pressure disorders (13.3 versus 6.3%; P = 0.003) and gestational diabetes (13.3. versus 7.7%; P = 0.026) was higher compared with natural conception. In the natural conception group, data on gestational diabetes were missing in 46.4% of cases.
      Table 1BACKGROUND CHARACTERISTICS OF PREGNANCIES ORIGINATED AFTER FROZEN EMBRYO TRANSFER, FRESH EMBRYO TRANSFER AND NATURAL CONCEPTION
      Frozen embryo transfer (n = 110)Fresh embryo transfer (n = 181)Natural conception (n = 543)P-value
      Maternal age, years, mean (SD)32.4 (4.0)32.0 (4.0)32.3 (4.1)0.708
      Chi-squared test for categorical variables and one-way analysis of variance with post-hoc Tukey's honest significant difference correction for multiple comparisons for continuous variables.
       Missing, n (%)
      Maternal BMI, kg/m2, mean (SD)23.6 (3.8)24.2 (4.5)24.3 (4.5)0.315
      Chi-squared test for categorical variables and one-way analysis of variance with post-hoc Tukey's honest significant difference correction for multiple comparisons for continuous variables.
       Missing, n (%)5 (0.9)
      Maternal smoking, n (%)9 (8.2)23 (12.8)52 (9.7)0.370
      Chi-squared test for categorical variables and one-way analysis of variance with post-hoc Tukey's honest significant difference correction for multiple comparisons for continuous variables.
       Missing, n (%)2 (1.1)9 (1.7)
      Maternal SES, upper or lower white-collar worker, n (%)89 (80.9)148 (81.8)407 (75.0)0.065
      Chi-squared test for categorical variables and one-way analysis of variance with post-hoc Tukey's honest significant difference correction for multiple comparisons for continuous variables.
       Missing, n (%)13 (2.4)
      Primiparous, n (%)71 (64.5)132 (72.9)382 (70.3)0.318
      Chi-squared test for categorical variables and one-way analysis of variance with post-hoc Tukey's honest significant difference correction for multiple comparisons for continuous variables.
       Missing, n (%)
      Paternal height cm, mean (SD)179 (5.6)179 (6.1)179.1 (6.2)0.986
      Chi-squared test for categorical variables and one-way analysis of variance with post-hoc Tukey's honest significant difference correction for multiple comparisons for continuous variables.
       Missing, n (%)1 (0.9)1 (0.6)3 (0.6)
      ICSI, n (%)47 (42.7)85 (47.0)NA0.347
      Standard normal deviation test was used where Chi-square test was statistically significant to compare percentages between any two groups (FET versus fresh embryo transfer; FET versus natural conception; fresh embryo transfer versus natural conception). P < 0.05 was considered to be significant.
       Missing, n (%)NA
      SET, n (%)58 (52.7)117 (64.6)NA0.038*,
      Standard normal deviation test was used where Chi-square test was statistically significant to compare percentages between any two groups (FET versus fresh embryo transfer; FET versus natural conception; fresh embryo transfer versus natural conception). P < 0.05 was considered to be significant.
       Missing, n (%)NA
      Gestational diabetes, n (%)14 (12.7)24 (13.3)42 (7.7)0.045*,
      Chi-squared test for categorical variables and one-way analysis of variance with post-hoc Tukey's honest significant difference correction for multiple comparisons for continuous variables.
      (0.999; 0.068; 0.026*)
      Standard normal deviation test was used where Chi-square test was statistically significant to compare percentages between any two groups (FET versus fresh embryo transfer; FET versus natural conception; fresh embryo transfer versus natural conception). P < 0.05 was considered to be significant.
       Missing, n (%)252 (46.4)
      Blood pressure disorders,
      Chronic hypertension and hypertensive disorder of pregnancy. BMI, body mass index; FET, frozen embryo transfer; ICSI, intracytoplasmic sperm injection; SD, standard deviation; SES, socioeconomic status; SET, single embryo transfer; SND, standard normal deviation; *, indicates significance; –, indicates no cases missing.
      n (%)
      15 (13.6)24 (13.3)34 (6.3)0.002*,
      Chi-squared test for categorical variables and one-way analysis of variance with post-hoc Tukey's honest significant difference correction for multiple comparisons for continuous variables.
      (0.999; 0.010;* 0.003*)
      Standard normal deviation test was used where Chi-square test was statistically significant to compare percentages between any two groups (FET versus fresh embryo transfer; FET versus natural conception; fresh embryo transfer versus natural conception). P < 0.05 was considered to be significant.
