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Potential role of the corpus luteum in maternal cardiovascular adaptation to pregnancy and preeclampsia risk

Open AccessPublished:August 23, 2021DOI:https://doi.org/10.1016/j.ajog.2021.08.018
      Studies in the gravid rat model revealed a key role for the corpus luteal hormone, relaxin, in the maternal circulatory changes of early pregnancy epitomized by profound systemic vasodilation and increased arterial compliance. To determine whether the corpus luteum may play a similar role in human pregnancy, women who conceived by in vitro fertilization were studied. Implementation of artificial (programmed) cycles for embryo transfers, which precluded the formation of a corpus luteum, was associated with notable attenuation of the gestational rise in cardiac output and fall in carotid-femoral pulse wave velocity (reflecting impairment of arterial dilation and increased compliance, respectively) and deficiencies in other cardiovascular changes normally observed during the first trimester. Cardiac output and carotid-femoral pulse wave velocity were restored after the first trimester of pregnancy, consistent with rescue by placental vasodilators, such as placental growth factor. In addition, a potential role of corpus luteal factors in reducing the risk of developing preeclampsia was hypothesized. In most single and multiple center, prospective and retrospective cohort (and registry) studies, the risk of developing preeclampsia and preeclampsia with severe features was increased specifically in women undergoing autologous frozen embryo transfer in artificial cycles without the formation of a corpus luteum relative to natural, modified natural, stimulated, or controlled ovarian stimulation cycles and spontaneous pregnancies—all associated with the formation of at least 1 corpus luteum. Taken together, these observational studies are sufficiently compelling to warrant randomized clinical trials comparing preeclampsia risk in autologous frozen embryo transfer in natural vs artificial cycles. Impaired endometrial function because of suboptimal hormonal administration is an alternative but not mutually exclusive explanation for increased preeclampsia risk in autologous frozen embryo transfer in artificial cycles. Potential mechanisms by which the corpus luteum may reduce the risk of developing preeclampsia and whether autologous frozen embryo transfer in artificial cycles is associated with increased risk of preterm preeclampsia, term preeclampsia, or both are discussed. Last, suggestions for future investigations are noted.

      Key words

      Introduction

      Preeclampsia (PE) is a major cause of maternal, fetal, and neonatal morbidities and mortality, affecting 4.6% (95% confidence interval [CI], 2.7–8.2) of all pregnancies worldwide.
      • Burton G.J.
      • Redman C.W.
      • Roberts J.M.
      • Moffett A.
      Pre-eclampsia: pathophysiology and clinical implications.
      • Abalos E.
      • Cuesta C.
      • Grosso A.L.
      • Chou D.
      • Say L.
      Global and regional estimates of preeclampsia and eclampsia: a systematic review.
      • Kuklina E.V.
      • Ayala C.
      • Callaghan W.M.
      Hypertensive disorders and severe obstetric morbidity in the United States.
      PE is diagnosed by new-onset hypertension after 20 weeks’ gestation associated with ≥1 of the following features: proteinuria, thrombocytopenia, pulmonary edema, renal or hepatic insufficiency, cerebral or visual symptoms, or intrauterine growth restriction.
      Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy.
      In developed countries, PE not infrequently necessitates iatrogenic premature delivery that gives rise to neonatal morbidity immediately after delivery and associated long-term morbidity. In the developing world, timely access to healthcare may be lacking, resulting in maternal and fetal-neonatal deaths.
      • Ghulmiyyah L.
      • Sibai B.
      Maternal mortality from preeclampsia/eclampsia.
      ,
      • Backes C.H.
      • Markham K.
      • Moorehead P.
      • Cordero L.
      • Nankervis C.A.
      • Giannone P.J.
      Maternal preeclampsia and neonatal outcomes.
      Of additional concern, mothers and their children who survive PE are at increased risk of developing adverse cardiovascular events later in life.
      • Anderson C.M.
      Preeclampsia: exposing future cardiovascular risk in mothers and their children.
      • Bellamy L.
      • Casas J.P.
      • Hingorani A.D.
      • Williams D.J.
      Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.
      • Davis E.F.
      • Lazdam M.
      • Lewandowski A.J.
      • et al.
      Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review.
      • Vikse B.E.
      • Irgens L.M.
      • Leivestad T.
      • Skjaerven R.
      • Iversen B.M.
      Preeclampsia and the risk of end-stage renal disease.
      • Williams D.
      Long-term complications of preeclampsia.
      • Rich-Edwards J.W.
      • Ness R.B.
      • Roberts J.M.
      Epidemiology of Pregnancy-Related Hypertension (Chapter 3)..
      • Rich-Edwards J.W.
      • Fraser A.
      • Lawlor D.A.
      • Catov J.M.
      Pregnancy characteristics and women’s future cardiovascular health: an underused opportunity to improve women’s health?.
      • Gluckman P.D.
      • Hanson M.A.
      • Cooper C.
      • Thornburg K.L.
      Effect of in utero and early-life conditions on adult health and disease.
      • Roberts J.M.
      • Pearson G.
      • Cutler J.
      • Lindheimer M.
      NHLBI Working Group on Research on Hypertension During Pregnancy
      Summary of the NHLBI working group on research on hypertension during pregnancy.
      • Sibai B.
      • Dekker G.
      • Kupferminc M.
      Pre-eclampsia.
      Whether preexisting cardiometabolic risk factors are solely responsible for these remote adverse maternal cardiovascular events or PE per se is detrimental to maternal organs like the vascular endothelium, or both of these factors contribute remains unclear.
      • Rich-Edwards J.W.
      • Fraser A.
      • Lawlor D.A.
      • Catov J.M.
      Pregnancy characteristics and women’s future cardiovascular health: an underused opportunity to improve women’s health?.
      Delivery of low birthweight or growth-restricted neonates, another frequent neonatal consequence of severe disease,
      • Eskenazi B.
      • Fenster L.
      • Sidney S.
      • Elkin E.P.
      Fetal growth retardation in infants of multiparous and nulliparous women with preeclampsia.
      is independently correlated with an increased occurrence of cardiovascular disease in mothers and their children later in life.
      • Rich-Edwards J.W.
      • Fraser A.
      • Lawlor D.A.
      • Catov J.M.
      Pregnancy characteristics and women’s future cardiovascular health: an underused opportunity to improve women’s health?.
      ,
      • Barker D.J.
      • Bull A.R.
      • Osmond C.
      • Simmonds S.J.
      Fetal and placental size and risk of hypertension in adult life.
      ,
      • Barker D.J.
      • Winter P.D.
      • Osmond C.
      • Margetts B.
      • Simmonds S.J.
      Weight in infancy and death from ischaemic heart disease.
      Currently, treatments for PE that counteract specific pathogenic mechanisms are lacking. Furthermore, interventions are employed to manage disease manifestations, such as high blood pressure, and to prevent seizures with delivery being curative in most cases. Although prophylactic strategies are generally lacking, low-dose aspirin exerts some protective effect in women at increased risk of developing PE.
      • Henderson J.T.
      • O’Connor E.
      • Whitlock E.P.
      Low-dose aspirin for prevention of morbidity and mortality from preeclampsia.
      ,
      • Rolnik D.L.
      • Wright D.
      • Poon L.C.
      • et al.
      Aspirin versus Placebo in Pregnancies at high risk for preterm preeclampsia.
      One reason for the general lack of effective prophylactic measures is that the origins of PE are incompletely understood.
      The concept that the corpus luteum (CL) may play a role in the genesis of PE initially arose by inference from investigations that identified the CL hormone, relaxin (RLN), as a key player in the maternal vasodilatory changes of early to middle term pregnancy in the gravid rat model. Based on this finding, the first question was whether RLN or other CL secretory factors could play a similar role in the maternal circulatory changes that transpire during the first trimester of human pregnancy.
      • Novak J.
      • Danielson L.A.
      • Kerchner L.J.
      • et al.
      Relaxin is essential for renal vasodilation during pregnancy in conscious rats.
      • Debrah D.O.
      • Novak J.
      • Matthews J.E.
      • Ramirez R.J.
      • Shroff S.G.
      • Conrad K.P.
      Relaxin is essential for systemic vasodilation and increased global arterial compliance during early pregnancy in conscious rats.
      • Conrad K.P.
      • Baker V.L.
      Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies.
      • Danielson L.A.
      • Sherwood O.D.
      • Conrad K.P.
      Relaxin is a potent renal vasodilator in conscious rats.
      This inquiry was presaged by the work of several work, including the meticulous studies of Chapman et al
      • Chapman A.B.
      • Zamudio S.
      • Woodmansee W.
      • et al.
      Systemic and renal hemodynamic changes in the luteal phase of the menstrual cycle mimic early pregnancy.
      and Bernstein et al,
      • Bernstein I.M.
      • Ziegler W.F.
      • Leavitt T.
      • Badger G.J.
      Uterine artery hemodynamic adaptations through the menstrual cycle into early pregnancy.
      which showed that maternal hemodynamic changes of human pregnancy were anticipated, although to a lesser extent, in the luteal phase (also see citations in 
      • Conrad K.P.
      • Stillman I.E.
      • Lindheimer M.D.
      The Kidney in Normal Pregnancy and Preeclampsia (Chapter 16)..
      ). As maternal vasodilation, which starts during early pregnancy or even before conception, underlies the gestational changes in systemic and renal hemodynamics,
      • Chapman A.B.
      • Zamudio S.
      • Woodmansee W.
      • et al.
      Systemic and renal hemodynamic changes in the luteal phase of the menstrual cycle mimic early pregnancy.
      ,
      • Petersen J.W.
      • Liu J.
      • Chi Y.Y.
      • et al.
      Comparison of multiple non-invasive methods of measuring cardiac output during pregnancy reveals marked heterogeneity in the magnitude of cardiac output change between women.
      a second question was whether CL secretory products, such as RLN, could reduce the risk of developing PE.
      • Conrad K.P.
      • Baker V.L.
      Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies.
      To investigate whether the CL contributes to maternal circulatory changes during early pregnancy in women and decreases the risk of developing PE, several logistical hurdles needed to be overcome. First, a critical role for RLN in the maternal hemodynamic changes of pregnancy in the rat model was revealed by administering RLN-neutralizing antibodies or by resecting the ovaries, the source of circulating RLN.
      • Novak J.
      • Danielson L.A.
      • Kerchner L.J.
      • et al.
      Relaxin is essential for renal vasodilation during pregnancy in conscious rats.
      ,
      • Debrah D.O.
      • Novak J.
      • Matthews J.E.
      • Ramirez R.J.
      • Shroff S.G.
      • Conrad K.P.
      Relaxin is essential for systemic vasodilation and increased global arterial compliance during early pregnancy in conscious rats.
      Obviously, these maneuvers could not be implemented in women. Second, rats do not develop PE spontaneously like women. Thus, to address the 2 fundamental questions, women planning to conceive by in vitro fertilization (IVF) were studied.
      • Conrad K.P.
      • Baker V.L.
      Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies.
      Conceptions can be achieved in a fresh IVF cycle in which an embryo transfer (ET) is performed several days after superovulation with fertility medications and oocyte retrieval with the formation of as many as 5 to 25 CL or in a frozen embryo transfer (FET) cycle. For endometrial preparation in a FET cycle, the following protocols are commonly used:
      • 1.
        Natural cycle (FET-NC): spontaneous ovulation and formation of 1 CL occur with the production of the hormones necessary to develop the endometrium (similar to a conception conceived without the use of fertility treatment).
      • 2.
        Programmed or artificial cycle (FET-AC): hypothalamic-pituitary suppression precludes the formation of a CL and the production of hormones, and the endometrium is developed with the administration of exogenous estradiol and progesterone.
      • 3.
        Stimulated cycle (FET-SC): fertility medications are used to induce ovulation with the formation of one or more CL, and the hormones needed to develop the endometrium are produced.
      The NC requires that a woman be ovulatory, the AC can be used for either ovulatory or anovulatory women, and the SC can be used for women who are either ovulatory on their own or anovulatory but not for women with ovarian failure. In the past, it was common for women to first have a fresh ET cycle and then undergo FET if the former failed or if they wished to have another child after a successful fresh ET. Recently, clinical practice has changed for multiple reasons such that it is very common that all embryos are frozen (ie, no fresh ET) and the primary first ET is an FET.
      Although there are practical considerations about whether to use the FET-AC or FET-NC protocol in clinical practice, Ghobara et al
      • Ghobara T.
      • Gelbaya T.A.
      • Ayeleke R.O.
      Cycle regimens for frozen-thawed embryo transfer.
      concluded that neither FET protocol is superior to the other concerning clinical efficacy, suggesting that the expected pregnancy rate would not factor into the protocol choice. The biggest advantage of FET-AC is that it allows for more control over the scheduling of FET monitoring and date of thaw for the ET procedure itself. Therefore, FET-AC is often preferred by patients with scheduling challenges and by clinic staff and embryologists.
      To ascertain the potential contribution of the CL to maternal cardiovascular changes in early human pregnancy and the development of PE (if any), the gestational changes of the maternal circulation and PE risk according to CL status were prospectively evaluated in women conceiving by IVF or spontaneously (as a control group). An overarching hypothesis was formulated to be tested in women who conceived with or without IVF: CL factors, such as RLN, mediate or contribute to the maternal circulatory changes of early pregnancy (analogous to the pregnant rat) with waning influence after the CL-placental shift, when placental vasodilatory hormones, such as placental growth factor (PGF), supersede (Figure 1). According to this hypothesis, women who conceived using an IVF regimen that precluded CL development would manifest a “hypodynamic” circulation in early gestation, because circulating RLN and/or other CL vasodilators are missing, but would recover after the CL-placental shift. In contrast, women using an IVF regimen that led to the formation of multiple CL would have a “hyperdynamic” circulation arising from excessively elevated circulating RLN or other CL factors
      • Conrad K.P.
      • Baker V.L.
      Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies.
      (Figure 2). However, an important limitation to this overall investigative approach was that a specific role for RLN vs another CL product could not be established.
      Figure thumbnail gr1
      Figure 1The concept of the corpus luteal-placental shift applied to maternal blood flow during pregnancy
      Maternal blood flow, eg, cardiac output and renal blood flow among other organ circulations. The vertical dotted line demarcates the end of the first trimester of pregnancy. Modified from Conrad et al.
      • Conrad K.P.
      • Baker V.L.
      Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies.
      Conrad. Evidence for corpus luteal antecedents of preeclampsia. Am J Obstet Gynecol 2021.
      Figure thumbnail gr2
      Figure 2Plasma relaxin concentrations in women who conceived with or without IVF
      Plasma relaxin concentrations for each study participant are shown before, during and after pregnancy. In the left panel (Without CL), all plasma relaxin concentrations were below the level of assay sensitivity (<8.0 pg/ml). Without CL: women who conceived by IVF using FET-AC protocols with hypothalamic-pituitary suppression. One CL: women who conceived spontaneously. Multiple CL: women who conceived by IVF using fresh ET protocols with controlled ovarian stimulation. PP, on average 49.8±1.8 weeks postpartum (mean±SEM). After the luteal-placental shift, RLN continues to circulate, but the plasma concentration falls by approximately 50% relative to first-trimester levels. Moreover, RLN still emanates from the CL after the luteal-placental shift, because women without a CL do not have detectable plasma RLN at any time during pregnancy. Although the placenta expresses RLN, it is evidentially not secreted into the maternal circulation. The CL involutes on ultrasound after the luteal-placental shift but remains active, insofar as it continues to produce RLN, although in lesser amounts. We use the term “corpus luteal-placental” shift by analogy to progesterone production but in the context of potential vasodilators of CL and placental origin like RLN and PGF, respectively ().
      • Conrad K.P.
      • Graham G.M.
      • Chi Y.Y.
      • et al.
      Potential influence of the corpus luteum on circulating reproductive and volume regulatory hormones, angiogenic and immunoregulatory factors in pregnant women.
      AC, artificial cycles; BP, before pregnancy in the follicular phase; CL, corpus luteum; ET, embryo transfer; FET, frozen embryo transfer; IVF, in vitro fertilization; PGF, placental growth factor; PP, postpartum; RLN, relaxin.
      Conrad. Evidence for corpus luteal antecedents of preeclampsia. Am J Obstet Gynecol 2021.
      In general, although IVF was known to increase the risk of PE, the underlying mechanisms remained elusive. Thus, another overarching hypothesis was that PE risk would be elevated in IVF at least partly based on the absence of a CL or presence of multiple CL and the corresponding perturbations of the maternal circulation in early pregnancy. In short, both absent and prodigious circulating levels of RLN or other CL products were predicted to adversely impact pregnancy outcomes, in particular PE risk.
      • Conrad K.P.
      • Baker V.L.
      Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies.
      However, as detailed subsequently in the article, although the first part of the hypothesis was supported, the second part was not.

