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Lower risk of adverse perinatal outcomes in natural versus artificial frozen–thawed embryo transfer cycles: a systematic review and meta-analysis

  • José Moreno-Sepulveda
    Correspondence
    Corresponding author.
    Affiliations
    Obstetrics and Gynecology Department, Universitat Autònoma de Barcelona, Campus Universitario UAB, Bellaterra Cerdanyola del Vallès 08193, Spain

    Clínica de la Mujer Medicina Reproductiva, Alejandro Navarrete 2606, Viña del Mar, Chile
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  • Juan Jose Espinós
    Affiliations
    Obstetrics and Gynecology Department, Universitat Autònoma de Barcelona, Campus Universitario UAB, Bellaterra Cerdanyola del Vallès 08193, Spain

    Fertty International, Carrer d'Ausiàs Marc, 25, Barcelona 08010, Spain

    Department of Obstetrics and Gynaecology, Hospital de la Santa Creu i Sant Pau, Carrer de Sant Quintí, 89 Barcelona 08041, Spain
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  • Miguel Angel Checa
    Affiliations
    Obstetrics and Gynecology Department, Universitat Autònoma de Barcelona, Campus Universitario UAB, Bellaterra Cerdanyola del Vallès 08193, Spain

    Fertty International, Carrer d'Ausiàs Marc, 25, Barcelona 08010, Spain

    GRI-BCN, Barcelona Infertility Research Group, IMIM, Institut Hospital del Mar d'Investigacions Mèdiques, Carrer del Dr. Aiguader, 88, Barcelona 08003, Spain
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Published:March 10, 2021DOI:https://doi.org/10.1016/j.rbmo.2021.03.002

      Highlights

      • NC-FET is associated with a lower risk of hypertensive disorders of pregnancy
      • The risk of LGA and macrosomia may be reduced in newborns after NC-FET
      • Postpartum hemorrhage and placenta accreta are other outcomes improved after NC-FET
      • Cesarean section rates are high in FET, both in natural and artificial cycles

      Abstract

      This systematic review of literature and meta-analysis of observational studies reports on perinatal outcomes after frozen embryo transfer (FET). The aim was to determine whether natural cycle frozen embryo transfer (NC-FET) in singleton pregnancies conceived after IVF decreased the risk of adverse perinatal outcomes compared with artificial cycle frozen embryo transfer (AC-FET). Thirteen cohort studies, including 93,201 cycles, met the inclusion criteria. NC-FET was associated with a lower risk of hypertensive disorders in pregnancy (HDP) (RR 0.61, 95% CI 0.50 to 0.73), preeclampsia (RR 0.47, 95% CI 0.42 to 0.53), large for gestational age (LGA) (RR 0.93, 95% CI 0.90 to 0.96) and macrosomia (RR 0.82, 95% CI 0.69 to 0.97) compared with AC-FET. No significant difference was found in the risk of gestational hypertension and small for gestational age. Secondary outcomes assessed were the risk of preterm birth (RR 0.83, 95% CI 0.79 to 0.88); post-term birth (RR 0.48, 95% CI 0.29 to 0.80); low birth weight (RR 0.84, 95% CI 0.80 to 0.89); caesarean section (RR 0.84, 95% CI 0.77 to 0.91); postpartum haemorrhage (RR 0.39, 95% CI 0.35 to 0.45); placental abruption (RR 0.61, 95% CI 0.38 to 0.98); and placenta accreta (RR 0.18, 95% CI 0.10 to 0.33). All were significantly lower with NC-FET compared with AC-FET. In assessing safety, NC-FET significantly decreased the risk of HDP, preeclampsia, LGA, macrosomia, preterm birth, post-term birth, low birth weight, caesarean section, postpartum haemorrhage, placental abruption and placenta accreta. Further randomized controlled trials addressing the effect of NC-FET and AC-FET on maternal and perinatal outcomes are warranted. Clinicians should carefully monitor pregnancies achieved by FET in artificial cycles prenatally, during labour and postnatally.

      KEYWORDS

      Introduction

      Frozen–thawed embryo transfer (FET) has increased steadily worldwide over the past few years (
      • De Geyter C.
      • Calhaz-Jorge C.
      • Kupka M.S.
      • Wyns C.
      • Mocanu E.
      • Motrenko T.
      • Scaravelli G.
      • Smeenk J.
      • Vidakovic S.
      • Goossens V.
      European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE)
      ART in Europe, 2015: results generated from European registries by ESHRE.
      ;
      • Zegers-Hochschild F.
      • Crosby J.A.
      • Musri C.
      • de Souza M.D.C.B.
      • Martinez A.G.
      • Silva A.A.
      • Mojarra J.M.
      • Masoli D.
      • Posada N.
      Latin American Network of Assisted Reproduction
      Assisted reproductive technology in Latin America: the Latin American Registry, 2017.
      ). In 2015, FET accounted for about 40% of all IVF cycles in Europe (
      • De Geyter C.
      • Calhaz-Jorge C.
      • Kupka M.S.
      • Wyns C.
      • Mocanu E.
      • Motrenko T.
      • Scaravelli G.
      • Smeenk J.
      • Vidakovic S.
      • Goossens V.
      European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE)
      ART in Europe, 2015: results generated from European registries by ESHRE.
      ). The freeze-all strategy has reported successful results with higher live birth rates and lower incidence of ovarian hyperstimulation syndrome compared with fresh embryo transfer (
      • Roque M.
      • Haahr T.
      • Geber S.
      • Esteves S.C.
      • Humaidan P.
      Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes.
      ;
      • Wei D.
      • Liu J.Y.
      • Sun Y.
      • Shi Y.
      • Zhang B.
      • Liu J.Q.
      • Tan J.
      • Liang X.
      • Cao Y.
      • Wang Z.
      • Qin Y.
      • Zhao H.
      • Zhou Y.
      • Ren H.
      • Hao G.
      • Ling X.
      • Zhao J.
      • Zhang Y.
      • Qi X.
      • Zhang L.
      • Deng X.
      • Chen X.
      • Zhu Y.
      • Wang X.
      • Tian L.F.
      • Lv Q.
      • Ma X.
      • Zhang H.
      • Legro R.S.
      • Chen Z.J.
      Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial.
      ). Some studies have suggested that singletons born after FET also have better neonatal outcomes compared with singletons born after fresh embryo transfer, e.g. low birth weight (LBW), small for gestational age (SGA) and preterm birth (PTB) (
      • Vidal M.
      • Vellvé K.
      • González-Comadran M.
      • Robles A.
      • Prat M.
      • Torné M.
      • Carreras R.
      • Checa M.A.
      Perinatal outcomes in children born after fresh or frozen embryo transfer: a Catalan cohort study based on 14,262 newborns.
      ;
      • Zhang B.
      • Wei D.
      • Legro R.S.
      • Shi Y.
      • Li J.
      • Zhang L.
      • Hong Y.
      • Sun G.
      • Zhang T.
      • Li W.
      • Chen Z.J.
      Obstetric complications after frozen versus fresh embryo transfer in women with polycystic ovary syndrome: results from a randomized trial.
      ;
      • Roque M.
      • Haahr T.
      • Geber S.
      • Esteves S.C.
      • Humaidan P.
      Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes.
      ;
      • Wei D.
      • Liu J.Y.
      • Sun Y.
      • Shi Y.
      • Zhang B.
      • Liu J.Q.
      • Tan J.
      • Liang X.
      • Cao Y.
      • Wang Z.
      • Qin Y.
      • Zhao H.
      • Zhou Y.
      • Ren H.
      • Hao G.
      • Ling X.
      • Zhao J.
      • Zhang Y.
      • Qi X.
      • Zhang L.
      • Deng X.
      • Chen X.
      • Zhu Y.
      • Wang X.
      • Tian L.F.
      • Lv Q.
      • Ma X.
      • Zhang H.
      • Legro R.S.
      • Chen Z.J.
      Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial.
      ).
      Compared with fresh embryo transfer, FET seems to carry a greater risk of hypertensive disorders in pregnancy (HDP), including gestational hypertension and preeclampsia (Opdahl et al., 2015;
      • Roque M.
      • Haahr T.
      • Geber S.
      • Esteves S.C.
      • Humaidan P.
      Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes.
      ), being born as large for gestational age (LGA) and macrosomia (
      • 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?.
      ;
      • Rodriguez-Wallberg K.A.
      • Berger A.S.
      • Fagerberg A.
      • Olofsson J.I.
      • Scherman-Pukk C.
      • Lindqvist P.G.
      • Nasiell J.
      Increased incidence of obstetric and perinatal complications in pregnancies achieved using donor oocytes and single embryo transfer in young and healthy women. A prospective hospital-based matched cohort study.
      ;
      • Wei D.
      • Liu J.Y.
      • Sun Y.
      • Shi Y.
      • Zhang B.
      • Liu J.Q.
      • Tan J.
      • Liang X.
      • Cao Y.
      • Wang Z.
      • Qin Y.
      • Zhao H.
      • Zhou Y.
      • Ren H.
      • Hao G.
      • Ling X.
      • Zhao J.
      • Zhang Y.
      • Qi X.
      • Zhang L.
      • Deng X.
      • Chen X.
      • Zhu Y.
      • Wang X.
      • Tian L.F.
      • Lv Q.
      • Ma X.
      • Zhang H.
      • Legro R.S.
      • Chen Z.J.
      Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial.
      ). The reasons behind these findings are not clearly understood, but it has been suggested that some cryoprotectants or the freeze–thawing process per se could develop some metabolic or epigenetic changes related to abnormal placentation and eventually preeclampsia (
      • Nelissen E.C.
      • van Montfoort A.P.
      • Dumoulin J.C.
      • Evers J.L.
      Epigenetics and the placenta.
      ;
      • Hiura H.
      • Hattori H.
      • Kobayashi N.
      • Okae H.
      • Chiba H.
      • Miyauchi N.
      • et al.
      Genome-wide microRNA expression profiling in placentae from frozen-thawed blastocyst transfer.
      ).
      The role of the endometrium has also been a focus of attention. Different options for preparing the endometrium for FET have been described, including a natural cycle (NC-FET) based on the detection of the endogenous LH surge in the blood, a modified natural cycle using HCG for final oocyte maturation and artificial cycle (AC-FET) based on an hormonal replacement treatment with or without co-treatment with a gonadotrophin releasing hormone analogue, and a stimulated cycle with anti-oestrogens, aromatase inhibitors or gonadotrophins (
      • Lawrenz B.
      • Coughlan C.
      • Melado L.
      • Fatemi H.M.
      The ART of frozen embryo transfer: back to nature!.
      ). The most commonly used type of endometrial preparation is the AC-FET (
      • Lawrenz B.
      • Coughlan C.
      • Melado L.
      • Fatemi H.M.
      The ART of frozen embryo transfer: back to nature!.
      ), in which oestrogens are administered with the aim of mimicking the changes generated by steroids of ovarian origin that occur in natural cycles. Endometrial thickness and pattern are monitored by vaginal ultrasound, and progesterone administration is usually started from an endometrial thickness of about 7–8 mm (
      • Liu K.E.
      • Hartman M.
      • Hartman A.
      • Luo Z.C.
      • Mahutte N.
      The impact of a thin endometrial lining on fresh and frozen-thaw IVF outcomes: an analysis of over 40 000 embryo transfers.
      ). In clinical practice, AC-FET is popular because it involves less monitoring and the embryo transfer can be scheduled on a convenient day for the patient and the clinic (
      • Singh B.
      • Reschke L.
      • Segars J.
      • Baker V.L.
      Frozen-thawed embryo transfer: the potential importance of the corpus luteum in preventing obstetrical complications.
      ).
      In recent years, multiple studies have investigated the effectiveness of different endometrial preparation schemes in relation to implantation rates, clinical pregnancy rates or live birth rates (
      • Yarali H.
      • Polat M.
      • Mumusoglu S.
      • Yarali I.
      • Bozdag G.
      Preparation of endometrium for frozen embryo replacement cycles: a systematic review and meta-analysis.
      ;
      • Ghobara T.
      • Gelbaya T.A.
      • Ayeleke R.O.
      Cycle regimens for frozen-thawed embryo transfer.
      ;
      • Mackens S.
      • Santos-Ribeiro S.
      • van de Vijver A.
      • Racca A.
      • Van Landuyt L.
      • Tournaye H.
      • Blockeel C.
      Frozen embryo transfer: a review on the optimal endometrial preparation and timing.
      ;
      • Groenewoud E.R.
      • Cohlen B.J.
      • Macklon N.S.
      Programming the endometrium for deferred transfer of cryopreserved embryos: hormone replacement versus modified natural cycles.
      ). Studies evaluating perinatal and maternal outcomes, however, are scarce and have reported contradictory results. Some observational data have suggested higher rates of HDP, LGA and macrosomia after programmed FET cycles compared with NC-FET (
      • 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.
      ;
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • Morisaki N.
      • Miyado M.
      • Miyado K.
      • Fukami M.
      • Miyasaka N.
      • Ishihara O.
      • Irahara M.
      • Saito H.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      ;
      • Wang Z.
      • Liu H.
      • Song H.
      • Li X.
      • Jiang J.
      • Sheng Y.
      • Shi Y.
      Increased Risk of Pre-eclampsia After Frozen-Thawed Embryo Transfer in Programming Cycles.
      ;
      • Zong L.
      • Liu P.
      • Zhou L.
      • Wei D.
      • Ding L.
      • Qin Y.
      Increased risk of maternal and neonatal complications in hormone replacement therapy cycles in frozen embryo transfer.
      ); however, other studies have not confirmed these findings (
      • Lin J.
      • Zhao J.
      • Hao G.
      • Tan J.
      • Pan Y.
      • Wang Z.
      • Jiang Q.
      • Xu N.
      • Shi Y.
      Maternal and Neonatal Complications After Natural vs. Hormone Replacement Therapy Cycle Regimen for Frozen Single Blastocyst Transfer.
      ;
      • Pan Y.
      • Li B.
      • Wang Z.
      • Wang Y.
      • Gong X.
      • Zhou W.
      • Shi Y.
      Hormone Replacement Versus Natural Cycle Protocols of Endometrial Preparation for Frozen Embryo Transfer.
      ;
      • Wang B.
      • Zhang J.
      • Zhu Q.
      • Yang X.
      • Wang Y.
      Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons.
      ).
      The reason behind the high rates of adverse obstetric outcomes is not known, but it has been suggested that some endometrial changes mediated by the altered levels of oestradiol and progesterone, possibly reached during the AC-FET, could be associated with the development of impaired decidualization and placentation, leading to placenta-related complications, such as HDP, placenta accreta, placenta previa and placental abruption (
      • Chen J.Z.
      • Sheehan P.M.
      • Brennecke S.P.
      • Keogh R.J.
      Vessel remodeling, pregnancy hormones and extravillous trophoblast function.
      ;
      • Kaser D.J.
      • Melamed A.
      • Bormann C.L.
      • Myers D.E.
      • Missmer S.A.
      • Walsh B.W.
      • Racowsky C.
      • Carusi D.A.
      Cryopreserved embryo transfer is an independent risk factor for placenta accrete.
      ;
      • Schatz F.
      • Guzeloglu-Kayisli O.
      • Arlier S.
      • Kayisli U.A.
      • Lockwood C.J.
      The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding.
      ).
      In addition, the hypothalamic–pituitary–gonadal axis is inhibited by exogenous oestradiol. This can lead to a lack of corpus luteum. The corpus luteum produces reproductive hormones, including the vasoactive hormone relaxin. Recently published studies have found that scheduled FET cycles, in which no corpus luteum is present, are associated with higher rates of preeclampsia compared with natural FET cycles, in which one or more corpus luteum occur (
      • Conrad K.P.
      • Baker V.L.
      Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies.
      ;
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • Chiu K.H.
      • Liu J.
      • Lingis M.
      • Stan Williams R.
      • Rhoton-Vlasak A.
      • Nichols W.W.
      • Fleischmann R.R.
      • Zhang W.
      • Winn V.D.
      • Segal M.S.
      • Conrad K.P.
      • Baker V.L.
      Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the Absence of a Corpus Luteum.
      ).
      Given the increasing use of FET, it is critical to determine whether specific FET protocols could be related to the development of adverse obstetric and maternal outcomes, and if elements of the treatment could be modified to optimize outcomes. Therefore, the aim of this systematic review was to determine whether NC-FET decreased the risk of adverse perinatal outcomes compared with AC-FET.