       Missing, n (%)-
      Caesarean delivery, n (%)28 (25.5)49 (27.1)125 (23.0)0.517
      Chi-squared test for categorical variables and one-way analysis of variance with post-hoc Tukey's honest significant difference correction for multiple comparisons for continuous variables.
       Missing, n (%)-
      Gestational age at birth, days, mean (SD)277 (8.1)279 (8.7)280 (8.6)0.001*,
      Chi-squared test for categorical variables and one-way analysis of variance with post-hoc Tukey's honest significant difference correction for multiple comparisons for continuous variables.
      (0.120; 0.001;* 0.190)
      Standard normal deviation test was used where Chi-square test was statistically significant to compare percentages between any two groups (FET versus fresh embryo transfer; FET versus natural conception; fresh embryo transfer versus natural conception). P < 0.05 was considered to be significant.
       Missing, n (%)1 (0.2)
      Newborn umbilical artery pH, mean (SD)7.2 (0.1)7.2 (0.1)7.2 (0.1)0.538
      Chi-squared test for categorical variables and one-way analysis of variance with post-hoc Tukey's honest significant difference correction for multiple comparisons for continuous variables.
       Missing, n (%)9 (8.2)14 (7.7)32 (5.9)
      Sex of child (male), n (%)55 (50)88 (48.6)266 (49.0)0.978
      Chi-squared test for categorical variables and one-way analysis of variance with post-hoc Tukey's honest significant difference correction for multiple comparisons for continuous variables.
       Missing, n (%)
      a Chi-squared test for categorical variables and one-way analysis of variance with post-hoc Tukey's honest significant difference correction for multiple comparisons for continuous variables.
      b Standard normal deviation test was used where Chi-square test was statistically significant to compare percentages between any two groups (FET versus fresh embryo transfer; FET versus natural conception; fresh embryo transfer versus natural conception).P < 0.05 was considered to be significant.
      c Chronic hypertension and hypertensive disorder of pregnancy.BMI, body mass index; FET, frozen embryo transfer; ICSI, intracytoplasmic sperm injection; SD, standard deviation; SES, socioeconomic status; SET, single embryo transfer; SND, standard normal deviation; *, indicates significance; –, indicates no cases missing.

      Growth measurements

      Stratified by sex of the child, the mean weight, length/height of boys did not differ between the FET, fresh embryo transfer and natural conception groups in crude measurements (corrected for exact age) nor when adjusted for maternal BMI and paternal height, up to 3 years of age. At the age of 5 years, the adjusted mean weight of FET, fresh embryo transfer and boys who were conceived naturally was 19,742, 19,607 and 20,218 g, respectively, which were not significantly different (P = 0.653 for FET versus natural conception and P = 0.261 for fresh embryo transfer versus natural conception) (Table 2 and Figure 2).
      Table 2CRUDE AND ADJUSTED MEAN WEIGHT AND HEIGHT OF BOYS BORN AFTER FROZEN EMBRYO TRANSFER, FRESH EMBRYO TRANSFER AND NATURAL CONCEPTION
      Weight, g, mean (95% CI)Height, cm, mean (95% CI)
      Boys crude
      Corrected for exact age at measurement, gestational age at birth.
      AgeFrozen embryo transfer (n = 55)Fresh embryo transfer (n = 88)Natural conception (n = 266)P-valueFrozen embryo transfer (n = 55)Fresh embryo transfer (n = 88)Natural conception (n = 266)P-value
      Birth3616 (3493–3739)3557 (3459–3654)3610 (3554–3666)0.62350.7 (50.1–51.2)50.7 (50.3–51.1)50.7 (50.4–50.9)0.997
      4 months7441 (7216–7665)7518 (7340–7695)7512 (7410–7614)0.83865.6 (65.0–66.2)65.7 (65.2–66.1)65.7 (65.5–66.0)0.909
      8 months9263 (8971–9555)9257 (9025–9489)9267 (9136–9398)0.99772.4 (71.8–73.0)72.6 (72.1–73.1)72.5 (72.2–72.7)0.869
      18 months11,786 (11,420–12,152)11,649 (11,362–11,935)11,878 (11,714–12,042)0.38883.8 (83.0–84.5)83.6 (83.0–84.2)84.0 (83.6–84.3)0.590
      3 years15,285 (14,730–15,840)15,075 (14,671–15,479)15,398 (15,171–15,624)0.38997.3 (96.2–98.4)96.7 (95.9–97.5)97.0 (96.6–97.5)0.674
      5 years19,569 (18,706–20,433)19,558 (18,895–20,221)20,244 (19,880–20,609)0.113111.9 (110.6–113.2)111.5 (110.5–112.5)111.9 (111.4–112.4)0.755
      Boys adjusted
      Adjusted for maternal body mass index and paternal height. Linear mixed model. P < 0.05 was considered to be significant. Over 80% of included children were measured at each measurement point.