      Hypertensive Disorders of Pregnancy Including Preeclampsia are Associated with Autologous Frozen Embryo Transfer Cycles

      It has long been recognized that IVF is associated with elevated rates of hypertensive disorders of pregnancy and PE. However, with the notable exception of donor oocytes, whether the increased risk was associated with a specific IVF protocol had not been investigated.
      • Conrad K.P.
      • Baker V.L.
      Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies.
      ,
      • Jackson R.A.
      • Gibson K.A.
      • Wu Y.W.
      • Croughan M.S.
      Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis.
      • Helmerhorst F.M.
      • Perquin D.A.
      • Donker D.
      • Keirse M.J.
      Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies.
      • Maman E.
      • Lunenfeld E.
      • Levy A.
      • Vardi H.
      • Potashnik G.
      Obstetric outcome of singleton pregnancies conceived by in vitro fertilization and ovulation induction compared with those conceived spontaneously.
      • Pinborg A.
      • Wennerholm U.B.
      • Romundstad L.B.
      • et al.
      Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis.
      • Salha O.
      • Sharma V.
      • Dada T.
      • et al.
      The influence of donated gametes on the incidence of hypertensive disorders of pregnancy.
      More recently, investigators evaluated PE risk in women who conceived using fresh ET or FET with autologous oocytes. FET was found to be associated with the majority of increased risk for PE
      • Sites C.K.
      • Wilson D.
      • Barsky M.
      • et al.
      Embryo cryopreservation and preeclampsia risk.
      • Barsky M.
      • St Marie P.
      • Rahil T.
      • Markenson G.R.
      • Sites C.K.
      Are perinatal outcomes affected by blastocyst vitrification and warming?.
      • Chen Z.J.
      • Shi Y.
      • Sun Y.
      • et al.
      Fresh versus Frozen Embryos for Infertility in the polycystic ovary syndrome.
      • Sazonova A.
      • Källen K.
      • Thurin-Kjellberg A.
      • Wennerholm U.B.
      • Bergh C.
      Obstetric outcome in singletons after in vitro fertilization with cryopreserved/thawed embryos.
      • Wei D.
      • Liu J.Y.
      • Sun Y.
      • et al.
      Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled 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.
      • 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.
      and hypertensive disorders of pregnancy (HDP).
      • 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.
      • Ishihara O.
      • Araki R.
      • Kuwahara A.
      • Itakura A.
      • Saito H.
      • Adamson G.D.
      Impact of frozen-thawed single-blastocyst transfer on maternal and neonatal outcome: an analysis of 277,042 single-embryo transfer cycles from 2008 to 2010 in Japan.
      • Lin J.
      • Zhao J.
      • Hao G.
      • et al.
      Maternal and neonatal complications after natural vs. hormone replacement therapy cycle regimen for frozen single blastocyst transfer.
      • Opdahl S.
      • Henningsen A.A.
      • Tiitinen A.
      • et al.
      Risk of hypertensive disorders in pregnancies following assisted reproductive technology: a cohort study from the CoNARTaS group.
      • Maheshwari A.
      • Pandey S.
      • Amalraj Raja E.
      • Shetty A.
      • Hamilton M.
      • Bhattacharya S.
      Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer?.
      • Sha T.
      • Yin X.
      • Cheng W.
      • Massey I.Y.
      Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis.
      • Yang M.
      • Lin L.
      • Sha C.
      • et al.
      Which is better for mothers and babies: fresh or frozen-thawed blastocyst transfer?.
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • et al.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      This association was initially thought to be because of the cryopreservation procedures that are specific to FET.
      • Sites C.K.
      • Wilson D.
      • Barsky M.
      • et al.
      Embryo cryopreservation and preeclampsia risk.
      ,
      • Barsky M.
      • St Marie P.
      • Rahil T.
      • Markenson G.R.
      • Sites C.K.
      Are perinatal outcomes affected by blastocyst vitrification and warming?.
      However, CL status is another important difference between fresh ET and FET cycles, which could conceivably play a pivotal role.
      • Conrad K.P.
      • Baker V.L.
      Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies.
      Investigations are listed in Table 1, Table 2, Table 3 to 3 that reported the specific FET protocols employed and the diagnosis of PE, HDP, or pregnancy-induced hypertension (PIH), respectively. Sazonova et al
      • Sazonova A.
      • Källen K.
      • Thurin-Kjellberg A.
      • Wennerholm U.B.
      • Bergh C.
      Obstetric outcome in singletons after in vitro fertilization with cryopreserved/thawed embryos.
      was listed in Table 1 to include another spontaneous conception cohort for comparison. When evaluated in the context of specific IVF protocol and corresponding number of CL, that is, 0, 1, or >1 CL, the increased risk of PE and HDP among women with singleton births was mainly associated with autologous FET-AC protocols, in which a CL did not develop, and consequently, circulating CL products, such as RLN, were absent. This general observation was reinforced by forest plots depicted in Figures 3 and 4, in which the overall odds ratios for developing PE or HDP were 2.23 (95% CI, 1.99–2.50; n=7 studies) and 2.11 (95% CI, 1.90–2.36; n=8 studies), respectively, for FET-AC vs FET-NC and FET-SC combined. Because cryopreservation was a common denominator, an absent CL associated with FET-AC was implicated in the etiology of the higher rates of PE and HDP. However, 1 caveat was that the raw data without adjustment for potential confounders were used to generate the forest plots in Figures 3 and 4.
      Table 1PE risk in singleton or singleton and/or multiple births according to in vitro fertilization protocol
      PublicationFET-AC

      Cohort number

      %PE
      FET-NC

      Cohort number

      %PE
      FET-SC

      Cohort number

      %PE
      Fresh ET

      Cohort number

      %PE
      SpC

      Cohort number

      %PE
      PE risk (95% CI): FET-AC vs FET-NCPE risk (95% CI): FET-AC vs FET-SCPE risk (95% CI):FET-AC vs fresh ET
      Singleton births
      Sazonova et al,
      • Sazonova A.
      • Källen K.
      • Thurin-Kjellberg A.
      • Wennerholm U.B.
      • Bergh C.
      Obstetric outcome in singletons after in vitro fertilization with cryopreserved/thawed embryos.
      2012

      Multicenter retrospective cohort study (Sweden)
      n=262

      4.3%
      n=571,914

      2.8%
      Barsky et al,
      • Barsky M.
      • St Marie P.
      • Rahil T.
      • Markenson G.R.
      • Sites C.K.
      Are perinatal outcomes affected by blastocyst vitrification and warming?.
      2016

      Single-center retrospective cohort study (United States)
      n=109

      7.6%
      n=289

      2.6%
      AOR, 3.10 (1.20–8.40)
      Sites et al,
      • Sites C.K.
      • Wilson D.
      • Barsky M.
      • et al.
      Embryo cryopreservation and preeclampsia risk.
      2017

      Multicenter retrospective cohort (registry) study (United States)
      n=1052
      Most FET-AC; Sites, 2019, personal communication


      7.5%
      n=7453

      4.3%
      AOR, 2.17 (1.67–2.82)
      sPE

      3.0%
      sPE

      1.4%

      P=.0002
      Preterm PE

      2.8%
      Preterm PE

      1.5%
      AOR, 2.19 (1.43–3.35)
      von Versen-Höynck et al,
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      2019

      Single-center prospective cohort study (United States)
      n=94

      12.8%
      n=127

      3.9%
      n=146

      4.7%
      n=143

      4.9%
      AOR, 3.55 (1.20–11.94)
      sPE

      9.6%
      sPE

      0.8%
      sPE

      2.7%
      sPE

      2.1%
      sPE AOR, 15.05 (2.59–286.27)
      Ginström Ernstad et al,
      • 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.
      2019

      Retrospective cohort (registry) study (Sweden)
      n=1446

      8.2%
      n=6297

      4.4%
      n=1983

      4.3%
      n=24,365

      3.7%
      n=1,127,566

      2.8%
      Wang et al,
      • Wang Z.
      • Liu H.
      • Song H.
      • et al.
      Increased risk of pre-eclampsia after frozen-thawed embryo transfer in programming cycles.
      2020

      Single-center retrospective cohort study (China)
      n=4162

      8.6%
      n=10,211

      3.8%
      AOR, 2.55 (2.06–3.16)
      Roelens et al,

      Roelens C, Racca A, Mackens S, et al. Hum Reprod 36th Annual Meeting of the European Society for Human Reproduction and Embryology; 2020: 108–109.

      2020

      Single-center retrospective cohort study (Belgium)
      n=190

      8.9%
      n=317

      3.7%
      AOR, 2.9 (1.4–6.0)
      Asserhøj et al,
      • Asserhøj L.L.
      • Spangmose A.L.
      • Aaris Henningsen A.K.
      • Clausen T.D.
      • Ziebe S.
      • Jensen R.B.
      • et al.
      Adverse obstetric and perinatal outcomes in 1,136 singleton pregnancies conceived after programmed frozen embryo transfer (FET) compared with natural cycle FET.
      2021

      Retrospective cohort (registry) study (Denmark)
      n=357

      9.2%
      n=779

      4.0%
      AOR, 2.40 (1.43–4.02)
      Zaat et al,
      • Zaat T.R.
      • Brink A.J.
      • de Bruin J.P.
      • et al.
      Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers?.
      2021 Multicenter RCT follow-up (The Netherlands)
      n=37

      8.1%
      n=45

      2.2%
      RR (Ref=AC), 0.27 (0.03–2.53)
      Zhang et al,
      • Zhang J.
      • Wei M.
      • Bian X.
      • et al.
      Letrozole-induced frozen embryo transfer cycles are associated with a lower risk of hypertensive disorders of pregnancy among women with polycystic ovary syndrome.
      2021

      Single-center retrospective cohort study (China)
      n=832
      All patients with the diagnosis of polycystic ovary syndrome


      4.9%
      n=891
      All patients with the diagnosis of polycystic ovary syndrome


      2.9%
      AOR (Ref=AC), 0.58 (0.35–0.97)
      No. studies, n

      Mean±SEM
      Excluding sPE and preterm PE
      %
      n=9

      8.4±0.7
      n=6

      3.7±0.3
      n=2

      4.3, 2.9
      n=4

      3.8±0.5
      n=3

      3.5±0.7
      Singleton and/or multiple births
      Chen et al,
      • Chen Z.J.
      • Shi Y.
      • Sun Y.
      • et al.
      Fresh versus Frozen Embryos for Infertility in the polycystic ovary syndrome.
      2016

      Multicenter RCT (China)
      n=434
      All patients with the diagnosis of polycystic ovary syndrome
      ,
      The denominator represents the number of clinical pregnancies; no severe PE was observed in this study.