      Materials and methods

      Search strategy and selection criteria

      The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for the present systematic review and meta-analysis (
      • Shamseer L.
      • Moher D.
      • Clarke M.
      • Ghersi D.
      • Liberati A.
      • Petticrew M.
      • Shekelle P.
      • Stewart L.
      PRISMA-P Group
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation.
      ). The study protocol can be accessed at https://inplasy.com/ (registration number INPLASY202060088).
      The selection criteria were described according to Patients, Intervention, Comparison and Outcomes (PICO) statements. Studies that compared the reproductive outcomes of deliveries from autologous oocytes between NC-FET and AC-FET were included (Table 1).
      TABLE 1STUDIES INCLUDED IN THE META-ANALYSIS
      StudyArea/durationStudy designNC-FETAC-FETAge, yearsFET protocolStage of embryo developmentFreezing techniquePGT-AOutcomesQuality of studies (NOS)
      • Guan Y.
      • Fan H.
      • Styer A.K.
      • Xiao Z.
      • Li Z.
      • Zhang J.
      • Sun L.
      • Wang X.
      • Zhang Z.
      A modified natural cycle results in higher live birth rate in vitrified-thawed embryo transfer for women with regular menstruation.
      China, 2012–2013Retrospective case–control427
      Frozen embryo transfer cycles.
      794
      Frozen embryo transfer cycles.
      NC-FET: 31.2 ± 5.0

      AC-FET:

      31.3 ± 5.2
      Modified natural cycles: ovulation was stimulated with 10,000 IU of HCG.

      Artificial cycles: 4–6 mg/day of oral oestradiol starting on day 2–4 of the natural menstrual cycle. The oestradiol dosage was adjusted based on the endometrial thickness and level of serum oestradiol. Intramuscular progesterone administration was started after adequate endometrial proliferation (diameter ≥8 mm) and serum oestradiol concentration (200–300 ng/l) were documented.

      Not included in the meta-analysis: GnRH agonist artificial cycles; ovulation induction cycles.
      Day-3 embryoVitrificationNEHypertensive disorder of pregnancy; macrosomia; pre-term birth; post-term birth; stillbirth; neonatal mortality; birth defects; gestational diabetes.8/9
      • Saito K.
      • Miyado K.
      • Yamatoya K.
      • Kuwahara A.
      • Inoue E.
      • Miyado M.
      • Fukami M.
      • Ishikawa T.
      • Saito T.
      • Kubota T.
      • Saito H.
      Increased incidence of post-term delivery and Cesarean section after frozen-thawed embryo transfer during a hormone replacement cycle.
      Japan, 2013Retrospective cohort study6287
      Live births after frozen embryo transfer cycles.
      10235
      Live births after frozen embryo transfer cycles.
      NC-FET: 36.5 ± 3.7

      AC-FET: 35.3 ± 4.0
      Natural cycles (normal ovulatory cycle) and hormone replacement cycle (dose schemes not explained).Blastocyst and cleavage stageVitrification and slow freezingNELarge for gestational age; macrosomia; pre-term birth; post-term birth; low birth weight; small for gestational age; stillbirth caesarean section.8/9
      • Alur-Gupta S.
      • Hopeman M.
      • Berger D.S.
      • Gracia C.
      • Barnhart K.T.
      • Coutifaris C.
      • Senapati S.
      Impact of method of endometrial preparation for frozen blastocyst transfer on pregnancy outcome: a retrospective cohort study.
      USA, 2013–2017Retrospective cohort study105
      Frozen embryo transfer cycles.
      923
      Frozen embryo transfer cycles.
      NC-FET: 35.6 ± 3AC-FET:

      35.4 ± 4
      Unstimulated cycles normal ovulatory cycle.

      Programmed FET protocol: GnRH agonist suppression in the luteal phase and then oral oestroadiol initiated at a dose of 2 mg daily and titrated to 6 mg daily over 12 days. Intramuscular progesterone was started at 50 mg when appropriate parameters were met.
      BlastocystNEYesStillbirth8/9
      • Jing S.
      • Li X.F.
      • Zhang S.
      • Gong F.
      • Lu G.
      • Lin G.
      Increased pregnancy complications following frozen-thawed embryo transfer during an artificial cycle.
      China, 2013–2016Retrospective cohort study4708
      Clinical pregnancies after frozen embryo transfer cycles. AC-FET, artificial cycle frozen embryo transfer; FET, frozen embryo transfer; GnRH, gonadotrophin releasing hormone; NC-FET, natural cycle frozen embryo transfer; NE, not explained; NOS, Newcastle–Ottawa Scale; PGT-A, preimplantation genetic testing for aneuploidy.
      1326
      Clinical pregnancies after frozen embryo transfer cycles. AC-FET, artificial cycle frozen embryo transfer; FET, frozen embryo transfer; GnRH, gonadotrophin releasing hormone; NC-FET, natural cycle frozen embryo transfer; NE, not explained; NOS, Newcastle–Ottawa Scale; PGT-A, preimplantation genetic testing for aneuploidy.
      NC-FET: 31 (28–35)

      AC-FET:

      31 (28–35)
      Natural cycles: normal ovulatory cycle.

      Artificial cycle: oestrogen valerate 2 mg was administered orally: one pill on days 1, 2, 3 and 4; two pills on days 5, 6 and 7; three pills on days 8, 9, 10 and 11; four pills on days 12, 13, 14, 15 and 16; and two pills on days 17 to 31. Dydrogesterone was administered orally (10 mg per 12 h) when the endometrial thickness reached at least 8 mm.
      Blastocyst and cleavage stageVitrificationNEHypertensive disorder of pregnancy; large for gestational age; macrosomia; pre-term birth; post-term birth; low birth weight; very low birth weight; small for gestational age; stillbirth; neonatal mortality; caesarean section; gestational diabetes.9/9
      • 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.
      Sweden, 2005–2015Retrospective cohort study6297
      Live births after frozen embryo transfer cycles.
      1446
      Live births after frozen embryo transfer cycles.
      NC-FET: 34.9 ± 4.1

      AC-FET: 34.3 ± 4.3
      Natural cycles: normal ovulatory cycle (one corpus luteum).