      Birth3624 (3504–3744)3561 (3467–3656)3611 (3556–3666)0.62450.7 (50.2–51.2)50.7 (50.3–51.1)50.7 (50.5–50.9)0.994
      4 months7448 (7233–7663)7528 (7359–7698)7520 (7422–7618)0.81965.5 (65.0–66.1)65.7 (65.3–66.1)65.8 (65.5–66.0)0.734
      8 months9294 (9016–9573)9278 (9057–9498)9273 (9147–9398)0.99072.4 (71.9–73.0)72.6 (72.2–73.1)72.5 (72.2–72.7)0.785
      18 months11,806 (11,460–12,153)11,674 (11,404–11,944)11,889 (11,733–12,045)0.39783.8 (83.1–84.4)83.7 (83.1–84.2)84.0 (83.7–84.3)0.584
      3 years15,318 (14,797–15,839)15,125 (14,746–15,504)15,402 (15,189–15,615)0.45597.3 (96.3–98.3)96.8 (96.1–97.6)97.0 (96.6–97.4)0.757
      5 years19,742 (18,917–20,567)19,607 (18,976–20,238)20,218 (19,870–20,566)0.190112.0 (110.8–113.2)111.6 (110.7–112.5)111.9 (111.4–112.4)0.844
      a Corrected for exact age at measurement, gestational age at birth.
      b Adjusted for maternal body mass index and paternal height.Linear mixed model. P < 0.05 was considered to be significant.Over 80% of included children were measured at each measurement point.
      Figure 2
      Figure 2Mean weights, heights, head circumferences and body mass indices of children born after frozen embryo transfer (FET), fresh embryo transfer (ET) and natural conception (NC) at the age of years, corrected for exact age at measurement and adjusted for maternal body mass index (BMI) and paternal height. NA, not applicable.
      The mean weight, length/height of girls, crude and adjusted, did not differ between the FET, fresh embryo transfer and natural conception groups at 4, 8 and 18 months or at 3 and 5 years of age (Table 3 and Figure 2).
      Table 3CRUDE AND ADJUSTED MEAN WEIGHT AND HEIGHT OF GIRLS BORN AFTER FROZEN EMBRYO TRANSFER, FRESH EMBRYO TRANSFER AND NATURAL CONCEPTION
      Weight, g, mean (95% CI)Height, cm, mean (95% CI)
      Girls crude
      Corrected for exact age at measurement, gestational age at birth.
      AgeFrozen embryo transfer (n = 55)Fresh embryo transfer (n = 93)Natural conception (n = 277)P-valueFrozen embryo transfer (n = 55)Fresh embryo transfer (n = 93)Natural conception (n = 277)P-value
      Birth3364 (3236–3493)3462 (3364–3561)3457 (3400–3 514)0.40649.4 (48.9–49.9)49.8 (49.4–50.2)49.7 (49.4–49.9)0.544
      4 months6772 (6559–6985)6826 (6663–6990)6905 (6812–6998)0.43863.9 (63.3–64.4)64.0 (63.6–64.5)64.0 (63.7–64.2)0.886
      8 months8453 (8171–8734)8546 (8325–8766)8 591 (8466–8715)0.66570.5 (70.0–71.1)70.8 (70.3–71.3)70.6 (70.4–70.9)0.758
      18 months10,834 (10,481–11,187)10,969 (10,701–11,237)11,063 (10,910–11,216)0.47181.8 (81.0–82.6)82.0 (81.4–82.6)82.3 (81.9–82.6)0.475
      3 years14,256 (13,754–14,759)14,753 (14,372–15,135)14,498 (14,284–14,712)0.28094.5 (93.5–95.5)95.9 (95.1–96.7)95.3 (94.9–95.7)0.096
      5 years19,200 (18,379–20,021)19,286 (18,660–19,912)19,232 (18,881–19,584)0.984109.7 (108.4–110.9)110.6 (109.6–111.5)110.0 (109.5–110.5)0.458
      Girls adjusted
      Adjusted for maternal body mass index and paternal height Linear mixed model. P < 0.05 was considered to be significant. Over 80% of included children were measured at each measurement point.