      4.4%
      n=427
      All patients with the diagnosis of polycystic ovary syndrome
      ,
      The denominator represents the number of clinical pregnancies; no severe PE was observed in this study.


      1.4%
      RR, 3.12 (1.26–7.73)
      Sites et al,
      • Sites C.K.
      • Wilson D.
      • Barsky M.
      • et al.
      Embryo cryopreservation and preeclampsia risk.
      2017

      Multicenter retrospective cohort study (United States)
      n=542
      Most FET-AC; Sites, 2019, personal communication


      19.6%
      n=5196

      16.4%

      P=.06
      sPE

      9.3%
      sPE

      5.7%

      P=.0009
      Preterm PE

      14.8%
      Preterm PE

      11.7%

      P=.04
      Zhang et al,
      • Zhang J.
      • Wei M.
      • Bian X.
      • et al.
      Letrozole-induced frozen embryo transfer cycles are associated with a lower risk of hypertensive disorders of pregnancy among women with polycystic ovary syndrome.
      2021

      Single-center retrospective cohort study (China)
      n=336
      All patients with the diagnosis of polycystic ovary syndrome


      9.2%
      n=368
      All patients with the diagnosis of polycystic ovary syndrome


      4.9%
      AOR (Ref=AC), 0.46 (0.24–0.86)
      Lin et al,
      • Lin J.
      • Zhao J.
      • Hao G.
      • et al.
      Maternal and neonatal complications after natural vs. hormone replacement therapy cycle regimen for frozen single blastocyst transfer.
      2020

      Multicenter retrospective cohort study (China)
      n=169

      3.6%
      n=350

      2.6%
      AOR, 0.75 (0.24–2.30)
      No. studies, n

      Mean±SEM
      Excluding sPE and preterm PE
      %
      n=4

      9.2±3.7
      n=1

      2.6
      n=1

      4.9
      n=2

      1.4, 16.4
      The use of autologous oocytes only, was stipulated in all studies except for Ginström Ernstad et al,
      • 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.
      and Wang et al.
      • Wang Z.
      • Liu H.
      • Song H.
      • et al.
      Increased risk of pre-eclampsia after frozen-thawed embryo transfer in programming cycles.
      Sazonova et al
      • Sazonova A.
      • Källen K.
      • Thurin-Kjellberg A.
      • Wennerholm U.B.
      • Bergh C.
      Obstetric outcome in singletons after in vitro fertilization with cryopreserved/thawed embryos.
      was listed to include another spontaneous conception cohort for comparison. Cohort number indicates number of births except where indicated.
      AC, artificial cycles; AOR, adjusted odds ratio; FET, frozen embryo transfer; NC, natural or modified natural cycles; PE, preeclampsia; RCT, randomized controlled trial; RR, relative risk; SC, stimulated cycles; SpC, spontaneous conception; sPE, PE with severe features.
      Conrad. Evidence for corpus luteal antecedents of preeclampsia. Am J Obstet Gynecol 2021.
      a Most FET-AC; Sites, 2019, personal communication
      b All patients with the diagnosis of polycystic ovary syndrome
      c Excluding sPE and preterm PE
      d The denominator represents the number of clinical pregnancies; no severe PE was observed in this study.
      Table 2Risk of hypertensive disorders of pregnancy for singleton or singleton and/or multiple births according to in vitro fertilization protocol
      PublicationFET-AC

      Cohort number

      %HDP
      FET-NC

      Cohort number

      %HDP
      FET-SC

      Cohort number

      %HDP
      Fresh ET

      Cohort number

      %HDP
      SpC

      Cohort number

      %HDP
      HDP risk (95% CI): FET-AC vs FET-NCHDP risk (95% CI): FET-AC vs FET-SCHDP risk (95% CI): FET-NC vs FET-SC
      Singleton births
      Ginström Ernstad et al,
      • 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.
      2019

      Retrospective cohort (registry) study (Sweden)
      n=1446

      10.5%
      n=6297

      6.1%
      n=1983

      6.6%
      n=24,365

      5.2%
      n=1,127,566

      3.9%
      AOR, 1.78 (1.43–2.21)AOR, 1.61 (1.22–2.10)AOR, 1.05 (0.84–1.31)
      Wang et al,
      • Wang B.
      • Zhang J.
      • Zhu Q.
      • Yang X.
      • Wang Y.
      Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons.
      2020

      Single-center retrospective cohort study (China)
      n=1682
      FET-AC vs FET-NC. Authors used propensity score matching


      3.5%

      n=2333
      FET-AC vs FET-SC. Authors used propensity score matching


      3.3%
      n=1682
      FET-AC vs FET-NC. Authors used propensity score matching


      1.4%

      n=1947
      FET-NC vs FET-SC. Authors used propensity score matching


      1.5%
      n=2333
      FET-AC vs FET-SC. Authors used propensity score matching


      2.4%

      n=1947
      FET-NC vs FET-SC. Authors used propensity score matching


      2.1%
      P=.000P=.08P=.188
      Zong et al,
      • 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.
      2020

      Single-center retrospective cohort study (China)
      n=1642
      Only singleton live births after 28 weeks’ gestation were included; hence, very early PE may have been missed


      7.9%
      n=4727
      Only singleton live births after 28 weeks’ gestation were included; hence, very early PE may have been missed


      3.5%
      n=517
      Only singleton live births after 28 weeks’ gestation were included; hence, very early PE may have been missed


      4.6%
      AOR, 2.00 (1.54–2.60)AOR, 1.02 (0.62–1.65)
      Makhijani et al,
      • Makhijani R.
      • Bartels C.
      • Godiwala P.
      • et al.
      Maternal and perinatal outcomes in programmed versus natural vitrified-warmed blastocyst transfer cycles.
      2020

      Single-center retrospective cohort study (United States)
      n=391

      15.3%
      n=384

      6.3%
      AOR, 2.39 (1.37–4.17)
      Zhang et al,
      • Zhang J.
      • Wei M.
      • Bian X.
      • et al.
      Letrozole-induced frozen embryo transfer cycles are associated with a lower risk of hypertensive disorders of pregnancy among women with polycystic ovary syndrome.
      2021

      Single-center retrospective cohort study (China)
      n=832
      All patients with the diagnosis of polycystic ovary syndrome.


      6.3%
      n=891
      All patients with the diagnosis of polycystic ovary syndrome.


      3.9%
      AOR (Ref=AC), 0.63 (0.40–0.98)
      Hu et al,
      • Hu K.L.
      • Zhang D.
      • Li R.
      Endometrium preparation and perinatal outcomes in women undergoing single-blastocyst transfer in frozen cycles.
      2021

      Single-center retrospective cohort study (China)
      n=2561

      6%
      n=3790

      2%
      n=670

      2%
      AOR, 2.84 (2.11–3.83)AOR, 1.23 (0.71–2.13)
      Zaat et al,
      • Zaat T.R.
      • Brink A.J.
      • de Bruin J.P.
      • et al.
      Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers?.
      2021

      Multicenter RCT follow-up study (The Netherlands)
      n=37

      24.3%
      n=45

      6.7%
      RR (Ref=AC), 0.27 (0.08–0.94)
      Asserhøj et al,
      • Asserhøj L.L.
      • Spangmose A.L.
      • Aaris Henningsen A.K.
      • Clausen T.D.
      • Ziebe S.
      • Jensen R.B.
      • et al.
      Adverse obstetric and perinatal outcomes in 1,136 singleton pregnancies conceived after programmed frozen embryo transfer (FET) compared with natural cycle FET.
      2021

      Retrospective cohort (registry) study (Denmark)
      n=357

      10.4%
      n=779

      5.6%
      AOR, 1.87 (1.17–3.00)
      No. studies, n Mean±SEM
      FET-NC vs FET-SC. Authors used propensity score matching
       %
      n=8

      10.5±2.3
      n=7

      4.5±0.8
      n=5

      3.9±0.8
      n=1

      5.2
      n=1

      3.9
      Singleton and/or multiple births
      Guan et al,
      • Guan Y.
      • Fan H.
      • Styer A.K.
      • et al.
      A modified natural cycle results in higher live birth rate in vitrified-thawed embryo transfer for women with regular menstruation.
      2016

      Single-center retrospective cohort study (China)
      n=794

      5.7%
      n=427

      6.0%
      n=132

      7.4%
      P=.561 (over all cycles)
      Saito et al,
      • Saito K.
      • Kuwahara A.
      • Ishikawa T.
      • et al.
      Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
      2019

      Retrospective cohort (registry) study (Japan)
      n=24,225

      4.0%
      n=10,755

      3.0%
      AOR, 1.43 (1.14–1.80)
      Jing et al,
      • 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.
      2019

      Single-center retrospective cohort Study (China)
      n=1025

      7.2%
      n=3872

      4.2%
      AOR, 1.86 (1.38–2.49)
      Pan et al,
      • Pan Y.
      • Li B.
      • Wang Z.
      • et al.
      Hormone replacement versus natural cycle protocols of endometrial preparation for frozen embryo transfer.
      2020 Secondary analysis of multicenter RCT (China)
      n=125

      4.8%
      n=408

      5.9%
      P=.646
      Zhang et al,
      • Zhang J.
      • Wei M.
      • Bian X.
      • et al.
      Letrozole-induced frozen embryo transfer cycles are associated with a lower risk of hypertensive disorders of pregnancy among women with polycystic ovary syndrome.
      2021

      Single-center retrospective cohort study (China)
      n=336
      All patients with the diagnosis of polycystic ovary syndrome.


      13.4%
      n=368
      All patients with the diagnosis of polycystic ovary syndrome.


      7.6%
      AOR (Ref=AC), 0.52 (0.30–0.87)
      No. studies, n

      Mean±SEM
      FET-NC vs FET-SC. Authors used propensity score matching
      %
      n=5

      7.0±1.7
      n=4

      4.8±0.7
      n=2

      7.4, 7.6
      Cohort number indicates the number of births. The use of autologous oocytes only was stipulated in all studies except for Ginström Ernstad et al,
      • 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.
      and Wang et al.
      • Wang B.
      • Zhang J.
      • Zhu Q.
      • Yang X.
      • Wang Y.
      Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons.
      AC, artificial cycles; AOR, adjusted odds ratio; FET, frozen embryo transfer; HPD, hypertensive disorders of pregnancy; NC, natural or modified natural cycles; RCT, randomized controlled trial; Ref, reference group; RR, relative risk; SC, stimulated cycles; SpC, spontaneous conceptions.
      Conrad. Evidence for corpus luteal antecedents of preeclampsia. Am J Obstet Gynecol 2021.
      a FET-AC vs FET-NC. Authors used propensity score matching
      b FET-AC vs FET-SC. Authors used propensity score matching
      c FET-NC vs FET-SC. Authors used propensity score matching
      d Only singleton live births after 28 weeks’ gestation were included; hence, very early PE may have been missed
      e All patients with the diagnosis of polycystic ovary syndrome.
      Table 3Risk of pregnancy-induced hypertension for singleton or singleton and/or multiple births according to in vitro fertilization protocol
      PublicationFET-AC

      Cohort number

      %PIH
      FET-NC

      Cohort number

      %PIH
      FET-SC

      Cohort number

      %PIH
      Fresh ET

      Cohort number

      %PIH
      SpC

      Cohort number

      %PIH
      PIH risk (95% CI): FET-AC vs FET-NCPIH risk (95% CI): FET-AC vs FET-SCPIH risk (95% CI): FET-NC vs FET-SCPIH risk (95% CI): FET-AC vs fresh ET
      Singleton births
      Sites et al,
      • Sites C.K.
      • Wilson D.
      • Barsky M.
      • et al.
      Embryo cryopreservation and preeclampsia risk.
      2017

      Multicenter retrospective (registry) cohort Study (United States)
      n=1052
      Most FET-AC; Sites, 2019, personal communication


      5.1%
      n=7453

      4.7%
      P=.58
      Ginström Ernstad et al,
      • 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.
      2019

      Retrospective cohort (registry) study (Sweden)
      n=1446

      2.4%
      n=6297

      1.7%
      n=1983

      2.2%
      n=24,365

      1.5%
      n=1,127,566

      1.2%
      von Versen-Höynck et al,
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      2019

      Single-center prospective cohort study (United States)
      n=94

      3.2%
      n=127

      3.2%
      n=146

      0%
      n=143

      2.1%
      P=.11 (all groups)
      Zhang et al,
      • Zhang J.
      • Wei M.
      • Bian X.
      • et al.
      Letrozole-induced frozen embryo transfer cycles are associated with a lower risk of hypertensive disorders of pregnancy among women with polycystic ovary syndrome.
      2021

      Single-center retrospective cohort study (China)
      n=832
      All patients with the diagnosis of polycystic ovary syndrome


      1.3%
      n=891
      All patients with the diagnosis of polycystic ovary syndrome


      1.0%
      AOR (Ref=AC), 0.79 (0.32–1.95)
      Zaat et al,
      • Zaat T.R.
      • Brink A.J.
      • de Bruin J.P.
      • et al.
      Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers?.
      2021

      Multicenter RCT follow-up (The Netherlands)
      n=37

      16.2%
      n=45

      4.4%
      RR (Ref=AC), 0.27 (0.06–1.28)
      No. studies, n

      Mean±SEM
      Denominator represents the number of clinical pregnancies; no severe preeclampsia was observed in this study.
      %
      n=5

      5.6±2.7
      n=3

      3.1±0.8
      n=2

      2.2, 1.0
      n=3

      2.1±1.4
      n=2

      1.2, 2.1
      Singleton and/or multiple births
      Chen et al,
      • Chen Z.J.
      • Shi Y.
      • Sun Y.
      • et al.
      Fresh versus Frozen Embryos for Infertility in the polycystic ovary syndrome.
      2016

      Multicenter RCT (China)
      n=434
      All patients with the diagnosis of polycystic ovary syndrome
      ,
      Denominator represents the number of clinical pregnancies; no severe preeclampsia was observed in this study.