      Programmed cycles: included oestrogen and progesterone with or without suppression with a GnRH agonist or antagonist (no corpus luteum).

      Stimulated cycles were not included in the meta-analysis.
      Blastocyst and cleavage stageVitrification and slow freezingNEHypertensive disorder of pregnancy; preeclampsia; gestational hypertension; large for gestational age; macrosomia; pre-term birth; post-term birth; low birth weight; very low birth weight; small for gestational age; stillbirth; birth defects; neonatal mortality; caesarean section; postpartum haemorrhage; placental abruption; placenta previa.9/9
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • Morisaki N.
      • Miyado M.
      • Miyado K.
      • Fukami M.
      • Miyasaka N.
      • Ishihara O.
      • Irahara M.
      • Saito H.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      Japan, 2014Retrospective cohort study10,755
      Clinical pregnancies after frozen embryo transfer cycles. AC-FET, artificial cycle frozen embryo transfer; FET, frozen embryo transfer; GnRH, gonadotrophin releasing hormone; NC-FET, natural cycle frozen embryo transfer; NE, not explained; NOS, Newcastle–Ottawa Scale; PGT-A, preimplantation genetic testing for aneuploidy.
      24,225
      Clinical pregnancies after frozen embryo transfer cycles. AC-FET, artificial cycle frozen embryo transfer; FET, frozen embryo transfer; GnRH, gonadotrophin releasing hormone; NC-FET, natural cycle frozen embryo transfer; NE, not explained; NOS, Newcastle–Ottawa Scale; PGT-A, preimplantation genetic testing for aneuploidy.
      NC-FET: 38.0 ± 4.1

      AC-FET: 37.2 ± 4.4
      Natural cycles (normal ovulatory cycle) and hormone replacement cycle (dose schemes not explained).Blastocyst and cleavage stageNENEHypertensive disorder of pregnancy; large for gestational age; macrosomia; preterm birth; post-term birth; low birth weight; small for gestational age; stillbirth; caesarean section; gestational diabetes; placental abruption; placenta previa; placenta accrete.9/9
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • Chiu K.H.
      • Liu J.
      • Lingis M.
      • Stan Williams R.
      • Rhoton-Vlasak A.
      • Nichols W.W.
      • Fleischmann R.R.
      • Zhang W.
      • Winn V.D.
      • Segal M.S.
      • Conrad K.P.
      • Baker V.L.
      Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the Absence of a Corpus Luteum.
      USA, 2011–2017Prospective cohort study127
      Live births after frozen embryo transfer cycles.
      94
      Live births after frozen embryo transfer cycles.
      NC-FET: 32 ± 5

      AC-FET: 37 ± 7
      Natural cycles: spontaneous conceptions, intrauterine insemination, or FETs in modified natural cycles with one corpus luteum.

      Programmed cycle with no corpus luteum.

      Patients with ovulation induction with timed intercourse, intrauterine insemination or IVF with fresh embryo transfer were not included in the meta-analysis.
      Blastocyst and cleavage stageNENEHypertensive disorder of pregnancy; preeclampsia; gestational hypertension.9/9
      • Makhijani R.
      • Bartels C.
      • Godiwala P.
      • Bartolucci A.
      • Nulsen J.
      • Grow D.
      • Benadiva C.
      • Engmann L.
      Maternal and perinatal outcomes in programmed versus natural vitrified-thawed blastocyst transfer cycles.
      USA 2013–2018Retrospective cohort study384
      Live births after frozen embryo transfer cycles.
      391
      Live births after frozen embryo transfer cycles.
      NC-FET: 35.0 ± 3.7

      AC-FET: 33.9 ± 3.9
      Natural cycles (normal ovulatory cycle).

      Programmed cycle: downregulation with GnRH agonist in the luteal phase followed by increasing doses of oral or transdermal oestradiol after menses. Intramuscular progesterone was started when endometrial thickness measured 8 mm.
      BlastocystVitrificationYesHypertensive disorder of pregnancy; macrosomia; pre-term birth; low birth weight; stillbirth; birth defects; caesarean section; postpartum haemorrhage; gestational diabetes; placental abruption; placenta previa; placenta accrete.9/9
      • Wang Z.
      • Liu H.
      • Song H.
      • Li X.
      • Jiang J.
      • Sheng Y.
      • Shi Y.
      Increased Risk of Pre-eclampsia After Frozen-Thawed Embryo Transfer in Programming Cycles.
      China, 2013–2018Retrospective cohort study10211
      Live births after frozen embryo transfer cycles.
      4162
      Live births after frozen embryo transfer cycles.
      NC-FET: 30.93 ± 4.16

      AC-FET: 30.63 ± 4.14
      Natural cycle: the dominant follicle was monitored by transvaginal ultrasound until ovulation was achieved with or without the trigger of HCG.

      Programmed cycle regimen: oestrogen, at a dose of 4–6 mg daily, was initiated on the second or third day of the menstrual cycle and lasted for 10–14 days until the endometrial thickness reached at least 8 mm.
      BlastocystVitrificationNEPreeclampsia; large for gestational age; macrosomia; pre-term birth; post-term birth; low birth weight; very low birth weight; small for gestational age; caesarean section; postpartum haemorrhage; gestational diabetes; placental abruption; placenta previa.9/9
      • Lin J.
      • Zhao J.
      • Hao G.
      • Tan J.
      • Pan Y.
      • Wang Z.
      • Jiang Q.
      • Xu N.
      • Shi Y.
      Maternal and Neonatal Complications After Natural vs. Hormone Replacement Therapy Cycle Regimen for Frozen Single Blastocyst Transfer.
      China, 2016–2017Retrospective cohort study513
      Frozen embryo transfer cycles.
      287
      Frozen embryo transfer cycles.
      NC-FET: 28.74 ± 2.89

      AC-FET: 29.08 ± 3.01
      Natural cycle: when the dominant follicle was detected, the investigators decided whether to use HCG for ovulation triggering according to their clinical routine.

      Hormone replacement cycle: the endometrium was prepared with oral oestradiol valerate at a dose of 4–8 mg daily, starting on days 1–3 of the menstrual cycle. Vaginal progesterone gel 90 mg/day and oral dydrogesterone 10 mg twice daily were added when the endometrial thickness reached 7 mm or more.
      BlastocystVitrificationNEHypertensive disorder of pregnancy; preeclampsia; gestational hypertension; large for gestational age; preterm birth; small for gestational age; postpartum haemorrhage; gestational diabetes; placenta previa.9/9
      • Pan Y.
      • Li B.
      • Wang Z.
      • Wang Y.
      • Gong X.
      • Zhou W.
      • Shi Y.
      Hormone Replacement Versus Natural Cycle Protocols of Endometrial Preparation for Frozen Embryo Transfer.
      China, 2015–2017Retrospective cohort study683
      Frozen embryo transfer cycles.
      225
      Frozen embryo transfer cycles.
      NC-FET: 28.49 ± 2.98

      AC-FET: 28.18 ± 3.07
      Natural cycle: when the dominant follicle was detected the investigators decided whether to use HCG for ovulation triggering according to their clinical routine.

      Hormone replacement cycle: oral oestradiol valerate was given daily at a dose of 4–8 mg started on the 1–3 day of the period. When the endometrial thickness reached 7 mm or more, twice-daily oral dydrogesterone (10 mg) and vaginal progesterone gel (90 mg/day) were added.
      Cleavage stageVitrificationNEHypertensive disorder of pregnancy; large for gestational age; macrosomia; preterm birth; post-term birth; low birth weight; small for gestational age; caesarean section; gestational diabetes.9/9
      • Wang B.
      • Zhang J.
      • Zhu Q.
      • Yang X.
      • Wang Y.
      Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons.
      China, 2014–2017Retrospective cohort study1682
      Live births after frozen embryo transfer cycles.
      1682
      Live births after frozen embryo transfer cycles.
      NC-FET: 32.51 ± 4.26

      AC-FET: 32.54 ± 4.25
      Natural cycle: cycles without ovarian stimulation and with physiological oestradiol levels during the follicular phase. HCG was used to trigger ovulation.

      Artificial cycle: oral 17b-oestradiol 2 mg, three times daily was commenced on the second or third day of menstrual cycle. When the endometrial thickness was 8 mm, vaginal progesterone suppositories were initiated.

      Stimulated FET cycles were excluded from the meta-analysis.
      Cleavage stage and blastocystVitrificationNoHypertensive disorder of pregnancy; large for gestational age; macrosomia; preterm birth; low birth weight; very low birth weight; small for gestational age; gestational diabetes; placenta previa.9/9
      • Zong L.
      • Liu P.
      • Zhou L.
      • Wei D.
      • Ding L.
      • Qin Y.
      Increased risk of maternal and neonatal complications in hormone replacement therapy cycles in frozen embryo transfer.
      China, 2015–2018Retrospective cohort study4727
      Live births after frozen embryo transfer cycles.
      1642
      Live births after frozen embryo transfer cycles.
      NC-FET: 30.8 ± 4.0

      AC-FET: 30.5 ± 4.1
      Natural cycles: HCG was administrated when the diameter of dominant follicle reaching 18 mm or more.

      Hormonal replacement cycles: patients were prescribed with 4 mg oral oestradiol valerate from day 2–4 of menstruation for 5–6 days, and then 6 mg for the following 5–6 days. The dose of oestradiol valerate was modulated according to the endometrial thickness and the oestradiol levels. When the endometrial thickness reached at least 7 mm, FET was scheduled in 5 days.

      Cycles with ovulation induction were not included in the meta-analysis.
      BlastocystVitrificationNoHypertensive disorder of pregnancy; large for gestational age; pre-term birth; low birth weight; small for gestational age; gestational diabetes; placenta previa9/9
      a Frozen embryo transfer cycles.
      b Live births after frozen embryo transfer cycles.
      c Clinical pregnancies after frozen embryo transfer cycles.AC-FET, artificial cycle frozen embryo transfer; FET, frozen embryo transfer; GnRH, gonadotrophin releasing hormone; NC-FET, natural cycle frozen embryo transfer; NE, not explained; NOS, Newcastle–Ottawa Scale; PGT-A, preimplantation genetic testing for aneuploidy.
      An electronic search of databases was conducted from 1982 to March 2020. These included PubMed, Scopus and the Cochrane Database. Reference lists of relevant articles were also searched for any additional studies not covered by the literature search. The search combined terms and descriptors related to variants for the interventions, population study and outcomes: IVF with or without intracytoplasmic sperm injection; frozen–thawed embryo transfer; endometrial preparation; natural cycle; hormone replacement cycle; hypertensive disorders in pregnancy; preeclampsia; large for gestational age; macrosomia; preterm birth; post-term birth; low birth weight, very low birth weight, small for gestational age, stillbirth, neonatal mortality, gestational diabetes; caesarean section; placenta previa; placenta accrete; placental abruptio; and postpartum haemorrhage. The search strategy was modified to fit with the syntaxes used in each database consulted.