      Birth3385 (3259–3512)3468 (3371–3564)3459 (3403–3516)0.53949.5 (49.0–50.0)49.8 (49.4–50.2)49.7 (49.4–49.9)0.635
      4 months6794 (6580–7008)6824 (6661–6987)6912 (6818–7005)0.46463.9 (63.4–64.5)64.0 (63.6–64.4)64.0 (63.8–64.2)0.973
      8 months8479 (8197–8761)8545 (8326–8763)8608 (8483–8733)0.67170.6 (70.0–71.2)70.8 (70.3–71.2)70.7 (70.4–70.9)0.883
      18 months10,881 (10,532–11,230)10,960 (10,698–11,222)11,088 (10,937–11,239)0.46381.9 (81.2–82.7)82.0 (81.4–82.6)82.3 (82.0–82.6)0.526
      3 years14,366 (13,881–14,851)14,739 (14,372–15,105)14,527 (14,321–14,732)0.44394.8 (93.9–95.7)95.8 (95.1–96.5)95.3 (94.9–95.7)0.181
      5 years19,390 (18,596–20,184)19,215 (18,613–19,818)19,268 (18,929–19,607)0.942110.0 (108.9–111.2)110.4 (109.5–111.2)110.0 (109.5–110.5)0.776
      a Corrected for exact age at measurement, gestational age at birth.
      b Adjusted for maternal body mass index and paternal heightLinear mixed model. P < 0.05 was considered to be significant.Over 80% of included children were measured at each measurement point.
      Considering head circumference measurements and BMI, at the age of 5 years (Figure 2), no significant differences were found between the study groups, nor at any of the earlier measurement points (data not shown). For the entire study population, no statistically significant differences were found between children born after FET, fresh embryo transfer and natural conception at any of the measurement points (data not shown).

      Discussion

      In this regional cohort, growth did not differ between term singletons born after FET, fresh embryo transfer and their natural conception controls matched for sex, birth year, maternal age and parity at several measurement points up to the age of 5 years.
      Previously, it was shown in a large Finnish register-based cohort study that children born after FET have higher mean birth weight and a higher risk of being LGA than children born after fresh embryo transfer (
      • Pelkonen S.
      • Koivunen R.
      • Gissler M.
      • Nuojua-Huttunen S.
      • Suikkari A.M.
      • Hydén-Granskog C.
      • Martikainen H.
      • Tiitinen A.
      • Hartikainen A.-L.
      Perinatal outcome of children born after frozen and fresh embryo transfer: the Finnish cohort study 1995–2006.
      ). This has been confirmed in studies from other countries (
      • Sazonova A.
      • Källen K.
      • Thurin-Kjellberg A.
      • Wennerholm U.B.
      • Bergh C.
      Obstetric outcome in singletons after in vitro fertilization with cryopreserved/thawed embryos.
      ;
      • Wennerholm U.B.
      • Henningsen A.K.
      • Romundstad L.B.
      • Bergh C.
      • Pinborg A.
      • Skjaerven R.
      • Forman J.
      • Gissler M.
      • Nygren K.G.
      • Tiitinen A.
      Perinatal outcomes of children born after frozen-thawed embryo transfer: a Nordic cohort study from the CoNARTaS group.
      ;
      • Pinborg A.
      • Henningsen A.A.
      • Loft A.
      • Malchau S.S.
      • Forman J.
      • Andersen A.N.
      Large baby syndrome in singletons born after frozen embryo transfer (FET): is it due to maternal factors or the cryotechnique?.
      ;
      • 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?.
      ;
      • Sha T.
      • Yin X.
      • Cheng W.
      • Massey I.Y.
      Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis.
      ;
      • Terho A,
      • Pelkonen S,
      • Opdahl S,
      • Romundstad L,B,
      • Bergh C,
      • Wennerholm U,B,
      • Henningsen A.A.
      • Pinborg A.
      • Gissler M.
      • Tiitinen A.
      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.
      ). In the present study, surprisingly, the adjusted birth weight of children born after FET did not significantly differ from that of children born after fresh embryo transfer and natural conception. In the previous Finnish study (
      • Pelkonen S.
      • Koivunen R.
      • Gissler M.
      • Nuojua-Huttunen S.
      • Suikkari A.M.
      • Hydén-Granskog C.
      • Martikainen H.
      • Tiitinen A.