      2.3%
      n=427
      All patients with the diagnosis of polycystic ovary syndrome
      ,
      Denominator represents the number of clinical pregnancies; no severe preeclampsia was observed in this study.


      1.2%
      RR, 1.97 (0.68–5.71)
      Sites et al,
      • Sites C.K.
      • Wilson D.
      • Barsky M.
      • et al.
      Embryo cryopreservation and preeclampsia risk.
      2017

      Multicenter retrospective (registry) cohort study (United States)
      n=540
      Most FET-AC; Sites, 2019, personal communication


      11.9%
      n=5196

      6.6%
      P<.0001
      Lin et al,
      • Lin J.
      • Zhao J.
      • Hao G.
      • et al.
      Maternal and neonatal complications after natural vs. hormone replacement therapy cycle regimen for frozen single blastocyst transfer.
      2020

      Multicenter retrospective cohort study (China)
      n=169

      3.0%
      n=350

      2.3%
      AOR, 0.66 (0.19–2.35)
      Zhang et al,
      • Zhang J.
      • Wei M.
      • Bian X.
      • et al.
      Letrozole-induced frozen embryo transfer cycles are associated with a lower risk of hypertensive disorders of pregnancy among women with polycystic ovary syndrome.
      2021

      Single-center retrospective cohort study (China)
      n=832
      All patients with the diagnosis of polycystic ovary syndrome


      4.2%
      n=891
      All patients with the diagnosis of polycystic ovary syndrome


      2.7%
      AOR (Ref=AC), 0.76 (0.32–1.78)
      No. studies, n

      Mean+SEM
      Denominator represents the number of clinical pregnancies; no severe preeclampsia was observed in this study.
      %
      n=4

      5.4±2.2
      n=1

      2.3
      n=1

      2.7
      n=2

      1.2, 6.6
      Cohort number indicates the number of births.
      AC, artificial cycles; AOR, adjusted odds ratio; FET, frozen embryo transfer; NC, natural or modified natural cycles; PIH, pregnancy-induced hypertension; Ref, reference group; RR, relative risk; SC, stimulated cycles; SpC, spontaneous conceptions.
      Conrad. Evidence for corpus luteal antecedents of preeclampsia. Am J Obstet Gynecol 2021.
      a Most FET-AC; Sites, 2019, personal communication
      b All patients with the diagnosis of polycystic ovary syndrome
      c Denominator represents the number of clinical pregnancies; no severe preeclampsia was observed in this study.
      Figure thumbnail gr3
      Figure 3Forest plot
      Forest plot depicting the odds ratio for developing preeclampsia as a function of corpus luteal status (singleton births). Of note, 0 CL indicates an autologous FET in an artificial cycle, and ≥1 CL indicates an autologous FET in a natural or stimulated cycle. provides further details.
      CI, confidence interval; FET, frozen embryo transfer; M-H, Mantel-Haenszel method.
      Conrad. Evidence for corpus luteal antecedents of preeclampsia. Am J Obstet Gynecol 2021.
      Figure thumbnail gr4
      Figure 4Forest plot
      Forest plot depicting the odds ratio for developing hypertensive disorders of pregnancy as a function of corpus luteal status (singleton births). Of note, 0 CL indicates an autologous FET in an artificial cycle, and 1 CL indicates an autologous FET in a natural (N) or stimulated (S) cycle. For Wang B, 2020, N and S cycles were listed separately.
      • Wang B.
      • Zhang J.
      • Zhu Q.
      • Yang X.
      • Wang Y.
      Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons.
      provides further details.
      CI, confidence interval; FET, frozen embryo transfer; M-H, Mantel-Haenszel method.
      Conrad. Evidence for corpus luteal antecedents of preeclampsia. Am J Obstet Gynecol 2021.
      Furthermore, a greater risk of PE, HDP, and PIH in FET-AC protocols was generally observed in studies where singleton and multiple births were not reported separately, but with exceptions, such as Guan et al
      • Guan Y.
      • Fan H.
      • Styer A.K.
      • et al.
      A modified natural cycle results in higher live birth rate in vitrified-thawed embryo transfer for women with regular menstruation.
      and Pan et al.
      • Pan Y.
      • Li B.
      • Wang Z.
      • et al.
      Hormone replacement versus natural cycle protocols of endometrial preparation for frozen embryo transfer.
      However, the number of studies were too few to reveal anymore than just trends (Table 1, Table 2, Table 3). In addition, the early 1997 study by Wennerholm et al
      • Wennerholm U.B.
      • Hamberger L.
      • Nilsson L.
      • Wennergren M.
      • Wikland M.
      • Bergh C.
      Obstetric and perinatal outcome of children conceived from cryopreserved embryos.
      is consistent with the overall conclusion, insofar as PE rates were similar in the FET group that was mostly FET-NC (7.2%) (82% FET-NC and 18% FET-SC), fresh ET (7.7%), and spontaneously conceived pregnancies (6.2%) (n=208 participants per group). Finally, it should be noted that FET-AC protocols are employed for recipients of embryos derived from donor oocytes; therefore, the absence of a CL and circulating CL and circulating CL factors could contribute to the especially high risk of PE and HDP associated with IVF involving embryos derived from donor oocytes.
      • Conrad K.P.
      Evidence for corpus luteal and endometrial origins of adverse pregnancy outcomes in women conceiving with or without assisted reproduction.

      Maternal Cardiovascular Function is Perturbed During Early Gestation in Women Who Conceive Using Artificial Cycles

      Maternal cardiovascular function was evaluated in the context of CL status, employing a separate IVF population.
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      ,
      • Conrad K.P.
      • Petersen J.W.
      • Chi Y.Y.
      • et al.
      Maternal cardiovascular dysregulation during early pregnancy after in vitro fertilization cycles in the absence of a corpus luteum.
      Gestational changes of several cardiovascular variables were attenuated or delayed in women who conceived using FET-AC protocols that precluded CL formation; in particular, there were subdued gestational increases of cardiac output (CO) and global arterial compliance (global AC) and attenuated decreases in systemic vascular resistance (SVR) and carotid-femoral pulse wave velocity (PWV) reflecting reduced arterial dilation and impaired augmentation of arterial compliance during the first trimester of pregnancy (Figures 5 and 6).
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      ,
      • Conrad K.P.
      • Petersen J.W.
      • Chi Y.Y.
      • et al.
      Maternal cardiovascular dysregulation during early pregnancy after in vitro fertilization cycles in the absence of a corpus luteum.
      As predicted by the overall hypothesis, after the CL-placental shift that occurred toward the end of the first trimester of pregnancy, carotid-femoral PWV improved thereafter in the 0 CL cohort, whereas CO, global AC, and SVR were virtually restored to the levels observed in the spontaneous pregnancy group (Figures 5 and 6).
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      ,
      • Conrad K.P.
      • Petersen J.W.
      • Chi Y.Y.
      • et al.
      Maternal cardiovascular dysregulation during early pregnancy after in vitro fertilization cycles in the absence of a corpus luteum.
      However, women who conceived using fresh ET with the formation of multiple CL did not show a “hyperdynamic” circulation in the first trimester of pregnancy; rather, cardiovascular function was similar to women who conceived spontaneously (Figure 5 and 6).
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      ,
      • Conrad K.P.
      • Petersen J.W.
      • Chi Y.Y.
      • et al.
      Maternal cardiovascular dysregulation during early pregnancy after in vitro fertilization cycles in the absence of a corpus luteum.
      Perhaps not coincidentally, PE and HDP risks associated with fresh ET were also comparable with spontaneous conception
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      ,
      • Conrad K.P.
      • Petersen J.W.
      • Chi Y.Y.
      • et al.
      Maternal cardiovascular dysregulation during early pregnancy after in vitro fertilization cycles in the absence of a corpus luteum.
      (Tables 1 and 2). Additional reports have emerged, which documented dysregulation of other cardiovascular parameters and endocrine function, especially in women who conceived using FET-AC lacking a CL and circulating CL factors.
      • Conrad K.P.
      • Graham G.M.
      • Chi Y.Y.
      • et al.
      Potential influence of the corpus luteum on circulating reproductive and volume regulatory hormones, angiogenic and immunoregulatory factors in pregnant women.
      ,
      • von Versen-Höynck F.
      • Narasimhan P.
      • Selamet Tierney E.S.
      • et al.
      Absent or excessive corpus luteum number is associated with altered maternal vascular health in early pregnancy.
      • Conrad K.P.
      • Lingis M.
      • Sautina L.
      • et al.
      Maternal endothelial function, circulating endothelial cells, and endothelial progenitor cells in pregnancies conceived with or without in vitro fertilization.
      • Wiegel R.E.
      • Jan Danser A.H.
      • Steegers-Theunissen R.P.M.
      • et al.
      Determinants of maternal renin-angiotensin-aldosterone-system activation in early pregnancy: insights from 2 cohorts.
      Figure thumbnail gr5
      Figure 5cfPWV and cfPWTT in women who conceived with and without IVF
      A, cfPWV. B, cfPWTT. Mean±1.96 SE (95% confidence interval). Without CL: women who conceived by IVF using FET-AC protocols with hypothalamic-pituitary suppression. One CL: women who conceived spontaneously. Multiple CL: women who conceived by IVF using fresh ET protocols with controlled ovarian stimulation. The Wilcoxon signed-rank test with Bonferroni correction was used to compare the 3 time points in the first trimester of pregnancy for each of the 3 cohorts, separately, with the prepregnancy baseline (BP). Tha asterisk indicates P<.017 vs BP for >1 CL; the plus sign indicates P<.017 vs BP for 1 CL. The 0 CL was not significantly different from BP at any time point in the first trimester of pregnancy. PP, on average 49.8±1.8 weeks postpartum (mean±SEM). Further statistical analyses are provided in von Versen-Höynck et al.
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      AC, artificial cycles; BP, before pregnancy in the follicular phase; cfPWTT, carotid-femoral pulse wave transit time; cfPWV, carotid-femoral pulse wave velocity; CL, corpus luteum; ET, embryo transfer; FET, frozen embryo transfer; IVF, in vitro fertilization; PP, postpartum.
      Conrad. Evidence for corpus luteal antecedents of preeclampsia. Am J Obstet Gynecol 2021.
      Figure thumbnail gr6
      Figure 6Cardiac output in women who conceived with or without IVF
      A, Absolute values of CO before, during, and after pregnancy. B, Changes in CO from prepregnancy baseline: Without CL: women who conceived by IVF using FET-AC protocols with hypothalamic-pituitary suppression. One CL: women who conceived spontaneously. Multiple CL: women who conceived by IVF using fresh ET protocols with controlled ovarian stimulation. In bVbD_Cardiac Output, CO was determined by multiplying the single best velocity time integral by the single best left ventricular outflow cross-sectional area. Wilcoxon signed-rank test with Bonferroni correction was used to compare the 3 time points in the first trimester of pregnancy for each of the 3 cohorts, separately, with the prepregnancy baseline. The plus sign indicates P<.017 vs BP for the 1 and >1 CL cohorts. In the figure, 0 CL was not significantly different from BP at any time point in the first trimester of pregnancy. The asterisk indicates P≤.05 for 0 CL compared with cohorts 1 and >1 CL combined at all time points during the first trimester of pregnancy by nonparametric analysis of variance. PP, on average 49.8±1.8 weeks postpartum (mean±SEM). Further statistical analyses are provided in Conrad et al.
      • Conrad K.P.
      • Petersen J.W.
      • Chi Y.Y.
      • et al.
      Maternal cardiovascular dysregulation during early pregnancy after in vitro fertilization cycles in the absence of a corpus luteum.
      BP, before pregnancy in the follicular phase; CL, corpus luteum; CO, cardiac output; PP, postpartum, SEM, standard error of mean.
      Conrad. Evidence for corpus luteal antecedents of preeclampsia. Am J Obstet Gynecol 2021.