      Study selection and data extraction

      All the abstracts retrieved from the search in a first screening were assessed by two researchers (JM and MC) independently. The full text of citations that met the inclusion criteria were screened. Both authors judged study eligibility, assessed quality and extracted data, and any discrepancies were resolved by agreement; if required, a consensus was reached with the involvement of a third author (JE). The extracted data were summarized for each outcome (Table 2 and Table 3). The authors referred to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to evaluate the quality of evidence for each outcome (

      Schünemann, Brożek, Guyatt, Oxman. GRADE Handbook. 2018

      ).
      TABLE 2RESULTS OF THE OVERALL PICO QUESTION AND PRIMARY OUTCOMES COMPARING NATURAL CYCLE AND ARTIFICIAL CYCLE FROZEN EMBRYO TRANSFERS
      OutcomeAbsolute effect risk difference per 100 NC-FET versus AC-FET (95% CI)Risk ratio (95% CI)Number of studiesParticipantsQuality of evidence (GRADE)
      Study question: is a NC-FET safer than an AC-FET for perinatal and maternal outcomes in FET cycles?
      Population: FET in patients undergoing IVF/ICSI.

      Intervention: NC-FET.

      Comparator: AC-FET.

      Studies: observational studies.
      Primary outcomes
      Hypertensive disorder in pregnancy3 fewer per 100 (4 fewer to 1 fewer)0.61 (0.50 to 0.73)1050,219⊕⊕○○

      Low
      Preeclampsia4 fewer per 100 (5 fewer to 4 fewer)0.47 (0.42 to 0.53)422,856⊕⊕○○

      Low
      Gestational hypertension1 fewer per 100 (2 fewer to 0 more)0.72 (0.51 to 1.02)38483⊕⊕○○

      Low
      Large for gestational age1 fewer per 100 (2 fewer to 1 fewer)0.93 (0.90 to 0.96)977,629⊕⊕○○

      Low
      Macrosomia1 fewer per 100 (1 fewer to 0 more)0.82 (0.69 to 0.97)972,502⊕⊕○○

      Low
      AC-FET, artificial cycle frozen embryo transfer; FET, frozen embryo transfer; GRADE, Grading of Recommendations Assessment, Development and Evaluation; ICSI, intracytoplasmic sperm injection; NC-FET, natural cycle frozen embryo transfer; PICO, Patients, Intervention, Comparison and Outcomes.
      TABLE 3RESULTS OF THE OVERALL PICO QUESTION AND SECONDARY OUTCOMES COMPARING NATURAL AND ARTIFICIAL CYCLE FROZEN EMBRYO TRANSFERS
      OutcomeAbsolute effect risk difference per 100 NC-FET versus AC-FET (95% CI)Risk ratio (95% CI)Number of studiesParticipantsQuality of evidence (GRADE)
      Study question: is a NC-FET safer than an AC-FET for perinatal and maternal outcomes in FET cycles?
      Population: FET in IVF/ICSI patients.

      Intervention: NC-FET.

      Comparator: AC-FET.

      Studies: observational studies.
      Secondary outcomes
      Pre-term birth1 fewer per 100 (2 fewer to 1 fewer)0.83 (0.79 to 0.88)1178,200⊕⊕○○

      Low
      Post-term birth1 fewer per 100 (1 fewer to 0 more)0.48 (0.29 to 0.80)767,262⊕○○○

      Very low
      Low birth weight1 fewer per 100 (2 fewer to 1 fewer)0.84 (0.80 to 0.89)978,272⊕○○○

      Low
      Very low birth weight0 more per 1000.91 (0.65 to 1.27)429,069⊕⊕○○

      Low
      Small for gestational age0 more per 100 (1 fewer to 0 more)0.94 (0.88 to 1.00)977,629⊕⊕○○

      Low
      Stillbirth0 more per 1000.88 (0.66 to 1.18)765,281⊕○○○

      Very low
      Neonatal mortality0 more per 1000.55 (0.22 to 1.37)311,931⊕○○○

      Very low
      Birth defects1 fewer per 100 (2 fewer to 0 more)0.86 (0.67 to 1.11)39117⊕○○○

      Very low
      Caesarean section8 fewer per 100 (11 fewer to 6 fewer)0.84 (0.77 to 0.91)770,020⊕○○○

      Very low
      Postpartum haemorrhage3 fewer per 100 (4 fewer to 3 fewer)0.39 (0.35 to 0.45)423,343⊕⊕○○

      Low
      Gestational diabetes0 more per 100 (1 fewer to 1 more)1.08 (0.80 to 1.47)956,628⊕○○○

      Very low
      Placental abruption0 more per 10000.61 (0.38 to 0.98)446,986⊕⊕○○

      Low
      Placenta previa0 more per 10000.85 (0.59 to 1.23)757,356⊕⊕○○

      Low
      Placenta accreta0 more per 100 (1 fewer to 0 more)0.18 (0.10 to 0.33)235,755⊕⊕○○

      Low
      AC-FET, artificial cycle frozen embryo transfer; FET, frozen embryo transfer; GRADE, Grading of Recommendations Assessment, Development and Evaluation; ICSI, intracytoplasmic sperm injection; NC-FET, natural cycle frozen embryo transfer; PICO, Patients, Intervention, Comparison and Outcomes.

      Risk of bias assessment

      Study quality was assigned by two reviewers (JM and MC) following the guidelines described in the Newcastle–Ottawa Scale (NOS) for assessing the quality of included studies (
      • Stang A.
      Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta- analyses.
      ). The studies were assessed for bias in the selection process, comparability of cohorts and ascertainment of outcomes. The quality assessment and risk of bias of the included studies are presented in Table 1.

      Outcome measures

      The primary outcome measure was the rate of adverse pregnancy outcomes, including HDP (blood pressure of 140/90 mmHg or above on two or more occasions, at least 6 h apart and more than 20 weeks of gestation); gestational hypertension (hypertension arising de novo after 20 weeks’ gestation in the absence of proteinuria and without biochemical or haematological abnormalities); preeclampsia (the presence of de-novo hypertension after 20 weeks’ gestation accompanied by proteinuria and any of the following: evidence of maternal acute kidney injury; liver dysfunction; neurological features; haemolysis or thrombocytopaenia; fetal growth restriction (
      • Brown M.A.
      • Magee L.A.
      • Kenny L.C.
      • Karumanchi S.A.
      • McCarthy F.P.
      • Saito S.
      • Hall D.R.
      • Warren C.E.
      • Adoyi G.
      • Ishaku S.
      International Society for the Study of Hypertension in Pregnancy (ISSHP)
      Hypertensive Disorders of Pregnancy: ISSHP Classification, Diagnosis, and Management Recommendations for International Practice.
      ;
      ACOG Practice Bulletin No. 202
      Gestational hypertension and preeclampsia.
      ); large for gestational age (LGA) (birth weight above the 90th percentile); and macrosomia (birth weight above 4000 g).
      Secondary outcome measures were PTB (live birth before 37 weeks); post-term birth (a live birth after 42 weeks); low birth weight (LBW) (a birth weight below 2500 g); very low birth weight (a birth weight below 1500 g); small for gestational age (SGA) (birth weight under two SD or below the 10th percentile); stillbirth (the death of a fetus before the complete expulsion or extraction from its mother after 22 completed weeks of gestational age); neonatal mortality (death before 28 days postpartum); gestational diabetes; caesarean section; placenta previa; placenta accrete; placental abruption; and postpartum haemorrhage.
      The definitions used were in line with the definitions prescribed by the International Society for the Study of Hypertension in Pregnancy (
      • Brown M.A.
      • Magee L.A.
      • Kenny L.C.
      • Karumanchi S.A.
      • McCarthy F.P.
      • Saito S.
      • Hall D.R.
      • Warren C.E.
      • Adoyi G.
      • Ishaku S.
      International Society for the Study of Hypertension in Pregnancy (ISSHP)
      Hypertensive Disorders of Pregnancy: ISSHP Classification, Diagnosis, and Management Recommendations for International Practice.
      ), The American College of Obstetricians and Gynecologists (
      ACOG Practice Bulletin No. 202
      Gestational hypertension and preeclampsia.
      ), The International Committee Monitoring Assisted Reproductive Technologies/World Health Organization glossary (
      • Zegers-Hochschild F.
      • Adamson G.D.
      • Dyer S.
      • Racowsky C.
      • de Mouzon J.
      • Sokol R.
      • Rienzi L.
      • Sunde A.
      • Schmidt L.
      • Cooke I.D.
      • Simpson J.L.
      • van der Poel S.
      The International Glossary on Infertility and Fertility Care, 2017.
      ) and according to ICD-10 codes gathered from the maternal hospital discharge data in the different articles included in this study.

      Quantitative analysis

      To ascertain the pooled effect of different variables, a Mantel–Haenszel model and fixed-effects model were used. The risk ratios were calculated for dichotomous data, along with the 95% confidence intervals. The extent of dissimilarity between studies attributable to heterogeneity with the I squared statistic (I2) was assessed. The random-effects model (
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ) was used in cases in which the heterogeneity was greater than 50% (I2 >50%). The Review Manager (RevMan Version 5.3 Software, Copenhagen, Denmark) was used for statistical analysis.