      • Hartikainen A.-L.
      Perinatal outcome of children born after frozen and fresh embryo transfer: the Finnish cohort study 1995–2006.
      ), the incidence of LGA (birth weight >2 SD) was 2.1–3.6%, whereas, in the present study, only one case of LGA (0.9%) was found among the FET group and eight cases of LGA (4.4%) among the fresh embryo transfer group. This difference is likely due to chance, considering the smaller sample size.
      Previous studies on the long-term growth of children born after FET present variable settings and results. The growth data are often based on a scarce number of measurements or may be self-reported. Even in the larger studies, the number of children born after FET is often limited. In a Swedish study, the growth of children (singletons and multiples) born after FET (n = 255) did not differ from the growth of children born after fresh embryo transfer or natural conception up to 18 months’ of age. The groups were matched for maternal age, parity, singleton or twin status and date of delivery (
      • Wennerholm U.B.
      • Albertsson-Wikland K.
      • Bergh C.
      • Hamberger L.
      • Niklasson A.
      • Nilsson L.
      • Thiringer K.
      • Wennergren M.
      • Wikland M.
      • Borres M.P.
      Postnatal growth and health in children born after cryopreservation as embryos.
      ). A study from New Zealand compared the prepubertal growth of term singletons born after FET (n = 43) and fresh embryo transfer (n = 72) with a natural conception control group. Girls born after fresh embryo transfer were taller compared with natural conception and FET at a single measurement, which was taken between 3.5 and 11.0 years, corrected for parental height and BMI. No other statistically significant differences were found (
      • Green M.P.
      • Mouat F.
      • Miles H.L.
      • Hopkins S.A.
      • Derraik J.G.
      • Hofman P.L.
      • Peek J.C.
      • Cutfield W.S.
      Phenotypic differences in children conceived from fresh and thawed embryos in in vitro fertilization compared with naturally conceived children.
      ). In a recently published retrospective cohort from the USA (
      • Ainsworth A.J.
      • Wyatt M.A.
      • Shenoy C.C.
      • Hathcock M.
      • Coddington C.C.
      Fresh versus frozen embryo transfer has no effect on childhood weight.
      ), the growth of children born after FET (n = 49) and fresh embryo transfer (n = 87) was similar up to the age of 5 years, but loss to follow-up was significant, with only six children in the FET group and 18 children in the fresh embryo transfer group measured at 5 years.
      In a UK cohort study, preterm and term singletons born after FET (n = 1091) and fresh embryo transfer (n = 4127) were compared with matched natural conception controls. The measurements were made at birth, at 6–8 weeks and at 4–7 years, when growth information was available for 48–51% of the children. Primary covariates in the analyses were deprivation, maternal smoking, age, year, month of delivery and gender. By 4–7 years of age, no significant differences were identified in weight between the groups. Compared with natural conception, however, children born after FET were slightly taller and children born after fresh embryo transfer had a slightly lower BMI. Probabilistic matching of different health records based on names and dates of birth was used, as no unique identifiers were available, and no parental anthropometric data were available for adjustments (
      • Hann M.
      • Roberts S.A.
      • D'Souza S.W.
      • Clayton P.
      • Macklon N.
      • Brison D.R.
      The growth of assisted reproductive treatment-conceived children from birth to 5 years: a national cohort study.
      ). Another recently published UK study found no difference in growth at the age of 5 years between children born after FET (n = 179), fresh embryo transfer (n = 576) and natural conception, adjusting for maternal age, parity, smoking, weight, height, socioeconomic status and offspring sex (
      • Turner S.
      • Maclean E.
      • Dick S.
      • Aucott L.
      • Maheshwari A.
      Is conception by in vitro fertilization associated with altered antenatal and postnatal growth trajectories?.
      ). In a recent Norwegian study, preterm and term children born after FET (n = 179) were longer and heavier for the first 2 years compared with fresh embryo transfer (n = 1073). At the age of 17 years, no significant differences were found. Adjustments were made for maternal age, parity, educational level, smoking, parental BMI, height and gestational age at birth. The growth data were self-reported (
      • Magnus M.C.
      • Wilcox A.J.
      • Fadum E.A.
      • Gjessing H.K.
      • Opdahl S.
      • Juliusson P.B.
      • Romundstad L.B.
      • Håberg S.E.
      Growth in children conceived by ART.
      ).
      The present study is in line with previous studies (
      • Wennerholm U.B.
      • Albertsson-Wikland K.
      • Bergh C.
      • Hamberger L.