      Potential Mechanisms for the Association of Artificial in Vitro Fertilization Cycles with First-Trimester Cardiovascular Dysregulation and Increased Preeclampsia Risk

      As discussed previously, the presence or absence of embryo cryopreservation as a potential explanation for enhanced PE risk in FET vs fresh ET was found to be unlikely after comparing FET-AC with FET-NC (or FET-SC), in which cryopreservation was implemented in both protocols and the method of cryopreservation employed was the same for each. The association of increased PE risk was specifically identified in the FET-AC and not in the FET-NC cohort, thus suggesting the absence of the CL as 1 potential culprit (Table 4).
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      In further support of the CL hypothesis was the finding that the deficient maternal cardiovascular function observed in the first trimester of pregnancy of women who conceived using FET-AC was improved or restored thereafter, presumably when the placenta became sufficiently mature to secrete vasodilatory factors that came to the rescue, for example, PGF (Figures 5 and 6).
      Table 4Preeclampsia risk is higher in women who conceived using autologous frozen embryo transfer in a programmed or artificial cycle (absent corpus luteum) than in those who conceived using autologous frozen embryo transfer in natural cycle (1 corpus luteum)
      VariableComparisonAOR95% CIP value
      Preeclampsia
      CL numberO CL vs 1 CL2.731.14–6.49.02
      Frozen embryo transferProgrammed FET vs modified FET-NC3.551.20–11.94.03
      Preeclampsia with several features
      CL number0 CL vs 1 CL6.451.94–25.09.003
      Frozen embryo transferProgrammed FET vs modified FET-NC15.052.59–286.27.01
      One CL includes FET-NC (modified), intrauterine insemination cycles, and spontaneous conceptions. Data are reported for singleton births and adjusted for maternal age, nulliparity, history of hypertension, body mass index, polycystic ovary syndrome, diabetes mellitus (pregestational and gestational). Modified from von Versen-Hoynck et al.
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      AOR, adjusted odds ratio; CI, confidence interval; CL, corpus luteum. FET, frozen embryo transfer; NC, natural cycle.
      Conrad. Evidence for corpus luteal antecedents of preeclampsia. Am J Obstet Gynecol 2021.
      Although many publications have emerged consistent with the potential role for the absence of a CL in the elevated risk of PE and HDP in women who conceived using autologous FET-AC as detailed above (Table 1; Table 2, for HDP), all studies to date have been observational, and because of the inherent limitations of observational studies, there are alternative explanations (details provided under the “Limitations” section). Furthermore, deficient or defective decidualization in the secretory phase and during early pregnancy was recently implicated in the genesis of PE at least for some women
      • Founds S.A.
      • Conley Y.P.
      • Lyons-Weiler J.F.
      • Jeyabalan A.
      • Hogge W.A.
      • Conrad K.P.
      Altered global gene expression in first trimester placentas of women destined to develop preeclampsia.
      • Rabaglino M.B.
      • Post Uiterweer E.D.
      • Jeyabalan A.
      • Hogge W.A.
      • Conrad K.P.
      Bioinformatics approach reveals evidence for impaired endometrial maturation before and during early pregnancy in women who developed preeclampsia.
      • Conrad K.P.
      • Rabaglino M.B.
      • Post Uiterweer E.D.
      Emerging role for dysregulated decidualization in the genesis of preeclampsia.
      • Garrido-Gomez T.
      • Dominguez F.
      • Quiñonero A.
      • et al.
      Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology.
      • Rabaglino M.B.
      • Conrad K.P.
      Evidence for shared molecular pathways of dysregulated decidualization in preeclampsia and endometrial disorders revealed by microarray data integration.
      and, in this context, PE may be another manifestation of the endometrial spectrum disorders.
      • Rabaglino M.B.
      • Conrad K.P.
      Evidence for shared molecular pathways of dysregulated decidualization in preeclampsia and endometrial disorders revealed by microarray data integration.
      It is possible that the dosage or timing of estradiol and/or progesterone administration for endometrial support in FET-AC protocols was not sufficiently precise to optimize decidualization and, hence, placentation leading to the development of PE.
      • Conrad K.P.
      Evidence for corpus luteal and endometrial origins of adverse pregnancy outcomes in women conceiving with or without assisted reproduction.
      Another possibility is that decidualization was inadequate in FET-AC, because circulating CL factors, such as RLN, which themselves can be potent agents of decidualization,
      • Conrad K.P.
      G-protein-coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin/insulin-like family peptide receptor 1 for treatment and prevention.
      were missing. Absent CL products and inadequate hormonal endometrial support are not mutually exclusive, that is, circulating CL factors, such as RLN, might synergize with administered sex steroids to optimize decidualization. Of note, it may be more than coincidence that, in 2 completely independent lines of investigation, both the endometrium and CL were implicated in the genesis of PE.
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      ,
      • Founds S.A.
      • Conley Y.P.
      • Lyons-Weiler J.F.
      • Jeyabalan A.
      • Hogge W.A.
      • Conrad K.P.
      Altered global gene expression in first trimester placentas of women destined to develop preeclampsia.
      ,
      • Rabaglino M.B.
      • Post Uiterweer E.D.
      • Jeyabalan A.
      • Hogge W.A.
      • Conrad K.P.
      Bioinformatics approach reveals evidence for impaired endometrial maturation before and during early pregnancy in women who developed preeclampsia.
      Because the CL and endometrium are inextricably linked, the plausibility that absence of a CL, underlying uterine lining abnormalities, and/or suboptimal endometrial support in FET-AC may be etiologic factors in the development of PE is reinforced. However, the mechanisms by which underlying uterine abnormalities or suboptimal endometrial support could account for first trimester cardiovascular dysregulation and its partial or complete recovery thereafter in women who conceived using artificial cycles are less apparent. Finally, the possibility that dysregulation of CL or endometrial function outside of IVF may be precursors of PE is suggested (Figure 7).
      Figure thumbnail gr7
      Figure 7Integrative hypothesis of CL and endometrial origins of preeclampsia
      Artificial (programmed) in vitro fertilization cycles inhibit the formation of a CL, thereby increasing the risk of the development of preeclampsia. The possibility that inadequate dosage or timing of estrogen and progesterone administration in artificial cycles may adversely affect endometrial function that increases the risk of preeclampsia is not shown. Alternatively, inadequate endometrial support and absence of circulating factors, such as relaxin, may collude to increase preeclampsia risk. Details are provided in the text.
      CL, corpus luteum.
      Conrad. Evidence for corpus luteal antecedents of preeclampsia. Am J Obstet Gynecol 2021.
      Whether cardiovascular dysregulation in early pregnancy contributed to increased PE risk in the FET-AC cohort is unproven. However, an association between cardiovascular dysfunction in early pregnancy and enhanced PE risk was previously noted outside of IVF. Namely, women who developed preterm PE with small-for-gestational-age (SGA) infants manifested a relatively vasoconstricted circulation at 11 to 14 weeks’ gestation, that is, SVR was significantly increased relative to the normal pregnant condition. In this study, although there was a clear trend, SVR was not statistically increased in women who delivered SGA infants (without PE) relative to women who delivered normally grown babies.
      • Khaw A.
      • Kametas N.A.
      • Turan O.M.
      • Bamfo J.E.
      • Nicolaides K.H.
      Maternal cardiac function and uterine artery Doppler at 11-14 weeks in the prediction of pre-eclampsia in nulliparous women.
      Thus, the explanation for the increase in SVR at 11 to 14 weeks’ gestation in the preterm PE cohort with SGA babies could be because of the onset of PE at <37 weeks’ gestation that is frequently associated with more severe disease, SGA, or both. In contrast, women who developed term PE with normally grown babies manifested a relatively vasodilated circulation marked by increased CO and/or reduced SVR.
      • Khaw A.
      • Kametas N.A.
      • Turan O.M.
      • Bamfo J.E.
      • Nicolaides K.H.
      Maternal cardiac function and uterine artery Doppler at 11-14 weeks in the prediction of pre-eclampsia in nulliparous women.
      • Bosio P.M.
      • McKenna P.J.
      • Conroy R.
      • O’Herlihy C.
      Maternal central hemodynamics in hypertensive disorders of pregnancy.
      • Easterling T.R.
      • Benedetti T.J.
      • Schmucker B.C.
      • Millard S.P.
      Maternal hemodynamics in normal and preeclamptic pregnancies: a longitudinal study.
      Interestingly, women who conceived by IVF using the FET-AC protocol showed a relatively “hypodynamic” and vasoconstricted circulation in the first trimester of pregnancy (recovering thereafter) despite having normal pregnancies.
      • Conrad K.P.
      • Petersen J.W.
      • Chi Y.Y.
      • et al.
      Maternal cardiovascular dysregulation during early pregnancy after in vitro fertilization cycles in the absence of a corpus luteum.
      In this study, there were too few women in the FET-AC cohort who developed PE; thus, whether the maternal circulation might have been even more “hypodynamic” or vasoconstricted during the first trimester of pregnancy in these women was unknown. However, if so, this finding would be inconsistent with the concept of a relatively vasodilated circulation in early pregnancy of women who developed term PE (at least outside of IVF, vide supra)—the variety of PE observed in many women who conceived using FET-AC (details provided under the (details provided under the section “Does frozen embryo transfer in artificial cycles increase the risk of preterm preeclampsia, term preterm preeclampsia, or both?”).
      If the CL is playing an important role, then the identity of the specific circulating CL products that might regulate maternal cardiovascular changes in early pregnancy and reduce the risk of developing PE needs to be established. Unfortunately, except for only a handful of products, for example, estradiol, progesterone, and their metabolites, RLN, possibly vascular endothelial growth factor and a few others, knowledge of CL factors secreted directly into the maternal circulation (or indirectly via small extracellular vesicles) during the luteal phase and early pregnancy of women is lacking. RLN is a logical candidate based on what is known about its cardiovascular actions, including promoting vasodilation and reducing vascular inflammation.
      • Conrad K.P.
      G-protein-coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin/insulin-like family peptide receptor 1 for treatment and prevention.
      ,
      • Du X.J.
      • Bathgate R.A.
      • Samuel C.S.
      • Dart A.M.
      • Summers R.J.
      Cardiovascular effects of relaxin: from basic science to clinical therapy.
      Although plasma RLN concentrations have been reported to be comparable in women with active disease relative to normal pregnancy,
      • Szlachter B.N.
      • Quagliarello J.
      • Jewelewicz R.
      • Osathanondh R.
      • Spellacy W.N.
      • Weiss G.
      Relaxin in normal and pathogenic pregnancies.
      ,
      • Lafayette R.A.
      • Hladunewich M.A.
      • Derby G.
      • Blouch K.
      • Druzin M.L.
      • Myers B.D.
      Serum relaxin levels and kidney function in late pregnancy with or without preeclampsia.
      whether the complete absence of circulating RLN could be associated with increased PE risk was not addressed until recently.
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      A role of RLN in reducing PE risk was consistent with the finding that low circulating concentrations of RLN in the first trimester of pregnancy were associated with an increased risk of developing PE at ≥34 weeks’ gestation.
      • Post Uiterweer E.D.
      • Koster M.P.H.
      • Jeyabalan A.
      • et al.
      Circulating pregnancy hormone relaxin as a first trimester biomarker for preeclampsia.
      However, because low circulating RLN concentrations arose from reduced CL function, other potentially critical circulating CL substances that were not measured could be deficient as well. Moreover, plasma pro-RLN concentrations measured during the second trimester of pregnancy were similar between women who developed PE or experienced normal pregnancies.
      • Rehfeldt M.
      • Eklund E.
      • Struck J.
      • et al.
      Relaxin-2 connecting peptide (pro-RLX2) levels in second trimester serum samples to predict preeclampsia.
      Thus, more work may be needed to establish whether there is an association between low plasma RLN concentrations during early pregnancy and the development of PE.
      It is important to consider that most women who conceived using FET-AC did not develop PE (Tables 1 and 4, Figures 3 and 4). Viewed in this light, FET-AC might be regarded as another risk factor or predisposition for developing PE, and a second or even third “hit” is needed to trigger the disease. In contrast, compensatory mechanisms may intervene. As 1 example, circulating PGF emanating from the placenta may compensate for the lack of circulating CL vasodilators, such as RLN, after the first trimester of pregnancy. Toward the end of pregnancy, the vasodilatory attribute of RLN may be 1 important factor in offsetting the normal rise of plasma vasoconstrictor concentrations, such as soluble fms-like tyrosine kinase 1 (sFLT1), thereby tempering the physiological restoration of the maternal circulation to the nonpregnant condition of relative vasoconstriction.
      • Conrad K.P.
      • Graham G.M.
      • Chi Y.Y.
      • et al.
      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.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      ,
      • Conrad K.P.
      • Petersen J.W.
      • Chi Y.Y.
      • et al.
      Maternal cardiovascular dysregulation during early pregnancy after in vitro fertilization cycles in the absence of a corpus luteum.
      ,
      • Levine R.J.
      • Maynard S.E.
      • Qian C.
      • et al.
      Circulating angiogenic factors and the risk of preeclampsia.
      Consistent with this potentially critical role of RLN, women who conceived using FET-AC without a CL and circulating RLN showed (strong and statistically significant) direct and indirect correlations of plasma PGF concentration with CO and SVR, respectively, after the first trimester of pregnancy.
      • Conrad K.P.
      • Taher S.
      • Chi Y.Y.
      • et al.
      Relationships between reproductive hormones and maternal pregnancy physiology in women conceiving with or without in vitro fertilization.
      Thus, in the absence of circulating RLN, and after the rise of circulating PGF in the second and third trimesters of pregnancy, women who conceived using FET-AC may have become reliant on PGF to restore and maintain the maternal circulation in a relatively vasodilated state with advancing gestation (Figures 1, 2, 5, and 6).
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      ,
      • Conrad K.P.
      • Petersen J.W.
      • Chi Y.Y.
      • et al.
      Maternal cardiovascular dysregulation during early pregnancy after in vitro fertilization cycles in the absence of a corpus luteum.
      ,
      • Conrad K.P.
      • Taher S.
      • Chi Y.Y.
      • et al.
      Relationships between reproductive hormones and maternal pregnancy physiology in women conceiving with or without in vitro fertilization.
      Possibly by restoring maternal vasodilation after the first trimester of pregnancy, PGF circumvented PE or prevented PE risk from being even higher in this IVF cohort.
      In contrast, the combination of absent circulating RLN, inadequate PGF, or enhanced placental sFLT1 production could have tipped the scale, leading to the development of PE in women who conceived using FET-AC. Indeed, the proportion of women with an elevated circulating sFLT1 concentration and sFLT1-to-PGF ratio was greater toward the end of pregnancy in those who conceived using FET-AC vs controlled ovarian stimulation,
      • Conrad K.P.
      • Graham G.M.
      • Chi Y.Y.
      • et al.
      Potential influence of the corpus luteum on circulating reproductive and volume regulatory hormones, angiogenic and immunoregulatory factors in pregnant women.
      possibly reflecting greater pathologic degrees of villous overcrowding, placental ischemia, and stress. More severe placental stress in women who conceived using FET-AC was reflected by the pathology of placental and decidual tissues obtained after delivery, which was correspondingly worse.
      • Sacha C.R.
      • Harris A.L.
      • James K.
      • et al.
      Placental pathology in live births conceived with in vitro fertilization after fresh and frozen embryo transfer.
      ,
      • Nakamura Y.
      • Yaguchi C.
      • Itoh H.
      • et al.
      Morphologic characteristics of the placental basal plate in in vitro fertilization pregnancies: a possible association with the amount of bleeding in delivery.
      Furthermore, RLN was shown to increase trophoblast survival in the face of hypoxia and reoxygenation, which might protect against the development of PE.
      • Ogunleye O.
      • Campo B.
      • Herrera D.
      • Post Uiterweer E.D.
      • Conrad K.P.
      Relaxin confers cytotrophoblast protection from hypoxia-reoxygenation injury through the phosphatidylinositol 3-kinase-Akt/protein kinase B cell survival pathway.
      To our knowledge, whether RLN might restrain sFLT1 production or release by trophoblast has not been tested. Although circulating RLN was absent in FET-AC cycles, plasma concentrations in fresh ET cycles were either comparable with those observed in spontaneous pregnancies or markedly higher, possibly explaining the rates of PE in these IVF cycles being similar to spontaneous pregnancies (Table 1, Figure 2). Last, it is important to reiterate that the absence of other unidentified CL factors besides or in addition to RLN may contribute to the elevated PE risk in FET-AC.