      Results

      The search yielded a total of 1903 records but 1868 were excluded after the titles and abstracts of these manuscripts were screened. Of the remaining 35 studies that were considered eligible by one or both reviewers, 22 were excluded, five of which were reviews and 17 did not report maternal and neonatal outcomes. The remaining 13 studies were included in the present systematic review and meta-analysis (
      • Guan Y.
      • Fan H.
      • Styer A.K.
      • Xiao Z.
      • Li Z.
      • Zhang J.
      • Sun L.
      • Wang X.
      • Zhang Z.
      A modified natural cycle results in higher live birth rate in vitrified-thawed embryo transfer for women with regular menstruation.
      ;
      • Saito K.
      • Miyado K.
      • Yamatoya K.
      • Kuwahara A.
      • Inoue E.
      • Miyado M.
      • Fukami M.
      • Ishikawa T.
      • Saito T.
      • Kubota T.
      • Saito H.
      Increased incidence of post-term delivery and Cesarean section after frozen-thawed embryo transfer during a hormone replacement cycle.
      ;
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • Morisaki N.
      • Miyado M.
      • Miyado K.
      • Fukami M.
      • Miyasaka N.
      • Ishihara O.
      • Irahara M.
      • Saito H.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      ;
      • Alur-Gupta S.
      • Hopeman M.
      • Berger D.S.
      • Gracia C.
      • Barnhart K.T.
      • Coutifaris C.
      • Senapati S.
      Impact of method of endometrial preparation for frozen blastocyst transfer on pregnancy outcome: a retrospective cohort study.
      ;
      • 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.
      ;
      • Jing S.
      • Li X.F.
      • Zhang S.
      • Gong F.
      • Lu G.
      • Lin G.
      Increased pregnancy complications following frozen-thawed embryo transfer during an artificial cycle.
      ;
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • Chiu K.H.
      • Liu J.
      • Lingis M.
      • Stan Williams R.
      • Rhoton-Vlasak A.
      • Nichols W.W.
      • Fleischmann R.R.
      • Zhang W.
      • Winn V.D.
      • Segal M.S.
      • Conrad K.P.
      • Baker V.L.
      Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the Absence of a Corpus Luteum.
      ;
      • Lin J.
      • Zhao J.
      • Hao G.
      • Tan J.
      • Pan Y.
      • Wang Z.
      • Jiang Q.
      • Xu N.
      • Shi Y.
      Maternal and Neonatal Complications After Natural vs. Hormone Replacement Therapy Cycle Regimen for Frozen Single Blastocyst Transfer.
      ;
      • Makhijani R.
      • Bartels C.
      • Godiwala P.
      • Bartolucci A.
      • Nulsen J.
      • Grow D.
      • Benadiva C.
      • Engmann L.
      Maternal and perinatal outcomes in programmed versus natural vitrified-thawed blastocyst transfer cycles.
      ;
      • Pan Y.
      • Li B.
      • Wang Z.
      • Wang Y.
      • Gong X.
      • Zhou W.
      • Shi Y.
      Hormone Replacement Versus Natural Cycle Protocols of Endometrial Preparation for Frozen Embryo Transfer.
      ;
      • Wang Z.
      • Liu H.
      • Song H.
      • Li X.
      • Jiang J.
      • Sheng Y.
      • Shi Y.
      Increased Risk of Pre-eclampsia After Frozen-Thawed Embryo Transfer in Programming Cycles.
      ;
      • Wang B.
      • Zhang J.
      • Zhu Q.
      • Yang X.
      • Wang Y.
      Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons.
      ;
      • Zong L.
      • Liu P.
      • Zhou L.
      • Wei D.
      • Ding L.
      • Qin Y.
      Increased risk of maternal and neonatal complications in hormone replacement therapy cycles in frozen embryo transfer.
      ). The study selection process is presented in Figure 1.
      Figure 1
      Figure 1Preferred Outcome Items for Systematic Reviews and Meta-analysis flow diagram detailing selection of studies for inclusion.
      Thirteen studies investigating perinatal and maternal outcomes in pregnancies after NC-FET compared with AC-FET met the inclusion criteria. Details of the included studies are presented in Table 1. All the studies had NOS scores above 7, which is considered to be of high quality.

      Primary outcomes

      Hypertensive disorders in pregnancy

      Ten studies reported HDP, including 26,661 patients in the NC-FET group and 23,558 patients in the AC-FET group. The overall relative risk for HDP was 0.61 (95% CI 0.50 to 0.73; I2 = 65%) (Figure 2a), favouring the NC-FET group. The quality of evidence was low according to GRADE. A sub-analysis considering preeclampsia or gestational hypertension separately was conducted.
      Figure 2
      Figure 2Forest-plots comparing primary outcomes after natural cycle (NC) frozen embryo transfer and artificial cycle (AC) frozen embryo transfer. (A) Hypertensive disorders in pregnancy; (B) preeclampsia; and (C) gestational hypertension. AC-FET, artificial cycle frozen embryo transfer; NC-FET, natural cycle frozen embryo transfer.
      Women who gave birth after NC-FET were at a decreased risk of preeclampsia compared with those after AC-FET (four studies, 22,856 patients, RR 0.47, 95% CI 0.42 to 0.53, I2 = 4%; low quality of evidence) (Figure 2b). No differences were found between the NC-FET and AC-FET groups in risk of gestational hypertension (three studies, 8383 patients, RR 0.72, 95% CI 0.51 to 1.02, I2 = 0%; low quality of evidence) (Figure 2c).

      Large for gestational age

      Nine studies (n = 77,629 patients) related to the complication of LGA. A lower risk of LGA (RR = 0.93, 95% CI 0.90 to 0.96, I2 = 0%) was found in pregnancies after NC-FET cycles than after AC-FET (low quality of evidence) (Figure 3a).
      Figure 3
      Figure 3Forest-plots comparing primary outcomes after natural cycle (NC) frozen embryo transfer and artificial cycle (AC) frozen embryo transfer. (A) Large for gestational age; and (B) macrosomia. AC-FET, artificial cycle frozen embryo transfer; NC-FET, natural cycle frozen embryo transfer.

      Macrosomia

      Nine studies (n = 72,502 patients) provided the outcome of macrosomia. A lower risk of macrosomia was found in pregnancies after NC-FET cycles than after AC-FET cycles (RR = 0.82, 95% CI 0.69 to 0.97, I2 = 72%; low quality of evidence) (Figure 3b).
      The results for the primary outcomes are presented in Table 2.

      Secondary outcomes

      Preterm birth

      Eleven studies were involved in the meta-analysis (n = 78,200 patients). Analysis showed that the overall risk of PTB was significantly lower among pregnancies resulting from the NC-FET cycles (RR = 0.83, 95% CI 0.79 to 0.88, I2 = 41%; low quality of evidence) (Supplementary Figure 1A).

      Post-term birth

      Seven studies (n = 67,262 patients) reported results comparing the post-term rates for each group. The overall relative risk for post-term birth was 0.48 (95% CI 0.29 to 0.80, I2 = 81%; very low quality of evidence) (Supplementary Figure 1B) favouring the NC-FET group.

      Low birth weight

      Nine studies reported the prevalence of LBW (n = 78,272 patients). The risk of LBW was lower after NC-FET compared with AC-FET (RR = 0.84, 95% CI 0.80 to 0.89, I2 = 22%; low quality of evidence) (Supplementary Figure 1C).

      Very low birth weight

      Four studies (n = 29,069 patients) were analysed. The overall risk of very low birth weight was not significantly different among pregnancies resulting from the NC-FET and AC-FET cycles (RR = 0.91, 95% CI 0.65 to 1.27, I2 = 28%; low quality of evidence) (Supplementary Figure 1D).

      Small for gestational age

      Nine studies (n = 77,629 patients) reported SGA data. The overall risk of SGA observed after NC-FET compared with AC-FET was not significantly different (RR = 0.94, 95% CI 0.88 to 1.00, I2 = 0%; low quality of evidence) (Supplementary Figure 2A).

      Stillbirth

      Seven studies (n = 65,311 patients) were used in this analysis. The overall risk of stillbirth was not significantly different among the pregnancies resulting from the NC-FET and AC-FET cycles (RR = 0.88, 95% CI 0.66 to 1.18, I2 = 15%; very low quality of evidence) (Supplementary Figure 2B).

      Neonatal mortality

      Three studies (n = 11,931 patients) were analysed. Overall, no difference in the risk of neonatal mortality was found among pregnancies resulting from NC-FET and AC-FET cycles (RR = 0.55, 95% CI 0.22 to 1.37, I2 = 0%; very low quality of evidence) (Supplementary Figure 2C).

      Birth defects

      Three studies (n = 9117 patients) reported birth defects data. The risk of birth defects was not significantly different in pregnancies resulting from the NC-FET than from AC-FET (RR 0.86, 95% CI 0.67 to 1.11, I2 = 0%; very low quality of evidence) (Supplementary Figure 2D).

      Caesarean section

      Seven studies (n = 70,020 patients) were pooled in this analysis. A significantly lower risk in caesarean section was observed after NC-FET group compared with the AC-FET group (RR = 0.84, 95% CI 0.77 to 0.91, I2 = 95%; very low quality of evidence) (Supplementary Figure 3A) but heterogeneity was substantial.

      Postpartum haemorrhage

      Four studies (n = 23,343 patients) were involved in the meta-analysis. A significantly lower risk of postpartum haemorrhage was observed in the NC-FET group compared with the AC-FET group (RR = 0.39, 95% CI 0.35 to 0.45, I2 =30%; low quality of evidence) (Supplementary Figure 3B).

      Gestational diabetes

      Nine studies (n = 65,628 patients) were analysed. The overall risk of gestational diabetes was not significantly different among pregnancies resulting from the NC-FET and AC-FET cycles (RR = 1.08, 95% CI 0.80 to 1.47). Marked heterogeneity was observed among the studies (I2 = 90%; very low quality of evidence) (Supplementary Figure 3C).

      Placental abruption

      Four studies (n = 46,986 patients) were involved in the meta-analysis. Analysis showed that the overall risk of placental abruption was significantly lower among pregnancies resulting from the NC-FET cycles (RR = 0.61, 95% CI 0.38 to 0.98; I2 = 0%; low quality of evidence) (Supplementary Figure 3D).

      Placenta previa

      Seven studies, including 57,356 patients, evaluated rates of placenta previa. No difference was found in the placenta previa rates between NC-FET and AC-FET cycles (RR = 0.85, 95% CI 0.59 to 1.23, I2 = 69%; low quality of evidence) (Supplementary Figure 3E).

      Placenta accreta

      Two studies (n = 35,755 patients) were pooled in this meta-analysis. Overall, the risk of placenta accreta was significantly lower in the NC-FET cycles compared with the AC-FET cycles (RR = 0.18, 95% CI 0.10 to 0.33, I2 = 0%; low quality of evidence) (Supplementary Figure 3). The results for the secondary outcomes are presented in Table 3.

      Sensitivity analysis

      Sensitivity analyses were conducted for the primary outcomes to examine the influence of variation among studies on the overall risk estimates. The pooled effect size was not significant (Supplementary Figure 4 to Supplementary 6 and Supplementary Table).

      Discussion

      This systematic review and meta-analysis show a decrease in the risk of HDP, preeclampsia, LGA and macrosomia with the use of NC-FET in preference to AC-FET in the overall population undergoing FET. Low-quality evidence also shows that the use of NC-FET does not lead to any differences in the chances of gestational hypertension.
      The GRADE quality of evidence was low mainly because this is a review based on observational studies and because of the substantial inter-study heterogeneity obtained, which was assumed to be caused by the variation between study populations.

      Strengths

      The large sample size is a major strength of this study; the selected articles included two population-based national registries from Sweden and Japan. This large sample allowed the investigation of relatively infrequent events, i.e. minor obstetrical complications.
      Studies that used suitable research designs that matched for potential confounders, i.e. multiple births and maternal age, were considered. Furthermore, the meta-analysis indicates acceptable values through low I2 values and narrow confidence levels for primary outcomes, i.e. preeclampsia, gestational hypertension and LGA, and secondary outcomes, i.e. PTB, LBW, postpartum haemorrhage, placental abruption and placenta accreta. This implies that the precision of the meta-analysis is of good quality and that the estimated value is comparatively stable for these variables. The present systematic review and meta-analysis was carried out in accordance with the PRISMA statement. This ensured that the methodological quality was high. Moreover, the quality of evidence was rated according to GRADE. The validity of our results is notably improved owing to these factors.