      • Niklasson A.
      • Nilsson L.
      • Thiringer K.
      • Wennergren M.
      • Wikland M.
      • Borres M.P.
      Postnatal growth and health in children born after cryopreservation as embryos.
      ;
      • Green M.P.
      • Mouat F.
      • Miles H.L.
      • Hopkins S.A.
      • Derraik J.G.
      • Hofman P.L.
      • Peek J.C.
      • Cutfield W.S.
      Phenotypic differences in children conceived from fresh and thawed embryos in in vitro fertilization compared with naturally conceived children.
      ;
      • Hann M.
      • Roberts S.A.
      • D'Souza S.W.
      • Clayton P.
      • Macklon N.
      • Brison D.R.
      The growth of assisted reproductive treatment-conceived children from birth to 5 years: a national cohort study.
      ;
      • Ainsworth A.J.
      • Wyatt M.A.
      • Shenoy C.C.
      • Hathcock M.
      • Coddington C.C.
      Fresh versus frozen embryo transfer has no effect on childhood weight.
      ;
      • Turner S.
      • Maclean E.
      • Dick S.
      • Aucott L.
      • Maheshwari A.
      Is conception by in vitro fertilization associated with altered antenatal and postnatal growth trajectories?.
      ) in finding similar childhood weights between the groups. Regarding height, this study somewhat contradicts
      • Green M.P.
      • Mouat F.
      • Miles H.L.
      • Hopkins S.A.
      • Derraik J.G.
      • Hofman P.L.
      • Peek J.C.
      • Cutfield W.S.
      Phenotypic differences in children conceived from fresh and thawed embryos in in vitro fertilization compared with naturally conceived children.
      ,
      • Hann M.
      • Roberts S.A.
      • D'Souza S.W.
      • Clayton P.
      • Macklon N.
      • Brison D.R.
      The growth of assisted reproductive treatment-conceived children from birth to 5 years: a national cohort study.
      and
      • Magnus M.C.
      • Wilcox A.J.
      • Fadum E.A.
      • Gjessing H.K.
      • Opdahl S.
      • Juliusson P.B.
      • Romundstad L.B.
      • Håberg S.E.
      Growth in children conceived by ART.
      , as no significant difference in height between the groups for boys, girls or the entire population was found. Also, in contrast to the results of
      • Hann M.
      • Roberts S.A.
      • D'Souza S.W.
      • Clayton P.
      • Macklon N.
      • Brison D.R.
      The growth of assisted reproductive treatment-conceived children from birth to 5 years: a national cohort study.
      and
      • Magnus M.C.
      • Wilcox A.J.
      • Fadum E.A.
      • Gjessing H.K.
      • Opdahl S.
      • Juliusson P.B.
      • Romundstad L.B.
      • Håberg S.E.
      Growth in children conceived by ART.
      , the childhood BMIs did not differ significantly between the groups in the present study. Different adjustments and the inclusion of only term-born children in the present study might explain these differences.
      In recent years, accumulating evidence has shown that FET in a hormonally programmed cycle, in which there is no functioning corpus luteum, increases the risk of adverse perinatal outcomes, such as hypertensive disorders in pregnancy, preterm birth and fetal macrosomia (
      • Ginström Ernstad E.
      • Wennerholm U.B.
      • Khatibi A.
      • Petzold M.
      • Bergh C.
      Neonatal and maternal outcome after frozen embryo transfer: Increased risks in programmed cycles.
      ;
      • Asserhøj L.L.
      • Spangmose A.L.
      • Aaris Henningsen A.K.
      • Clausen T.D.
      • Ziebe S.
      • Jensen R.B.
      • Pinborg A.
      Adverse obstetric and perinatal outcomes in 1,136 singleton pregnancies conceived after programmed frozen embryo transfer (FET) compared with natural cycle FET.
      ;
      • Hu K.L.
      • Zhang D.
      • Li R.
      Endometrium preparation and perinatal outcomes in women undergoing single-blastocyst transfer in frozen cycles.
      ). In the present study population, most (over 90%) of the FETs were carried out in a natural cycle, which may offer additional explanation to the similar growth between the study groups. No data on the mode of FET cycles have been presented in the previous child growth studies (
      • Wennerholm U.B.
      • Albertsson-Wikland K.
      • Bergh C.
      • Hamberger L.
      • Niklasson A.
      • Nilsson L.
      • Thiringer K.
      • Wennergren M.
      • Wikland M.
      • Borres M.P.