      Does Frozen Embryo Transfer in Artificial Cycles Increase the Risk of Preterm Preeclampsia, Term Preeclampsia, or Both?

      Current belief holds that early-onset PE (<34 weeks’ gestation) stems from deficient placentation starting in early pregnancy, that is, impaired trophoblast invasion and spiral artery remodeling, leading to mechanical damage of the villi because of increased intervillous blood flow velocity and ischemia and reperfusion injury.
      • Brosens I.
      • Pijnenborg R.
      • Vercruysse L.
      • Romero R.
      The “Great Obstetrical Syndromes” are associated with disorders of deep placentation.
      In contrast, term PE (≥37 weeks’ gestation) is thought to arise from villous overcrowding, which occludes intervillous spaces, thereby impeding blood flow, causing placental ischemia, that is, villous growth outpaces uterine capacity.
      • Redman C.W.
      • Sargent I.L.
      • Staff A.C.
      IFPA Senior Award Lecture: making sense of pre-eclampsia - two placental causes of preeclampsia?.
      It seems plausible that these placental etiologies may not be so temporally restricted or dichotomous as implied by the gestational age cutoffs of <34 and ≥37 weeks. Furthermore, the 2 placental etiologies could perhaps collude to produce PE, especially between 34 and 37 weeks’ gestation, the relative contribution of each being related to the gestational age of PE onset.
      • Conrad K.P.
      Evidence for corpus luteal and endometrial origins of adverse pregnancy outcomes in women conceiving with or without assisted reproduction.
      ,
      • Conrad K.P.
      • Rabaglino M.B.
      • Post Uiterweer E.D.
      Emerging role for dysregulated decidualization in the genesis of preeclampsia.
      Several reports that evaluated PE within specific IVF protocols defined whether disease onset was preterm or term. Barsky et al,
      • Barsky M.
      • St Marie P.
      • Rahil T.
      • Markenson G.R.
      • Sites C.K.
      Are perinatal outcomes affected by blastocyst vitrification and warming?.
      Chen et al,
      • Chen Z.J.
      • Shi Y.
      • Sun Y.
      • et al.
      Fresh versus Frozen Embryos for Infertility in the polycystic ovary syndrome.
      and von Versen-Höynck et al
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      observed that FET-AC was specifically associated with term PE. In contrast, perhaps because of larger cohort sizes and increased study power, Sites et al
      • Sites C.K.
      • Wilson D.
      • Barsky M.
      • et al.
      Embryo cryopreservation and preeclampsia risk.
      noted an association of FET (mostly FET-AC; Sites, 2019, personal communication) with preterm PE relative to fresh ET. Because circulating CL factors, such as RLN, might optimize predecidualization as discussed earlier, women who conceived using FET-AC without circulating CL factors could have suboptimal predecidualization and, consequently, impairment of placentation in early pregnancy,
      • Conrad K.P.
      • Rabaglino M.B.
      • Post Uiterweer E.D.
      Emerging role for dysregulated decidualization in the genesis of preeclampsia.
      ,
      • Conrad K.P.
      G-protein-coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin/insulin-like family peptide receptor 1 for treatment and prevention.
      which is believed to contribute to early-onset (<34 weeks’ gestation) and perhaps preterm (<37 weeks’ gestation) PE (vide supra). In summary, whether FET-AC is associated with increased risk of preterm PE, term PE, or both is unresolved and needs further study. Clarifying this association is important, because it could shed light on the underlying mechanisms by which FET-AC confers increased PE risk concerning the different placental etiologies of preterm and term or early- and late-onset PE.

      Limitations

      Underlying maternal factors leading to the choice of FET-AC protocol (eg, polycystic ovarian syndrome [PCOS] or inadequate endometrial response to physiological levels of estradiol in a previous FET-NC) may partially or fully explain the association of artificial cycles with elevated PE risk. Some studies suggested that women with PCOS are at increased risk of PE possibly because of insulin resistance and obesity, which are more common in this population.
      • D’Alterio M.N.
      • Sigilli M.
      • Succu A.G.
      • et al.
      Pregnancy outcomes in women with polycystic ovarian syndrome (PCOS).
      In a recent publication that included only patients with PCOS undergoing FET,
      • Zhang J.
      • Wei M.
      • Bian X.
      • et al.
      Letrozole-induced frozen embryo transfer cycles are associated with a lower risk of hypertensive disorders of pregnancy among women with polycystic ovary syndrome.
      FET-SC was associated with a lower risk of HDP than FET-AC, suggesting that the CL may play a role in mitigating the risk of hypertensive disorders within the population with PCOS undergoing FET.
      The current literature does not definitively resolve the question of whether subfertility itself could modify the effect of the CL on the incidence of PE. As examples, the Swedish birth registry used by Ginström Ernstad et al
      • 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.
      included a spontaneous conception comparison group composed of both subfertile and fertile women, whereas the spontaneous conception comparison group used by von Versen-Höynck et al
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      was a population of subfertile women being treated in an infertility clinic. Although a potential modifying effect of subfertility on the effect of the CL cannot be ruled out, the incidence of PE reported in the various subfertile groups studied, including fresh ET, FET-NC, and FET-SC, and spontaneous conception was in the same range as reported for the incidence of PE in the general population.
      • Abalos E.
      • Cuesta C.
      • Grosso A.L.
      • Chou D.
      • Say L.
      Global and regional estimates of preeclampsia and eclampsia: a systematic review.
      ,
      • von Versen-Höynck F.
      • Schaub A.M.
      • Chi Y.Y.
      • et al.
      Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
      ,
      Gestational hypertension and preeclampsia: ACOG Practice Bulletin, Number 222.
      Importantly, the incidence of PE in these subfertile groups with one or more CL was distinctly lower than FET-AC lacking a CL (Figure 3, Tables 1 and 4).
      Although the concept that secreted CL factors contribute to the iconic maternal circulatory changes of early pregnancy in women and reduce the risk for developing PE has considerable merit, it is new and still a hypothesis in need of further support. Results from the randomized controlled trials (RCTs) currently in progress comparing FET-NC and FET-AC protocols may provide additional clarity (details provided in the “Future investigations” section).

      Future Investigations

      Both the prospective and retrospective cohort studies portrayed in Table 1 (Table 2, for HDP) seemed sufficiently compelling to justify RCTs comparing PE risk in FET-AC vs FET-NC protocols. Notably, 2 RCTs were started in late 2019 to ascertain whether FET-NC would reduce PE risk relative to FET-AC as hypothesized (ClinicalTrials.gov Identifiers: NCT04551807 and NCT04092829). In the clinical trial number NCT04551807, only women who spontaneously ovulate were enrolled; thus, the results will be generalizable to most women in the assisted reproductive technology population, because most women who undergo IVF with autologous oocytes ovulate spontaneously. However, even if FET-NC is shown to reduce PE risk in RCTs, some women cannot conceive using this IVF protocol, and therefore, artificial cycles are mandatory as in the instance of ovarian failure. In these infertile women, another strategy is needed to help reduce the PE risk. Ultimately, replacement of the missing CL factors may be warranted.
      From a physiology perspective, a definitive assessment of kidney function in women who conceived using artificial cycles is needed. The subdued decline in first-trimester SVR in this IVF cohort would likely be, at least in part, a consequence of the attenuated decline in renal vascular resistance.
      • Conrad K.P.
      • Petersen J.W.
      • Chi Y.Y.
      • et al.
      Maternal cardiovascular dysregulation during early pregnancy after in vitro fertilization cycles in the absence of a corpus luteum.
      A pilot longitudinal study showed a subdued gestational increase of 24-hour endogenous creatinine clearance in early pregnancy of women who conceived by IVF without a CL, and another cross-sectional study demonstrated that plasma creatinine concentration was higher in women who conceived using FET-AC protocols at 4 to 5 weeks’ gestation.
      • von Versen-Höynck F.
      • Strauch N.K.
      • Liu J.
      • et al.
      Effect of mode of conception on maternal serum relaxin, creatinine, and sodium concentrations in an infertile population.
      ,
      • Smith M.C.
      • Murdoch A.P.
      • Danielson L.A.
      • Conrad K.P.
      • Davison J.M.
      Relaxin has a role in establishing a renal response in pregnancy.
      Nevertheless, the gold standard for quantifying renal plasma flow and glomerular filtration rate are the renal clearances of para-aminohippurate and inulin (or inutest), respectively, both of which have long track records of use in human pregnancy.
      • Lafayette R.A.
      • Druzin M.
      • Sibley R.
      • et al.
      Nature of glomerular dysfunction in pre-eclampsia.
      • Roberts M.
      • Lindheimer M.D.
      • Davison J.M.
      Altered glomerular permselectivity to neutral dextrans and heteroporous membrane modeling in human pregnancy.
      • Moran P.
      • Baylis P.H.
      • Lindheimer M.D.
      • Davison J.M.
      Glomerular ultrafiltration in normal and preeclamptic pregnancy.
      • Irons D.W.
      • Baylis P.H.
      • Davison J.M.
      Effect of atrial natriuretic peptide on renal hemodynamics and sodium excretion during human pregnancy.
      • Irons D.W.
      • Baylis P.H.
      • Butler T.J.
      • Davison J.M.
      Atrial natriuretic peptide in preeclampsia: metabolic clearance, sodium excretion and renal hemodynamics.
      • Chapman A.B.
      • Abraham W.T.
      • Zamudio S.
      • et al.
      Temporal relationships between hormonal and hemodynamic changes in early human pregnancy.
      Lastly, identification of the entire repertoire of CL factors secreted directly into the maternal circulation during the luteal phase and early human pregnancy (or indirectly via extracellular vesicles) is critical. Notably, factors that circulate in women who conceived spontaneously or by FET-NC, but which are absent in women who conceived using FET-AC, would support their CL origin. In contrast, increased plasma concentrations of CL products (or products arising elsewhere as a consequence of being stimulated by CL factors) would be anticipated in many women who conceived by fresh ET with multiple CL (analogous to RLN) (Figure 2).
      • Conrad K.P.
      • Graham G.M.
      • Chi Y.Y.
      • et al.
      Potential influence of the corpus luteum on circulating reproductive and volume regulatory hormones, angiogenic and immunoregulatory factors in pregnant women.
      Identifying the complete array of factors emanating from the CL could profoundly influence our understanding of normal pregnancy and pregnancy complications. Moreover, some of these factors could have therapeutic potential both within and outside of pregnancy.
      • Conrad K.P.
      • Graham G.M.
      • Chi Y.Y.
      • et al.
      Potential influence of the corpus luteum on circulating reproductive and volume regulatory hormones, angiogenic and immunoregulatory factors in pregnant women.
      ,
      • Teichman S.L.
      • Unemori E.
      • Dschietzig T.
      • et al.
      Relaxin, a pleiotropic vasodilator for the treatment of heart failure.