      Limitations

      All published articles in this review comprised observational studies. A limitation of registry-based studies is the inherent lack of data. Hence, we were unable to adjust for potential confounding variables, i.e. parity, smoking status, alcohol intake, socioeconomic status, duration of infertility, women's ovulatory status, body mass index, embryo quality, previous caesarean section, the freezing protocol, the embryo stage of development for transfer and preimplantation genetic testing. The reason for the use of AC-FET deserves attention because it may be associated with a higher risk of perinatal complications, possibly distorting the outcomes of the analyses. In this study, this point could not be analysed. In addition, unpublished data as full-text articles and in languages other than English were excluded from the meta-analysis.

      Comparison of the meta-analysis with individual studies

      The present meta-analysis included a population-based registry study in Sweden, which reported on all IVF singleton deliveries from autologous oocytes from 2005 to 2015 grouped into FET in programmed, stimulated or natural cycles and fresh embryo transfers (
      • 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.
      ). In the study by
      • 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.
      , AC-FET cycles were associated with a higher risk of hypertensive disorders in pregnancy compared with NC-FET (adjusted OR, 1.78, 95% CI 1.43 to 2.21) and postpartum haemorrhage (adjusted OR, 2.63; 95% CI 2.20 to 3.13). These results are also in accordance with a recent study suggesting an increased rate of preeclampsia in programmed FET cycles in which no corpus luteum is present (
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • Chiu K.H.
      • Liu J.
      • Lingis M.
      • Stan Williams R.
      • Rhoton-Vlasak A.
      • Nichols W.W.
      • Fleischmann R.R.
      • Zhang W.
      • Winn V.D.
      • Segal M.S.
      • Conrad K.P.
      • Baker V.L.
      Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the Absence of a Corpus Luteum.
      ). In the same study, no differences were observed in the risk of gestational hypertension comparing programmed FET, natural FET, fresh embryo transfer cycles and natural conception.
      A retrospective cohort study of patients who conceived after AC-FET and those who conceived after NC-FET was conducted in 2014 based on the Japanese assisted reproductive technology (ART) registry and is included in the present meta-analysis. Multiple logistic regression analyses were carried out to investigate potential confounding factors. They reported that pregnancies achieved after AC-FET had increased odds of HDP (adjusted OR 1.43, 95% CI 1.14 to 1.80) and placenta accreta (adjusted OR 6.91, 95% CI 2.87 to 16.66) compared with pregnancies after NC-FET (
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • Morisaki N.
      • Miyado M.
      • Miyado K.
      • Fukami M.
      • Miyasaka N.
      • Ishihara O.
      • Irahara M.
      • Saito H.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      ).
      In assessing the risk of LGA, six of the studies included in the meta-analysis showed no statistical difference between the NC-FET and AC-FET groups (
      • Saito K.
      • Miyado K.
      • Yamatoya K.
      • Kuwahara A.
      • Inoue E.
      • Miyado M.
      • Fukami M.
      • Ishikawa T.
      • Saito T.
      • Kubota T.
      • Saito H.
      Increased incidence of post-term delivery and Cesarean section after frozen-thawed embryo transfer during a hormone replacement cycle.
      ;
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • Morisaki N.
      • Miyado M.
      • Miyado K.
      • Fukami M.
      • Miyasaka N.
      • Ishihara O.
      • Irahara M.
      • Saito H.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      ;
      • Jing S.
      • Li X.F.
      • Zhang S.
      • Gong F.
      • Lu G.
      • Lin G.
      Increased pregnancy complications following frozen-thawed embryo transfer during an artificial cycle.
      ;
      • Lin J.
      • Zhao J.
      • Hao G.
      • Tan J.
      • Pan Y.
      • Wang Z.
      • Jiang Q.
      • Xu N.
      • Shi Y.
      Maternal and Neonatal Complications After Natural vs. Hormone Replacement Therapy Cycle Regimen for Frozen Single Blastocyst Transfer.
      ;
      • Pan Y.
      • Li B.
      • Wang Z.
      • Wang Y.
      • Gong X.
      • Zhou W.
      • Shi Y.
      Hormone Replacement Versus Natural Cycle Protocols of Endometrial Preparation for Frozen Embryo Transfer.
      ;
      • Wang Z.
      • Liu H.
      • Song H.
      • Li X.
      • Jiang J.
      • Sheng Y.
      • Shi Y.
      Increased Risk of Pre-eclampsia After Frozen-Thawed Embryo Transfer in Programming Cycles.
      ), whereas three studies showed a significantly lower risk in NC-FET cycles (
      • 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.
      ;
      • Wang B.
      • Zhang J.
      • Zhu Q.
      • Yang X.
      • Wang Y.
      Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons.
      ;
      • Zong L.
      • Liu P.
      • Zhou L.
      • Wei D.
      • Ding L.
      • Qin Y.
      Increased risk of maternal and neonatal complications in hormone replacement therapy cycles in frozen embryo transfer.
      ). In the meta-analysis of all nine studies, the risk of LGA was significantly lower in NC-FET cycles.
      Two of the nine studies included in the meta-analysis found a significantly higher risk of macrosomia in the AC-FET group (
      • 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.
      ;
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • Morisaki N.
      • Miyado M.
      • Miyado K.
      • Fukami M.
      • Miyasaka N.
      • Ishihara O.
      • Irahara M.
      • Saito H.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      ).
      • 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.
      reported that a higher risk of macrosomia was seen after programmed FET with an adjusted OR of 1.62 (CI 95% 1.26 to 2.09). These findings are in accordance with the result of this meta-analysis, but heterogeneity was substantial.
      The results of the meta-analysis are consistent with the results of some of the individual studies on the risk of caesarean section (
      • Saito K.
      • Miyado K.
      • Yamatoya K.
      • Kuwahara A.
      • Inoue E.
      • Miyado M.
      • Fukami M.
      • Ishikawa T.
      • Saito T.
      • Kubota T.
      • Saito H.
      Increased incidence of post-term delivery and Cesarean section after frozen-thawed embryo transfer during a hormone replacement cycle.
      ;
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • Morisaki N.
      • Miyado M.
      • Miyado K.
      • Fukami M.
      • Miyasaka N.
      • Ishihara O.
      • Irahara M.
      • Saito H.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      ;
      • 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.
      ;
      • Makhijani R.
      • Bartels C.
      • Godiwala P.
      • Bartolucci A.
      • Nulsen J.
      • Grow D.
      • Benadiva C.
      • Engmann L.
      Maternal and perinatal outcomes in programmed versus natural vitrified-thawed blastocyst transfer cycles.
      ;
      • Pan Y.
      • Li B.
      • Wang Z.
      • Wang Y.
      • Gong X.
      • Zhou W.
      • Shi Y.
      Hormone Replacement Versus Natural Cycle Protocols of Endometrial Preparation for Frozen Embryo Transfer.
      ;
      • Wang Z.
      • Liu H.
      • Song H.
      • Li X.
      • Jiang J.
      • Sheng Y.
      • Shi Y.
      Increased Risk of Pre-eclampsia After Frozen-Thawed Embryo Transfer in Programming Cycles.
      ), preterm birth (
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • Morisaki N.
      • Miyado M.
      • Miyado K.
      • Fukami M.
      • Miyasaka N.
      • Ishihara O.
      • Irahara M.
      • Saito H.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      ;
      • Wang Z.
      • Liu H.
      • Song H.
      • Li X.
      • Jiang J.
      • Sheng Y.
      • Shi Y.
      Increased Risk of Pre-eclampsia After Frozen-Thawed Embryo Transfer in Programming Cycles.
      ;
      • Wang B.
      • Zhang J.
      • Zhu Q.
      • Yang X.
      • Wang Y.
      Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons.
      ;
      • Zong L.
      • Liu P.
      • Zhou L.
      • Wei D.
      • Ding L.
      • Qin Y.
      Increased risk of maternal and neonatal complications in hormone replacement therapy cycles in frozen embryo transfer.
      ), post-term birth (
      • Saito K.
      • Miyado K.
      • Yamatoya K.
      • Kuwahara A.
      • Inoue E.
      • Miyado M.
      • Fukami M.
      • Ishikawa T.
      • Saito T.
      • Kubota T.
      • Saito H.
      Increased incidence of post-term delivery and Cesarean section after frozen-thawed embryo transfer during a hormone replacement cycle.
      ;
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • Morisaki N.
      • Miyado M.
      • Miyado K.
      • Fukami M.
      • Miyasaka N.
      • Ishihara O.
      • Irahara M.
      • Saito H.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      ;
      • 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.
      ), LBW (
      • Saito K.
      • Miyado K.
      • Yamatoya K.
      • Kuwahara A.
      • Inoue E.
      • Miyado M.
      • Fukami M.
      • Ishikawa T.
      • Saito T.
      • Kubota T.
      • Saito H.
      Increased incidence of post-term delivery and Cesarean section after frozen-thawed embryo transfer during a hormone replacement cycle.
      ;
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • Morisaki N.
      • Miyado M.
      • Miyado K.
      • Fukami M.
      • Miyasaka N.
      • Ishihara O.
      • Irahara M.
      • Saito H.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      ;
      • Zong L.
      • Liu P.
      • Zhou L.
      • Wei D.
      • Ding L.
      • Qin Y.
      Increased risk of maternal and neonatal complications in hormone replacement therapy cycles in frozen embryo transfer.
      ), postpartum haemorrhage (
      • 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.
      ;
      • Wang Z.
      • Liu H.
      • Song H.
      • Li X.
      • Jiang J.
      • Sheng Y.
      • Shi Y.
      Increased Risk of Pre-eclampsia After Frozen-Thawed Embryo Transfer in Programming Cycles.
      ) and placenta accreta (
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • Morisaki N.
      • Miyado M.
      • Miyado K.
      • Fukami M.
      • Miyasaka N.
      • Ishihara O.
      • Irahara M.
      • Saito H.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      ) among pregnancies after FET.
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • Morisaki N.
      • Miyado M.
      • Miyado K.
      • Fukami M.
      • Miyasaka N.
      • Ishihara O.
      • Irahara M.
      • Saito H.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      found an elevated risk of gestational diabetes in patients undergoing AC-FET; however, a significant difference was not found in the meta-analysis. A possible cause for this could be that the meta-analysis included different recent studies that expanded the number of cases. These results must be assessed cautiously, however, bearing in mind the possible variations in how this condition has been defined by the different studies (
      • Guan Y.
      • Fan H.
      • Styer A.K.
      • Xiao Z.
      • Li Z.
      • Zhang J.
      • Sun L.
      • Wang X.
      • Zhang Z.
      A modified natural cycle results in higher live birth rate in vitrified-thawed embryo transfer for women with regular menstruation.
      ;
      • Jing S.
      • Li X.F.
      • Zhang S.
      • Gong F.
      • Lu G.
      • Lin G.
      Increased pregnancy complications following frozen-thawed embryo transfer during an artificial cycle.
      ;
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • Morisaki N.
      • Miyado M.
      • Miyado K.
      • Fukami M.
      • Miyasaka N.
      • Ishihara O.
      • Irahara M.
      • Saito H.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      ;
      • Lin J.
      • Zhao J.
      • Hao G.
      • Tan J.
      • Pan Y.
      • Wang Z.
      • Jiang Q.
      • Xu N.
      • Shi Y.
      Maternal and Neonatal Complications After Natural vs. Hormone Replacement Therapy Cycle Regimen for Frozen Single Blastocyst Transfer.
      ;
      • Makhijani R.
      • Bartels C.
      • Godiwala P.
      • Bartolucci A.
      • Nulsen J.
      • Grow D.
      • Benadiva C.
      • Engmann L.
      Maternal and perinatal outcomes in programmed versus natural vitrified-thawed blastocyst transfer cycles.
      ;
      • Pan Y.
      • Li B.
      • Wang Z.
      • Wang Y.
      • Gong X.
      • Zhou W.
      • Shi Y.
      Hormone Replacement Versus Natural Cycle Protocols of Endometrial Preparation for Frozen Embryo Transfer.
      ;
      • Wang Z.
      • Liu H.
      • Song H.
      • Li X.
      • Jiang J.
      • Sheng Y.
      • Shi Y.
      Increased Risk of Pre-eclampsia After Frozen-Thawed Embryo Transfer in Programming Cycles.
      ;
      • Wang B.
      • Zhang J.
      • Zhu Q.
      • Yang X.
      • Wang Y.
      Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons.
      ;
      • Zong L.
      • Liu P.
      • Zhou L.
      • Wei D.
      • Ding L.
      • Qin Y.
      Increased risk of maternal and neonatal complications in hormone replacement therapy cycles in frozen embryo transfer.
      ).