      Postnatal growth and health in children born after cryopreservation as embryos.
      ;
      • Hann M.
      • Roberts S.A.
      • D'Souza S.W.
      • Clayton P.
      • Macklon N.
      • Brison D.R.
      The growth of assisted reproductive treatment-conceived children from birth to 5 years: a national cohort study.
      ;
      • Ainsworth A.J.
      • Wyatt M.A.
      • Shenoy C.C.
      • Hathcock M.
      • Coddington C.C.
      Fresh versus frozen embryo transfer has no effect on childhood weight.
      ;
      • Turner S.
      • Maclean E.
      • Dick S.
      • Aucott L.
      • Maheshwari A.
      Is conception by in vitro fertilization associated with altered antenatal and postnatal growth trajectories?.
      ;
      • Magnus M.C.
      • Wilcox A.J.
      • Fadum E.A.
      • Gjessing H.K.
      • Opdahl S.
      • Juliusson P.B.
      • Romundstad L.B.
      • Håberg S.E.
      Growth in children conceived by ART.
      ), except for the study by
      • Green M.P.
      • Mouat F.
      • Miles H.L.
      • Hopkins S.A.
      • Derraik J.G.
      • Hofman P.L.
      • Peek J.C.
      • Cutfield W.S.
      Phenotypic differences in children conceived from fresh and thawed embryos in in vitro fertilization compared with naturally conceived children.
      , in which 81% of FETs were carried out in a natural cycle.
      Child growth is complexly regulated, with genetic, epigenetic and environmental components having an effect. Increasing maternal and paternal height, weight and BMI are positively correlated with child growth, with especially maternal obesity associating strongly with childhood obesity of the offspring (
      • Addo O.Y.
      • Stein A.D.
      • Fall C.H.
      • Gigante D.P.
      • Guntupalli A.M.
      • Horta B.L.
      • Kuzawa C.W.
      • Lee N.
      • Norris S.A.
      • Prabhakaran P.
      • Richter L.M.
      • Sachdev H.S.
      • Martorell R.
      Consortium on Health Orientated Research in Transitional Societies (COHORTS) Group. Maternal height and child growth patterns.
      ;
      • Sørensen T,I,A,
      • Ajslev T,A,
      • Ängquist L,
      • Morgen C,S,
      • Ciuchi I,G,
      • Smith G,D.
      Comparison of associations of maternal peri-pregnancy and paternal anthropometrics with child anthropometrics from birth through age 7 y assessed in the Danish National Birth Cohort.
      ;
      • Ohlendorf J.M.
      • Robinson K.
      • Garnier-Villarreal M.
      The impact of maternal BMI, gestational weight gain, and breastfeeding on early childhood weight: Analysis of a statewide WIC dataset.
      ). Furthermore, excessive maternal gestational weight gain and gestational diabetes increase the risk of childhood obesity (
      • Josey M.J.
      • McCullough L.E.
      • Hoyo C.
      • Williams-DeVane C.
      Overall gestational weight gain mediates the relationship between maternal and child obesity.
      ;
      • Ohlendorf J.M.
      • Robinson K.
      • Garnier-Villarreal M.
      The impact of maternal BMI, gestational weight gain, and breastfeeding on early childhood weight: Analysis of a statewide WIC dataset.
      ). First-borns tend to be smaller than their later-born peers, and it has been suggested that postnatal catch-up growth may increase their metabolic risks (
      • Wells J.C.
      • Hallal P.C.
      • Reichert F.F.
      • Dumith S.C.
      • Menezes A.M.
      • Victora C.G.
      Associations of birth order with early growth and adolescent height, body composition, and blood pressure: prospective birth cohort from Brazil.
      ;
      • Kwok M.K.
      • Leung G.M.
      • Schooling C.M.
      Associations of birth order with early adolescent growth, pubertal onset, blood pressure and size: evidence from Hong Kong's “Children of 1997” birth cohort.
      ). Low parental educational level has also been shown to be associated with elevated risk of child obesity (
      • Bramsved R.
      • Regber S.
      • Novak D.
      • Mehlig K.
      • Lissner L.
      • Mårild S.
      Parental education and family income affect birthweight, early longitudinal growth and body mass index development differently.
      ). Breastfeeding is protective of childhood obesity (
      • Yan J.
      • Liu L.
      • Zhu Y.
      • Huang G.
      • Wang P.P.
      The association between breastfeeding and childhood obesity: a meta-analysis.
      ;
      • Pattison K.L.
      • Kraschnewski J.L.