      Summary and Conclusions

      In pregnancies conceived by artificial cycles that precluded the development of a CL, gestational changes in maternal cardiovascular function during early pregnancy were notably subdued. The risk of PE and HDP was significantly elevated in autologous FET-AC relative to spontaneously conceived pregnancies or pregnancies that arose from autologous FET-NC or FET-SC with the formation of one or a few CL. In pregnancies conceived through controlled ovarian stimulation and fresh ET in which multiple CL developed, maternal cardiovascular adaptations during early pregnancy and PE and HDP risk were comparable with spontaneously conceived pregnancies or pregnancies that arose from autologous FET-NC or FET-SC. Because of the detrimental impact on maternal cardiovascular adaptations to early pregnancy and increased PE risk following artificial cycles, the question arose about whether suboptimal CL function outside of IVF could compromise maternal pregnancy physiology and outcome.
      The potential mechanisms underpinning the association of artificial IVF cycles with first-trimester cardiovascular perturbation and elevated PE risk are uncertain. The absence of CL and CL-secreted factors is supported by the finding that the cardiovascular deficiencies observed during the first trimester of pregnancy were improved or fully restored thereafter, presumably when the placenta became sufficiently mature to secrete vasodilatory factors that came to the rescue, for example, PGF. Whether the first-trimester maternal circulatory derangements and elevated PE risk are linked in women who conceived with artificial cycles is unproven, although women who conceived using fresh ET with the formation of multiple CL demonstrated normal circulatory changes in early pregnancy, and they did not have elevated PE risk. If missing CL factors underpin the circulatory perturbations and enhanced PE risk in women who became pregnant using artificial cycles, then the absence of RLN, which normally exerts vasodilation and vascular protection, would be 1 potential candidate. Importantly, most women who conceived by autologous FET-AC did not develop PE. Thus, FET-AC may be considered as a risk factor that requires additional “hits” to trigger PE, and/or compensatory mechanisms intervene in most women, for example, PGF. Thus, lack of circulating RLN and inadequate PGF or enhanced sFLT1 production might conspire to initiate PE manifestations.
      Cryopreservation in autologous FET-AC vs fresh ET cycles did not seem to underlie the increased risk of PE as initially believed, because the increased risk was observed in FET-AC but not in FET-NC or FET-SC. Because inadequate decidualization before and during early pregnancy has been recently linked to the development of PE, it is possible that the hormonal regimens for endometrial support in FET-AC are not optimal for all women. Another possibility is that deficiencies in these hormonal regimens might be unmasked by the lack of circulating CL factors, such as RLN, that may be important for fine-tuning decidualization.

      References

        • Burton G.J.
        • Redman C.W.
        • Roberts J.M.
        • Moffett A.
        Pre-eclampsia: pathophysiology and clinical implications.
        BMJ. 2019; 366: l2381
        • Abalos E.
        • Cuesta C.
        • Grosso A.L.
        • Chou D.
        • Say L.
        Global and regional estimates of preeclampsia and eclampsia: a systematic review.
        Eur J Obstet Gynecol Reprod Biol. 2013; 170: 1-7
        • Kuklina E.V.
        • Ayala C.
        • Callaghan W.M.
        Hypertensive disorders and severe obstetric morbidity in the United States.
        Obstet Gynecol. 2009; 113: 1299-1306
      1. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy.
        Obstet Gynecol. 2013; 122: 1122-1131
        • Ghulmiyyah L.
        • Sibai B.
        Maternal mortality from preeclampsia/eclampsia.
        Semin Perinatol. 2012; 36: 56-59
        • Backes C.H.
        • Markham K.
        • Moorehead P.
        • Cordero L.
        • Nankervis C.A.
        • Giannone P.J.
        Maternal preeclampsia and neonatal outcomes.
        J Pregnancy. 2011; 2011: 214365
        • Gluckman P.D.
        • Hanson M.A.
        • Cooper C.
        • Thornburg K.L.
        Effect of in utero and early-life conditions on adult health and disease.
        N Engl J Med. 2008; 359: 61-73
        • Roberts J.M.
        • Pearson G.
        • Cutler J.
        • Lindheimer M.
        • NHLBI Working Group on Research on Hypertension During Pregnancy
        Summary of the NHLBI working group on research on hypertension during pregnancy.
        Hypertension. 2003; 41: 437-445
        • Sibai B.
        • Dekker G.
        • Kupferminc M.
        Pre-eclampsia.
        Lancet. 2005; 365: 785-799
        • Anderson C.M.
        Preeclampsia: exposing future cardiovascular risk in mothers and their children.
        J Obstet Gynecol Neonatal Nurs. 2007; 36: 3-8
        • Bellamy L.
        • Casas J.P.
        • Hingorani A.D.
        • Williams D.J.
        Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.
        BMJ. 2007; 335: 974
        • Davis E.F.
        • Lazdam M.
        • Lewandowski A.J.
        • et al.
        Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review.
        Pediatrics. 2012; 129: e1552-e1561
        • Vikse B.E.
        • Irgens L.M.
        • Leivestad T.
        • Skjaerven R.
        • Iversen B.M.
        Preeclampsia and the risk of end-stage renal disease.
        N Engl J Med. 2008; 359: 800-809
        • Williams D.
        Long-term complications of preeclampsia.
        Semin Nephrol. 2011; 31: 111-122
        • Rich-Edwards J.W.
        • Ness R.B.
        • Roberts J.M.
        Epidemiology of Pregnancy-Related Hypertension (Chapter 3)..
        in: Taylor R.N. Roberts J.M. Cunningham G.F. Lindheimer M.D. Chesley’s hypertensive disorders in pregnancy. Academic Press, San Diego2015: 37-55
        • Rich-Edwards J.W.
        • Fraser A.
        • Lawlor D.A.
        • Catov J.M.
        Pregnancy characteristics and women’s future cardiovascular health: an underused opportunity to improve women’s health?.
        Epidemiol Rev. 2014; 36: 57-70
        • Eskenazi B.
        • Fenster L.
        • Sidney S.
        • Elkin E.P.
        Fetal growth retardation in infants of multiparous and nulliparous women with preeclampsia.
        Am J Obstet Gynecol. 1993; 169: 1112-1118
        • Barker D.J.
        • Bull A.R.
        • Osmond C.
        • Simmonds S.J.
        Fetal and placental size and risk of hypertension in adult life.
        BMJ. 1990; 301: 259-262
        • Barker D.J.
        • Winter P.D.
        • Osmond C.
        • Margetts B.
        • Simmonds S.J.
        Weight in infancy and death from ischaemic heart disease.
        Lancet. 1989; 334: 577-580
        • Henderson J.T.
        • O’Connor E.
        • Whitlock E.P.
        Low-dose aspirin for prevention of morbidity and mortality from preeclampsia.
        Ann Intern Med. 2014; 161: 613-614
        • Rolnik D.L.
        • Wright D.
        • Poon L.C.
        • et al.
        Aspirin versus Placebo in Pregnancies at high risk for preterm preeclampsia.
        N Engl J Med. 2017; 377: 613-622
        • Novak J.
        • Danielson L.A.
        • Kerchner L.J.
        • et al.
        Relaxin is essential for renal vasodilation during pregnancy in conscious rats.
        J Clin Invest. 2001; 107: 1469-1475
        • Debrah D.O.
        • Novak J.
        • Matthews J.E.
        • Ramirez R.J.
        • Shroff S.G.
        • Conrad K.P.
        Relaxin is essential for systemic vasodilation and increased global arterial compliance during early pregnancy in conscious rats.
        Endocrinology. 2006; 147: 5126-5131
        • Conrad K.P.
        • Baker V.L.
        Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies.
        Am J Physiol Regul Integr Comp Physiol. 2013; 304: R69-R72
        • Danielson L.A.
        • Sherwood O.D.
        • Conrad K.P.
        Relaxin is a potent renal vasodilator in conscious rats.
        J Clin Invest. 1999; 103: 525-533
        • Chapman A.B.
        • Zamudio S.
        • Woodmansee W.
        • et al.
        Systemic and renal hemodynamic changes in the luteal phase of the menstrual cycle mimic early pregnancy.
        Am J Physiol. 1997; 273: F777-F782
        • Bernstein I.M.
        • Ziegler W.F.
        • Leavitt T.
        • Badger G.J.
        Uterine artery hemodynamic adaptations through the menstrual cycle into early pregnancy.
        Obstet Gynecol. 2002; 99: 620-624
        • Conrad K.P.
        • Stillman I.E.
        • Lindheimer M.D.
        The Kidney in Normal Pregnancy and Preeclampsia (Chapter 16)..
        in: Taylor R.N. Roberts J.M. Cunningham F.G. Lindheimer M.D. Chesley’s hypertensive disorders in pregnancy. Academic Press, San Diego2015: 335-377
        • Petersen J.W.
        • Liu J.
        • Chi Y.Y.
        • et al.
        Comparison of multiple non-invasive methods of measuring cardiac output during pregnancy reveals marked heterogeneity in the magnitude of cardiac output change between women.
        Physiol Rep. 2017; 5: e13223
        • Ghobara T.
        • Gelbaya T.A.
        • Ayeleke R.O.
        Cycle regimens for frozen-thawed embryo transfer.
        Cochrane Database Syst Rev. 2017; 7: CD003414
        • Conrad K.P.
        • Graham G.M.
        • Chi Y.Y.
        • et al.
        Potential influence of the corpus luteum on circulating reproductive and volume regulatory hormones, angiogenic and immunoregulatory factors in pregnant women.
        Am J Physiol Endocrinol Metab. 2019; 317: E677-E685
        • Jackson R.A.
        • Gibson K.A.
        • Wu Y.W.
        • Croughan M.S.
        Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis.
        Obstet Gynecol. 2004; 103: 551-563
        • Helmerhorst F.M.
        • Perquin D.A.
        • Donker D.
        • Keirse M.J.
        Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies.
        BMJ. 2004; 328: 261
        • Maman E.
        • Lunenfeld E.
        • Levy A.
        • Vardi H.
        • Potashnik G.
        Obstetric outcome of singleton pregnancies conceived by in vitro fertilization and ovulation induction compared with those conceived spontaneously.
        Fertil Steril. 1998; 70: 240-245
        • Pinborg A.
        • Wennerholm U.B.
        • Romundstad L.B.
        • et al.
        Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis.
        Hum Reprod Update. 2013; 19: 87-104
        • Salha O.
        • Sharma V.
        • Dada T.
        • et al.
        The influence of donated gametes on the incidence of hypertensive disorders of pregnancy.
        Hum Reprod. 1999; 14: 2268-2273
        • Sites C.K.
        • Wilson D.
        • Barsky M.
        • et al.
        Embryo cryopreservation and preeclampsia risk.
        Fertil Steril. 2017; 108: 784-790
        • Barsky M.
        • St Marie P.
        • Rahil T.
        • Markenson G.R.
        • Sites C.K.
        Are perinatal outcomes affected by blastocyst vitrification and warming?.
        Am J Obstet Gynecol. 2016; 215: 603.e1-603.e5
        • Chen Z.J.
        • Shi Y.
        • Sun Y.
        • et al.
        Fresh versus Frozen Embryos for Infertility in the polycystic ovary syndrome.
        N Engl J Med. 2016; 375: 523-533
        • Sazonova A.
        • Källen K.
        • Thurin-Kjellberg A.
        • Wennerholm U.B.
        • Bergh C.
        Obstetric outcome in singletons after in vitro fertilization with cryopreserved/thawed embryos.
        Hum Reprod. 2012; 27: 1343-1350
        • Wei D.
        • Liu J.Y.
        • Sun Y.
        • et al.
        Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial.
        Lancet. 2019; 393: 1310-1318
        • 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.
        Hum Reprod Update. 2019; 25: 2-14
        • 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.
        Am J Obstet Gynecol. 2019; 221: 126.e1-126.e18
        • Ishihara O.
        • Araki R.
        • Kuwahara A.
        • Itakura A.
        • Saito H.
        • Adamson G.D.
        Impact of frozen-thawed single-blastocyst transfer on maternal and neonatal outcome: an analysis of 277,042 single-embryo transfer cycles from 2008 to 2010 in Japan.
        Fertil Steril. 2014; 101: 128-133
        • Lin J.
        • Zhao J.
        • Hao G.
        • et al.
        Maternal and neonatal complications after natural vs. hormone replacement therapy cycle regimen for frozen single blastocyst transfer.
        Front Med (Lausanne). 2020; 7: 338
        • Opdahl S.
        • Henningsen A.A.
        • Tiitinen A.
        • et al.
        Risk of hypertensive disorders in pregnancies following assisted reproductive technology: a cohort study from the CoNARTaS group.
        Hum Reprod. 2015; 30: 1724-1731
        • Maheshwari A.
        • Pandey S.
        • Amalraj Raja E.
        • Shetty A.
        • Hamilton M.
        • Bhattacharya S.
        Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer?.
        Hum Reprod Update. 2018; 24: 35-58
        • Sha T.
        • Yin X.
        • Cheng W.
        • Massey I.Y.
        Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis.
        Fertil Steril. 2018; 109: 330-342.e9
        • Yang M.
        • Lin L.
        • Sha C.
        • et al.
        Which is better for mothers and babies: fresh or frozen-thawed blastocyst transfer?.
        BMC Pregnancy Childbirth. 2020; 20: 559
        • Saito K.
        • Kuwahara A.
        • Ishikawa T.
        • et al.
        Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.
        Hum Reprod. 2019; 34: 1567-1575
        • von Versen-Höynck F.
        • Schaub A.M.
        • Chi Y.Y.
        • et al.
        Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.
        Hypertension. 2019; 73: 640-649
        • Wang Z.
        • Liu H.
        • Song H.
        • et al.
        Increased risk of pre-eclampsia after frozen-thawed embryo transfer in programming cycles.
        Front Med (Lausanne). 2020; 7: 104
      2. Roelens C, Racca A, Mackens S, et al. Hum Reprod 36th Annual Meeting of the European Society for Human Reproduction and Embryology; 2020: 108–109.