      Interpretation of results

      Hypertensive disorders in pregnancy, preeclampsia and placental disease

      The results indicate a possible link between endometrial preparation and adverse perinatal and maternal outcomes, mainly placenta-related diseases. The success of pregnancy is dependent on proper implantation and placentation. If any problem arises during this process, the production of vasculogenic and angiogenic factors could be affected, leading to changes that are linked with the appearance of major placental syndromes (
      • Morgan TK.
      Role of the Placenta in Preterm Birth: A Review.
      ;
      • Thilaganathan B.
      Placental syndromes: getting to the heart of the matter.
      ). The term ‘placental insufficiency’ refers to the atypical movement of uteroplacental nutrients, which can cause damage to the placenta as well as known pregnancy complications, such as intrauterine fetal growth restriction and preeclampsia. The severity of placental disease could influence the common underlying cause for many cases of preeclampsia and PTB (
      • Morgan TK.
      Role of the Placenta in Preterm Birth: A Review.
      ;
      • Dude A.M.
      • Yeh J.S.
      • Muasher S.J.
      Donor oocytes are associated with preterm birth when compared to fresh autologous in vitro fertilization cycles in singleton pregnancies.
      ).
      The adverse perinatal and maternal outcomes associated with cryopreservation might be caused by supraphysiological steroid hormones levels during early trophoblast invasion, which lead to an anomalous placental development (
      • Lyall F.
      • Robson S.C.
      • Bulmer J.N.
      Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome.
      ;
      • Hiura H.
      • Hattori H.
      • Kobayashi N.
      • Okae H.
      • Chiba H.
      • Miyauchi N.
      • et al.
      Genome-wide microRNA expression profiling in placentae from frozen-thawed blastocyst transfer.
      ;
      • Choux C.
      • Ginod P.
      • Barberet J.
      • Rousseau T.
      • Bruno C.
      • Sagot P.
      • Astruc K.
      • Fauque P.
      Placental volume and other first-trimester outcomes: are there differences between fresh embryo transfer, frozen-thawed embryo transfer and natural conception?.
      ). The AC-FET cycle may be less ‘physiological’ than a NC-FET cycle owing to the preparation of the endometrium with hormonal replacement requiring medication (
      • Groenewoud E.R.
      • Cantineau A.E.
      • Kollen B.J.
      • Macklon N.S.
      • Cohlen B.J.
      What is the optimal means of preparing the endometrium in frozen-thawed embryo transfer cycles? A systematic review and meta-analysis.
      ). In the physiologic implantation process, progestin is important in the decidualization of oestradiol-primed human endometrial stromal cells, assisting with the extravillous trophoblast (EVT) invasion and vascular remodelling (
      • Schatz F.
      • Guzeloglu-Kayisli O.
      • Arlier S.
      • Kayisli U.A.
      • Lockwood C.J.
      The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding.
      ). Uterine spiral arteries and arterioles are converted to low resistance, high-capacity vessels that deliver increased blood flow required by the developing fetal–placental unit. A shallow EVT invasion and impaired spiral artery remodelling are linked to preeclampsia, placental abruption, stillbirth, fetal growth restriction and many cases of spontaneous PTB (
      • Chen J.Z.
      • Sheehan P.M.
      • Brennecke S.P.
      • Keogh R.J.
      Vessel remodeling, pregnancy hormones and extravillous trophoblast function.
      ;
      • Schatz F.
      • Guzeloglu-Kayisli O.
      • Arlier S.
      • Kayisli U.A.
      • Lockwood C.J.
      The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding.
      ;
      • Labarrere C.A.
      • DiCarlo H.L.
      • Bammerlin E.
      • Hardin J.W.
      • Kim Y.M.
      • Chaemsaithong P.
      • Haas D.M.
      • Kassab G.S.
      • Romero R.
      Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta.
      ).
      Sex steroids are critical modulators of a wide range of maternal and placental processes during pregnancy, which regulate the uteroplacental vasculature (
      • Maliqueo M.
      • Echiburu B.
      • Crisosto N.
      Sex steroids modulate uterine-placental vasculature: implications for obstetrics and neonatal outcomes.
      ). Exogenous hormonal supplementation leads to an increased oestrogenic and progestogenic milieu during implantation and early pregnancy. Even after discontinuing hormone supplementation and ovarian hormone production declines, oestradiol and progesterone levels remain persistently elevated in women with pregnancies conceived by IVF compared with those who conceived naturally, at a time when the placenta becomes the source of hormone production (
      • Lee B.
      • Buttle R.
      • Castellano K.
      • Gonzalez T.L.
      • Sun T.
      • Sundheimer L.W.
      • Wang E.T.
      • Williams J.
      • Pisarska M.D.
      Maternal 17-β-estradiol and progesterone remain elevated into the late first trimester in pregnancies conceived with in-vitro fertilization (IVF) despite discontinuation of supplemental therapy.
      ). Metabolomic studies suggest that the supraphysiologic hormonal state during hormone supplementation may cause reprogramming of the trophoblast after implantation, leading to a dysfunctional hormone production from syncytiotrophoblasts (
      • Sun T.
      • Lee B.
      • Kinchen J.
      • Wang E.T.
      • Gonzalez T.L.
      • Chan J.L.
      • Rotter J.I.
      • Chen Y.I.
      • Taylor K.
      • Goodarzi M.O.
      • Rich S.S.
      • Farber C.R.
      • Williams 3rd, J.
      • Pisarska M.D.
      Differences in First-Trimester Maternal Metabolomic Profiles in Pregnancies Conceived From Fertility Treatments.
      ). Previous studies in animals have assessed the effect of elevated oestradiol levels in the first trimester, reporting decreased extravillous trophoblast invasion of the uterine spiral arteries (
      • Albrecht E.D.
      • Bonagura T.W.
      • Burleigh D.W.
      • Enders A.C.
      • Aberdeen G.W.
      • Pepe G.J.
      Suppression of extravillous trophoblast invasion of uterine spiral arteries by estrogen during early baboon pregnancy.
      ). Recent studies have suggested that the impairment in placentation can occur via oestradiol-induced differential expression of the GATA3 transcription factor (
      • Lee B.
      • Kroener L.L.
      • Xu N.
      • Wang E.T.
      • Banks A.
      • Williams III, J.
      • Goodarzi M.O.
      • Chen Y.I.
      • Tang J.
      • Wang Y.
      • Gangalapudi V.
      • Pisarska M.D.
      Function and hormonal regulation of GATA3 in human first trimester placentation.
      ) and the Grb10 gene (
      • Mainigi M.A.
      • Sapienza C.
      • Butts S.
      • Coutifaris C.
      A molecular perspective on procedures and outcomes with assisted reproductive technologies.
      ). Elevated progesterone, like elevated oestradiol, also affects placentation, which, in conjunction with oestrogen, induces first-trimester trophoblast tubulogenesis through the lysophosphatidic acid pathway (
      • Beltrame J.S.
      • Sordelli M.S.
      • Ca–numil V.A.
      • Alonso C.A.I.
      • Perez Martinez S.
      • Ribeiro M.L.
      Steroid hormones induce in vitro human first trimester trophoblast tubulogenesis by the lysophosphatidic acid pathway.
      ). As the elevation in steroids leads to dysfunction in trophoblast cells, these increased hormonal states may be contributors to adverse obstetric and perinatal outcomes, including low birth weight, fetal growth restriction, preeclampsia and abnormal placentation (
      • Lee B.
      • Kroener L.L.
      • Xu N.
      • Wang E.T.
      • Banks A.
      • Williams III, J.
      • Goodarzi M.O.
      • Chen Y.I.
      • Tang J.
      • Wang Y.
      • Gangalapudi V.
      • Pisarska M.D.
      Function and hormonal regulation of GATA3 in human first trimester placentation.
      ;
      • Mainigi M.A.
      • Sapienza C.
      • Butts S.
      • Coutifaris C.
      A molecular perspective on procedures and outcomes with assisted reproductive technologies.
      ;
      • Beltrame J.S.
      • Sordelli M.S.
      • Ca–numil V.A.
      • Alonso C.A.I.
      • Perez Martinez S.
      • Ribeiro M.L.
      Steroid hormones induce in vitro human first trimester trophoblast tubulogenesis by the lysophosphatidic acid pathway.
      ). Further studies are necessary to determine the exact mechanisms leading to these outcomes.
      On the other hand, corpus luteum has become the focus of new research related to this topic. A link exists between the absence of a corpus luteum owing to the pituitary–ovarian axis suppression by oestradiol replacement in the context of a programmed cycle and the absence of products of the corpus luteum that are not administered, such as relaxin. This hormone has a significant role for maternal cardiovascular adaptation to pregnancy (
      • Conrad K.P.
      • Baker V.L.
      Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies.
      ;
      • Conrad K.P.
      • Lingis M.
      • Sautina L.
      • Li S.
      • Chi Y.Y.
      • Qiu Y.
      • Li M.
      • Williams R.S.
      • Rhoton-Vlasak A.
      • Segal M.S.
      Maternal endothelial function, circulating endothelial cells, and endothelial progenitor cells in pregnancies conceived with or without in vitro fertilization.
      ). Deficient circulatory adaptations during the first trimester in women conceiving after AC-FET (with the absence of the corpus luteum), is also linked to adverse pregnancy outcomes, including preeclampsia (
      • Conrad K.P.
      • Baker V.L.
      Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies.
      ;
      • Conrad K.P.
      • Petersen J.W.
      • Chi Y.Y.
      • Zhai X.
      • Li M.
      • Chiu K.H.
      • Liu J.
      • Lingis M.D.
      • Williams R.S.
      • Rhoton-Vlasak A.
      • Larocca J.J.
      • Nichols W.W.
      • Segal M.S.
      Maternal Cardiovascular Dysregulation During Early Pregnancy After In Vitro Fertilization Cycles in the Absence of a Corpus Luteum.
      ;
      • Conrad K.P.
      • Graham G.M.
      • Chi Y.Y.
      • Zhai X.
      • Li M.
      • Williams R.S.
      • Rhoton-Vlasak A.
      • Segal M.S.
      • Wood C.E.
      • Keller-Wood M.
      Potential influence of the corpus luteum on circulating reproductive and volume regulatory hormones, angiogenic and immunoregulatory factors in pregnant women.
      ;
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • Chiu K.H.
      • Liu J.
      • Lingis M.
      • Stan Williams R.
      • Rhoton-Vlasak A.
      • Nichols W.W.
      • Fleischmann R.R.
      • Zhang W.
      • Winn V.D.
      • Segal M.S.
      • Conrad K.P.
      • Baker V.L.
      Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the Absence of a Corpus Luteum.
      ;
      • von Versen-Höynck F.
      • Narasimhan P.
      • Selamet Tierney E.S.
      • Martinez N.
      • Conrad K.P.
      • Baker V.L.
      • Winn V.D.
      Absent or Excessive Corpus Luteum Number Is Associated With Altered Maternal Vascular Health in Early Pregnancy.
      ). Frozen embryo transfer with a natural cycle does not have hormonal substitution and enables the more physiological development of a corpus luteum. The results of a randomized trial in which 75% of the FETs were carried out in a natural, ovulatory cycle indicated no increased risk of preeclampsia compared with those with fresh embryo transfer (
      • Shi Y.
      • Sun Y.
      • Hao C.
      • Zhang H.
      • Wei D.
      • Zhang Y.
      • Zhu Y.
      • Deng X.
      • Qi X.
      • Li H.
      • Ma X.
      • Ren H.
      • Wang Y.
      • Zhang D.
      • Wang B.
      • Liu F.
      • Wu Q.
      • Wang Z.
      • Bai H.
      • Li Y.
      • Zhou Y.
      • Sun M.
      • Liu H.
      • Li J.
      • Zhang L.
      • Chen X.
      • Zhang S.
      • Sun X.
      • Legro R.S.
      • Chen Z.J.
      Transfer of fresh versus Frozen embryos in ovulatory women.
      ). Results from another study found a link between programmed FET cycles and higher rates of preeclampsia (12.8% versus 3.9%; P = 0.02) and preeclampsia with severe features (9.6% versus 0.8%; P = 0.002) compared with modified natural FET cycles (
      • Conrad K.P.
      • Baker V.L.
      Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies.
      ).