      • Lehman E.
      • Savage J.S.
      • Downs D.S.
      • Leonard K.S.
      • Adams E.L.
      • Paul I.M.
      • Kjerulff K.H.
      Breastfeeding initiation and duration and child health outcomes in the first baby study.
      ). In the present study, only pre-pregnancy maternal BMI was available with no data on gestational weight gain. Also, no data on breastfeeding were available. Information on a large number of other confounding factors, however, was available, and adjustments were made for exact age at measurement, maternal BMI and paternal height. Considering the study size, we were not able to adjust for the number of embryos transferred.
      One major strength of the present study is the reliability of the child growth data derived from high-coverage municipal child health clinic follow-up appointments in Finland (

      THL 2019b. THL (Finnish Institute for Health and Welfare) 2019. Terveystarkastusten ja muiden käyntien toteumat äitiys- ja lastenneuvolassa 2018 sekä kouluterveydenhuollossa lukuvuonna 2018-19 [Health examinations and other visits in maternity and child health clinics in 2018 and in school health care in the academic year 2018-19] (in Finnish).https://www.julkari.fi/bitstream/handle/10024/138990/Tr_46_2019.pdf?sequence=5&isAllowed=y. Accessed Dec 20, 2020.

      ). Growth data collection in the child health clinics is prospective, based on standardized methods used in the regular scheduled visits to see either a public health nurse or a physician (

      THL 2017. THL (Finnish Institute for Health and Welfare) 2017. Terveystarkastukset lastenneuvolassa ja kouluterveydenhuollossa: menetelmäkäsikirja. [Health examinations in child health clinics and school health care: Method manual.] (in Finnish).https://www.julkari.fi/handle/10024/135858. Accessed Jan 31, 2021.

      ). Therefore, loss to follow-up was minimal in this study, with growth data covering over 80% of all the children included in the study at each measurement point throughout the 5 years. This made accurate information provided by medical professionals available for both FET and fresh embryo transfer groups, as well as children born after natural conception, adding to the plausibility of these results. Only term-born singleton children were included to minimize confounders associated with multiple gestations, preterm birth, or both. Furthermore, siblings, i.e. subsequent births to the same mother, were excluded to ensure the groups were totally independent for statistical analyses. Another strength is the ability to link information reliably based on the unique personal identifier codes given to every Finnish citizen and permanent resident at birth or immigration.
      The main weakness of this study is the relatively small sample size, which was limited by the two-centre setting and the exclusion of preterm children and all multiple births. Also, within this study period, the effects of prolonged embryo culture times or vitrification could not be investigated. It should also be considered that these results represent a geographically restricted area in a high-income country with inhabitants whose ethnic background is mainly white.
      Although causality can seldom be shown in an observational epidemiological study, the similarities in childhood growth seem to imply that the mode of conception is not the only contributing factor in the growth pattern of the term-born singleton child. It has been suggested that the intrauterine growth differences shown in a number of previous studies might be explained by the underlying cause of infertility or subfertility, laboratory procedures, placentation or epigenetic changes of the offspring, or a combination of all these factors (
      • Berntsen S.
      • Söderström-Anttila V.
      • Wennerholm U.B.
      • Laivuori H.
      • Loft A.
      • Oldereid N.B.
      • Romundstad L.B.
      • Bergh C.
      • Pinborg A.
      The health of children conceived by ART: ‘the chicken or the egg?.
      ). Whatever the cause, it does not seem to have a clinically significant effect on long-term growth after birth.
      In conclusion, the rate of embryo cryopreservation is steadily increasing worldwide, as more SETs, donor treatments, fertility-sparing treatments and even freeze-all policies in routine treatments are advocated. This study provides important further evidence that FET does not cause long-term harm for the offspring.

      Acknowledgement

      Finnish Government Research funding was obtained for this study; a grant from The Alma and KA Snellman Foundation, Oulu, Finland, was awarded to Anna Maria Terho.

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      Biography

      Hannu Martikainen is Professor of Obstetrics and Gynaecology at the University of Oulu, Finland. He has practised infertility treatments for over 35 years and published more than 150 peer-reviewed papers. His main interest is the safety of infertility treatments, including single embryo transfer in fresh and frozen cycles.
      Key message
      Similar growth was found in term singletons born after frozen compared with fresh embryo transfer and natural conception up to 5 years of age. This offers reassurance about the safety and feasibility of the steadily increasing use of embryo cryopreservation in assisted reproduction.