        • Asserhøj L.L.
        • Spangmose A.L.
        • Aaris Henningsen A.K.
        • Clausen T.D.
        • Ziebe S.
        • Jensen R.B.
        • et al.
        Adverse obstetric and perinatal outcomes in 1,136 singleton pregnancies conceived after programmed frozen embryo transfer (FET) compared with natural cycle FET.
        Fertil Steril. 2021; 115: 947-956
        • Zaat T.R.
        • Brink A.J.
        • de Bruin J.P.
        • et al.
        Increased obstetric and neonatal risks in artificial cycles for frozen embryo transfers?.
        Reprod Biomed Online. 2021; 42: 919-929
        • Zhang J.
        • Wei M.
        • Bian X.
        • et al.
        Letrozole-induced frozen embryo transfer cycles are associated with a lower risk of hypertensive disorders of pregnancy among women with polycystic ovary syndrome.
        Am J Obstet Gynecol. 2021; 225: 59.e1-59.e9
        • Wang B.
        • Zhang J.
        • Zhu Q.
        • Yang X.
        • Wang Y.
        Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons.
        Hum Reprod. 2020; 35: 1612-1622
        • 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.
        Reprod Biol Endocrinol. 2020; 18: 36
        • Makhijani R.
        • Bartels C.
        • Godiwala P.
        • et al.
        Maternal and perinatal outcomes in programmed versus natural vitrified-warmed blastocyst transfer cycles.
        Reprod Biomed Online. 2020; 41: 300-308
        • Hu K.L.
        • Zhang D.
        • Li R.
        Endometrium preparation and perinatal outcomes in women undergoing single-blastocyst transfer in frozen cycles.
        Fertil Steril. 2021; 115: 1487-1494
        • Guan Y.
        • Fan H.
        • Styer A.K.
        • et al.
        A modified natural cycle results in higher live birth rate in vitrified-thawed embryo transfer for women with regular menstruation.
        Syst Biol Reprod Med. 2016; 62: 335-342
        • 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.
        J Assist Reprod Genet. 2019; 36: 925-933
        • Pan Y.
        • Li B.
        • Wang Z.
        • et al.
        Hormone replacement versus natural cycle protocols of endometrial preparation for frozen embryo transfer.
        Front Endocrinol (Lausanne). 2020; 11: 546532
        • Wennerholm U.B.
        • Hamberger L.
        • Nilsson L.
        • Wennergren M.
        • Wikland M.
        • Bergh C.
        Obstetric and perinatal outcome of children conceived from cryopreserved embryos.
        Hum Reprod. 1997; 12: 1819-1825
        • Conrad K.P.
        Evidence for corpus luteal and endometrial origins of adverse pregnancy outcomes in women conceiving with or without assisted reproduction.
        Obstet Gynecol Clin North Am. 2020; 47: 163-181
        • Conrad K.P.
        • Petersen J.W.
        • Chi Y.Y.
        • et al.
        Maternal cardiovascular dysregulation during early pregnancy after in vitro fertilization cycles in the absence of a corpus luteum.
        Hypertension. 2019; 74: 705-715
        • von Versen-Höynck F.
        • Narasimhan P.
        • Selamet Tierney E.S.
        • et al.
        Absent or excessive corpus luteum number is associated with altered maternal vascular health in early pregnancy.
        Hypertension. 2019; 73: 680-690
        • Conrad K.P.
        • Lingis M.
        • Sautina L.
        • et al.
        Maternal endothelial function, circulating endothelial cells, and endothelial progenitor cells in pregnancies conceived with or without in vitro fertilization.
        Am J Physiol Regul Integr Comp Physiol. 2020; 318: R1091-R1102
        • Wiegel R.E.
        • Jan Danser A.H.
        • Steegers-Theunissen R.P.M.
        • et al.
        Determinants of maternal renin-angiotensin-aldosterone-system activation in early pregnancy: insights from 2 cohorts.
        J Clin Endocrinol Metab. 2020; 105: 3505-3517
        • Founds S.A.
        • Conley Y.P.
        • Lyons-Weiler J.F.
        • Jeyabalan A.
        • Hogge W.A.
        • Conrad K.P.
        Altered global gene expression in first trimester placentas of women destined to develop preeclampsia.
        Placenta. 2009; 30: 15-24
        • Rabaglino M.B.
        • Post Uiterweer E.D.
        • Jeyabalan A.
        • Hogge W.A.
        • Conrad K.P.
        Bioinformatics approach reveals evidence for impaired endometrial maturation before and during early pregnancy in women who developed preeclampsia.
        Hypertension. 2015; 65: 421-429
        • Conrad K.P.
        • Rabaglino M.B.
        • Post Uiterweer E.D.
        Emerging role for dysregulated decidualization in the genesis of preeclampsia.
        Placenta. 2017; 60: 119-129
        • Garrido-Gomez T.
        • Dominguez F.
        • Quiñonero A.
        • et al.
        Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology.
        Proc Natl Acad Sci U S A. 2017; 114: E8468-E8477
        • Rabaglino M.B.
        • Conrad K.P.
        Evidence for shared molecular pathways of dysregulated decidualization in preeclampsia and endometrial disorders revealed by microarray data integration.
        FASEB J. 2019; 33: 11682-11695
        • Conrad K.P.
        G-protein-coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin/insulin-like family peptide receptor 1 for treatment and prevention.
        Hum Reprod Update. 2016; 22: 647-664
        • Khaw A.
        • Kametas N.A.
        • Turan O.M.
        • Bamfo J.E.
        • Nicolaides K.H.
        Maternal cardiac function and uterine artery Doppler at 11-14 weeks in the prediction of pre-eclampsia in nulliparous women.
        BJOG. 2008; 115: 369-376
        • Bosio P.M.
        • McKenna P.J.
        • Conroy R.
        • O’Herlihy C.
        Maternal central hemodynamics in hypertensive disorders of pregnancy.
        Obstet Gynecol. 1999; 94: 978-984
        • Easterling T.R.
        • Benedetti T.J.
        • Schmucker B.C.
        • Millard S.P.
        Maternal hemodynamics in normal and preeclamptic pregnancies: a longitudinal study.
        Obstet Gynecol. 1990; 76: 1061-1069
        • Du X.J.
        • Bathgate R.A.
        • Samuel C.S.
        • Dart A.M.
        • Summers R.J.
        Cardiovascular effects of relaxin: from basic science to clinical therapy.
        Nat Rev Cardiol. 2010; 7: 48-58
        • Szlachter B.N.
        • Quagliarello J.
        • Jewelewicz R.
        • Osathanondh R.
        • Spellacy W.N.
        • Weiss G.
        Relaxin in normal and pathogenic pregnancies.
        Obstet Gynecol. 1982; 59: 167-170
        • Lafayette R.A.
        • Hladunewich M.A.
        • Derby G.
        • Blouch K.
        • Druzin M.L.
        • Myers B.D.
        Serum relaxin levels and kidney function in late pregnancy with or without preeclampsia.
        Clin Nephrol. 2011; 75: 226-232
        • Post Uiterweer E.D.
        • Koster M.P.H.
        • Jeyabalan A.
        • et al.
        Circulating pregnancy hormone relaxin as a first trimester biomarker for preeclampsia.
        Pregnancy Hypertens. 2020; 22: 47-53
        • Rehfeldt M.
        • Eklund E.
        • Struck J.
        • et al.
        Relaxin-2 connecting peptide (pro-RLX2) levels in second trimester serum samples to predict preeclampsia.
        Pregnancy Hypertens. 2018; 11: 124-128
        • Levine R.J.
        • Maynard S.E.
        • Qian C.
        • et al.
        Circulating angiogenic factors and the risk of preeclampsia.
        N Engl J Med. 2004; 350: 672-683
        • Conrad K.P.
        • Taher S.
        • Chi Y.Y.
        • et al.
        Relationships between reproductive hormones and maternal pregnancy physiology in women conceiving with or without in vitro fertilization.
        Am J Physiol Regul Integr Comp Physiol. 2021; ([Epub ahead of print])
        • Sacha C.R.
        • Harris A.L.
        • James K.
        • et al.
        Placental pathology in live births conceived with in vitro fertilization after fresh and frozen embryo transfer.
        Am J Obstet Gynecol. 2020; 222: 360.e1-360.e16
        • Nakamura Y.
        • Yaguchi C.
        • Itoh H.
        • et al.
        Morphologic characteristics of the placental basal plate in in vitro fertilization pregnancies: a possible association with the amount of bleeding in delivery.
        Hum Pathol. 2015; 46: 1171-1179
        • Ogunleye O.
        • Campo B.
        • Herrera D.
        • Post Uiterweer E.D.
        • Conrad K.P.
        Relaxin confers cytotrophoblast protection from hypoxia-reoxygenation injury through the phosphatidylinositol 3-kinase-Akt/protein kinase B cell survival pathway.
        Am J Physiol Regul Integr Comp Physiol. 2017; 312: R559-R568
        • Brosens I.
        • Pijnenborg R.
        • Vercruysse L.
        • Romero R.
        The “Great Obstetrical Syndromes” are associated with disorders of deep placentation.
        Am J Obstet Gynecol. 2011; 204: 193-201
        • Redman C.W.
        • Sargent I.L.
        • Staff A.C.
        IFPA Senior Award Lecture: making sense of pre-eclampsia - two placental causes of preeclampsia?.
        Placenta. 2014; 35: S20-S25
        • D’Alterio M.N.
        • Sigilli M.
        • Succu A.G.
        • et al.
        Pregnancy outcomes in women with polycystic ovarian syndrome (PCOS).
        Minerva Obstet Gynecol. 2021; ([Epub ahead of print])
      3. Gestational hypertension and preeclampsia: ACOG Practice Bulletin, Number 222.
        Obstet Gyencol. 2020; 135: e237-e260
        • von Versen-Höynck F.
        • Strauch N.K.
        • Liu J.
        • et al.
        Effect of mode of conception on maternal serum relaxin, creatinine, and sodium concentrations in an infertile population.
        Reprod Sci. 2019; 26: 412-419
        • Smith M.C.
        • Murdoch A.P.
        • Danielson L.A.
        • Conrad K.P.
        • Davison J.M.
        Relaxin has a role in establishing a renal response in pregnancy.
        Fertil Steril. 2006; 86: 253-255
        • Roberts M.
        • Lindheimer M.D.
        • Davison J.M.
        Altered glomerular permselectivity to neutral dextrans and heteroporous membrane modeling in human pregnancy.
        Am J Physiol. 1996; 270: F338-F343
        • Moran P.
        • Baylis P.H.
        • Lindheimer M.D.
        • Davison J.M.
        Glomerular ultrafiltration in normal and preeclamptic pregnancy.
        J Am Soc Nephrol. 2003; 14: 648-652
        • Irons D.W.
        • Baylis P.H.
        • Davison J.M.
        Effect of atrial natriuretic peptide on renal hemodynamics and sodium excretion during human pregnancy.
        Am J Physiol. 1996; 271: F239-F242
        • Irons D.W.
        • Baylis P.H.
        • Butler T.J.
        • Davison J.M.
        Atrial natriuretic peptide in preeclampsia: metabolic clearance, sodium excretion and renal hemodynamics.
        Am J Physiol. 1997; 273: F483-F487
        • Chapman A.B.
        • Abraham W.T.
        • Zamudio S.
        • et al.
        Temporal relationships between hormonal and hemodynamic changes in early human pregnancy.
        Kidney Int. 1998; 54: 2056-2063
        • Lafayette R.A.
        • Druzin M.
        • Sibley R.
        • et al.
        Nature of glomerular dysfunction in pre-eclampsia.
        Kidney Int. 1998; 54: 1240-1249
        • Teichman S.L.
        • Unemori E.
        • Dschietzig T.
        • et al.
        Relaxin, a pleiotropic vasodilator for the treatment of heart failure.
        Heart Fail Rev. 2009; 14: 321-329