      Birthweight

      The causes of increased risk of high birth weight, LGA and macrosomia after FET are still unknown. Epigenetic disturbances during the early embryonic stages as a result of the freezing– thawing and vitrification–warming procedures might affect the developmental programming of fetal and placental tissues in FET offspring (
      • Pinborg A.
      • Loft A.
      • Romundstad L.B.
      • Wennerholm U.B.
      • Söderström-Anttila V.
      • Bergh C.
      • Aittomäki K.
      Epigenetics and assisted reproductive technologies.
      ). Asynchrony might occur between the embryo and the endometrium in FET cycles, influencing fetal growth and development resulting in increased birth weight (
      • Pinborg A.
      • Loft A.
      • Romundstad L.B.
      • Wennerholm U.B.
      • Söderström-Anttila V.
      • Bergh C.
      • Aittomäki K.
      Epigenetics and assisted reproductive technologies.
      ;
      • Berntsen S.
      • Pinborg A.
      Large for gestational age and macrosomia in singletons born after frozen/thawed embryo transfer (FET) in assisted reproductive technology (ART).
      ). Two studies found that placentas after FET were larger than after fresh embryo transfer (
      • Rizzo G.
      • Aiello E.
      • Pietrolucci M.E.
      • Arduini D.
      Are There Differences in Placental Volume and Uterine Artery Doppler in Pregnancies Resulting From the Transfer of Fresh Versus Frozen-Thawed Embryos Through In Vitro Fertilization.
      ;
      • Choux C.
      • Ginod P.
      • Barberet J.
      • Rousseau T.
      • Bruno C.
      • Sagot P.
      • Astruc K.
      • Fauque P.
      Placental volume and other first-trimester outcomes: are there differences between fresh embryo transfer, frozen-thawed embryo transfer and natural conception?.
      ). Increased placental size has been suggested to be associated with fetal hyperglycaemia and indirectly to fetal overgrowth (
      • Acosta O.
      • Ramirez V.I.
      • Lager S.
      • Gaccioli F.
      • Dudley D.J.
      • Powell T.L.
      • Jansson T.
      Increased glucose and placental GLUT-1 in large infants of obese nondiabetic mothers.
      ), and could explain the increased risk of LGA and macrosomia in FET offspring. In addition, a higher birth weight could be the result of epigenetic changes after IVF with altered methylation of genes involved in the metabolism of insulin growth factor 1 and 2 (
      • Miles H.L.
      • Hofman P.L.
      • Peek J.
      • Harris M.
      • Wilson D.
      • Robinson E.M.
      • Gluckman P.D.
      • Cutfield W.S.
      In vitro fertilization improves childhood growth and metabolism.
      ).
      In the NC-FET group, the intrauterine environment may be more favourable to embryo growth because it is not affected by hormonal replacement compared with AC-FET. As mentioned above, higher levels of sex steroids could negatively affect the peri-implantation uterine environment. One study reported an association between excessive fetal growth and preeclampsia, especially late-onset (
      • Rasmussen S.
      • Irgens L.M.
      Fetal growth and body proportion in preeclampsia.
      ). Both adverse outcomes may all be related to alterations in the implantation and early fetal developmental stages and need to be explored further.

      Secondary outcomes

      The overall caesarean section rate observed in this review was 48%, with rates of the included studies ranging from 27.7 to 75.1% (
      • 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.
      ;
      • Pan Y.
      • Li B.
      • Wang Z.
      • Wang Y.
      • Gong X.
      • Zhou W.
      • Shi Y.
      Hormone Replacement Versus Natural Cycle Protocols of Endometrial Preparation for Frozen Embryo Transfer.
      ). Such a high caesarean section rate, however, is associated with other risks, mainly maternal risks such as postpartum haemorrhage. Endometrial preparation using AC-FET itself or pregnancy complications may be responsible for the higher rate of caesarean section in AC-FET patients compared with NC-FET. In addition, sociocultural differences between the population of the different studies included in the meta-analysis could influence the caesarean section rates, i.e. Asian versus European population. As adverse maternal outcomes, such as HDP, are a significant risk factor for caesarean section, adjusting for confounding factors, including the incidence of hypertension, is required in future studies to clarify whether the higher incidence of caesarean section may be caused by the AC-FET itself.
      In this review, we also observed a lower risk of placenta accreta in the NC-FET group.
      • Kaser D.J.
      • Melamed A.
      • Bormann C.L.
      • Myers D.E.
      • Missmer S.A.
      • Walsh B.W.
      • Racowsky C.
      • Carusi D.A.
      Cryopreserved embryo transfer is an independent risk factor for placenta accrete.
      reported that FET constitutes an independent risk factor for placenta accreta, after controlling for patient age, before caesarean section, placenta previa and uterine factor infertility. This risk may be directly related to factors associated with cryopreservation, including the freeze–thawing process itself and the mode of uterine preparation. During the AC-FET, abnormal oestradiol levels may modulate the degree of trophoblastic invasion and extent of vascular remodelling at the time of implantation, resulting in a later exuberant trophoblastic growth (
      • Kaser D.J.
      • Melamed A.
      • Bormann C.L.
      • Myers D.E.
      • Missmer S.A.
      • Walsh B.W.
      • Racowsky C.
      • Carusi D.A.
      Cryopreserved embryo transfer is an independent risk factor for placenta accrete.
      ). In this review, we found no differences in the risk of placenta previa between NC-FET and AC-FET groups; therefore, the increased incidence of placenta accreta in the AC-FET population does not seem to have been influenced by this factor.

      Clinical considerations

      It is critically important to evaluate the safety of an intervention when balancing benefits against harm. Therefore, maternal and perinatal outcomes should be considered when making treatment decisions; however, these are rarely reported. In the FET population, we should consider maternal and perinatal risks when the endometrial preparation method is decided, as patients who undergo NC-FET are at decreased risks for obstetric complications, as we found in this study.
      The results of the present study encourage the use of NC-FET cycles, whereas AC-FET cycles ought to be used only when ovulation fails. The high rates of HDP show similarities with oocyte donation pregnancies, a known high-risk population for these and other maternal adverse outcomes in ART (
      • Giannakou K.
      • Evangelou E.
      • Papatheodorou S.I.
      Genetic and non-genetic risk factors for pre-eclampsia: umbrella review of systematic reviews and meta-analyses of observational studies.
      ;
      • Moreno-Sepulveda J.
      • Checa M.A.
      Risk of adverse perinatal outcomes after oocyte donation: a systematic review and meta-analysis.
      ).
      From the data obtained in our meta-analysis, practitioners can increase the safety of their interventions by identifying those patients who potentially require additional care. Patients undergoing AC-FET will benefit from single embryo transfer, avoiding the risks of multiple pregnancies. Also, their obstetricians should implement adequate monitoring strategies during prenatal, labour and postnatal care.

      Future research

      A large, multisite randomized controlled trial comparing pregnancy outcomes between NC-FET and AC-FET would be the optimal method to validate our findings. Further research should, if confirming these results, clarify the role of corpus luteum and its compounds on perturbed maternal cardiovascular function and placentation to replace these in patients undergoing FET cycles in which NC-FET is not possible to carry out, such as non-ovulatory women. In addition, we must be aware of epigenetic reprogramming in very early development and its relation to ART. Follow-up studies on children born after ART should be carried out throughout their life to monitor the development of adult diseases. Future meta-analyses should involve uncommon neonatal and childhood outcomes to provide more reliable data on the effect of cryopreservation.
      In conclusion, pregnancies after NC-FET have a more favourable outcome compared with AC-FET, with lower rates of HDP, preeclampsia, LGA and macrosomia. The development of gestational hypertension in FET cycles seems not to be influenced by the mode of endometrial preparation. This is valuable information, as the number of FET cycles has increased, including the ‘freeze-all’ strategy. Future studies are required to clarify the underlying biologic mechanisms of our findings, and further randomized controlled trials are needed to improve the quality of evidence.

      Appendix. Supplementary materials

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      Biography

      José Moreno-Sepúlveda obtained his medical degree from Valparaiso School of Medicine, 2009, and his PhD from the Department of Obstetrics and Gynecology, Universitat Autonoma de Barcelona, 2019. Currently, his main research project is on safety in assisted reproductive techniques, focusing on maternal and perinatal outcomes after IVF.
      Key message
      The risk of adverse perinatal outcomes, including hypertensive disorders of pregnancy, preeclampsia, large-for-gestational-age infants and macrosomia is significantly lower for frozen–thawed embryo transfers (FET) carried out in natural cycles compared with artificial cycles. Clinicians should carefully monitor pregnancies achieved by FET in artificial cycles prenatally, during labour and postnatally.