Frozen-thawed embryo transfer: the potential importance of the corpus luteum in preventing obstetrical complications
2020; Elsevier BV; Volume: 113; Issue: 2 Linguagem: Inglês
10.1016/j.fertnstert.2019.12.007
ISSN1556-5653
AutoresBhuchitra Singh, Lauren Reschke, James H. Segars, Valerie L. Baker,
Tópico(s)Reproductive System and Pregnancy
ResumoThe use of frozen-thawed embryo transfer (FET) has increased over the past decade with improvements in technology and increasing live birth rates. FET facilitates elective single-embryo transfer, reduces ovarian hyperstimulation syndrome, optimizes endometrial receptivity, allows time for preimplantation genetics testing, and facilitates fertility preservation. FET cycles have been associated, however, with an increased risk of hypertensive disorders of pregnancy for reasons that are not clear. Recent evidence suggests that absence of the corpus luteum (CL) could be at least partly responsible for this increased risk. In a recent prospective cohort study, programmed FET cycles (no CL) were associated with higher rates of preeclampsia and preeclampsia with severe features compared with modified natural FET cycles. FET cycles are commonly performed in the context of a programmed cycle in which the endometrium is prepared with the use of exogenous E2 and P. In these cycles, ovulation is suppressed and therefore the CL is absent. The CL produces not only E2 and P, but also vasoactive products, such as relaxin and vascular endothelial growth factor, which are not replaced in a programmed FET cycle and which are hypothesized to be important for initial placentation. Emerging evidence has also revealed other adverse obstetrical and perinatal outcomes, including postpartum hemorrhage, macrosomia, and post-term birth specifically in programmed FET cycles compared with natural FET cycles. Despite the widespread use of FET, the optimal protocol with respect to live birth rate, maternal health, and perinatal outcomes has yet to be determined. Future practice regarding FET should be based on high-quality evidence, including rigorous controlled trials. The use of frozen-thawed embryo transfer (FET) has increased over the past decade with improvements in technology and increasing live birth rates. FET facilitates elective single-embryo transfer, reduces ovarian hyperstimulation syndrome, optimizes endometrial receptivity, allows time for preimplantation genetics testing, and facilitates fertility preservation. FET cycles have been associated, however, with an increased risk of hypertensive disorders of pregnancy for reasons that are not clear. Recent evidence suggests that absence of the corpus luteum (CL) could be at least partly responsible for this increased risk. In a recent prospective cohort study, programmed FET cycles (no CL) were associated with higher rates of preeclampsia and preeclampsia with severe features compared with modified natural FET cycles. FET cycles are commonly performed in the context of a programmed cycle in which the endometrium is prepared with the use of exogenous E2 and P. In these cycles, ovulation is suppressed and therefore the CL is absent. The CL produces not only E2 and P, but also vasoactive products, such as relaxin and vascular endothelial growth factor, which are not replaced in a programmed FET cycle and which are hypothesized to be important for initial placentation. Emerging evidence has also revealed other adverse obstetrical and perinatal outcomes, including postpartum hemorrhage, macrosomia, and post-term birth specifically in programmed FET cycles compared with natural FET cycles. Despite the widespread use of FET, the optimal protocol with respect to live birth rate, maternal health, and perinatal outcomes has yet to be determined. Future practice regarding FET should be based on high-quality evidence, including rigorous controlled trials. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/56968-29433 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/56968-29433 Frozen-thawed embryo transfer (FET) has increased dramatically over the past decade as the indications for the procedure have expanded, in part owing to improvements associated with vitrification compared with older slow-freeze methods (1Rienzi L. Gracia C. Maggiulli R. LaBarbera A.R. Kaser D.J. Ubaldi F.M. et al.Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance.Hum Reprod Update. 2017; 23: 139-155PubMed Google Scholar). In the United States, embryo cryopreservation with subsequent FET has increased from 7.9% of cycles in 2004 to 40.7% in 2013 (2Christianson MS, Sun F, Zhang H, Stern JE, Polotsky AJ. Trends in utilization of cryopreserved embryos in the United States from 2004–2013: an analysis of 411,811 cycles. Presented at the European Society of Human Reproduction and Embryology, Geneva, Switzerland, July 2–5, 2017.Google Scholar), with similar increases globally (3Casper R.F. Yanushpolsky E.H. Optimal endometrial preparation for frozen embryo transfer cycles: window of implantation and progesterone support.Fertil Steril. 2016; 105: 867-872Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 4Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion2016 assisted reproductive technology: national summary report. Centers for Disease Control and Prevention, Atlanta2018https://www.cdc.gov/art/pdf/2016-report/ART-2016-National-Summary-Report.pdfDate accessed: January 2, 2019Google Scholar, 5Adamson G.D. de Mouzon J. Chambers G.M. Zegers-Hochschild F. Mansour R. Ishihara O. et al.International Committee for Monitoring Assisted Reproductive Technology: world report on assisted reproductive technology 2011.Fertil Steril. 2018; 110: 1067-1080Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). Moreover, the use of the freeze-only strategy, with cryopreservation of all potentially viable embryos, has steadily increased in recent years (6Roque 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: 2-14Crossref PubMed Scopus (185) Google Scholar, 7Shapiro B.S. Daneshmand S.T. Garner F.C. Aguirre M. Hudson C. Clinical rationale for cryopreservation of entire embryo cohorts in lieu of fresh transfer.Fertil Steril. 2014; 102: 3-9Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). This strategy facilitates elective single-embryo transfer, reduces the risk of ovarian hyperstimulation syndrome, and allows time for results from preimplantation genetic testing (PGT) to return. In addition, women are dramatically increasing their use of fertility preservation, necessitating the need for interval FETs (8Donnez J. Dolmans M.M. Fertility preservation in women.N Engl J Med. 2017; 377: 1657-1665Crossref PubMed Scopus (405) Google Scholar). Further potential benefits of FET include a decrease in the incidence of low birth weight, small for gestational age, preterm birth, placenta previa, placental abruption, and perinatal mortality compared with fresh embryo transfer (ET) (9Ginstrom 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.e18Abstract Full Text Full Text PDF Scopus (119) Google Scholar, 10Sha 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.e9Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). Although less convincingly proven, some studies have suggested that FET is associated with a higher live birth rate compared with fresh ET, potentially because of better endometrial receptivity associated with FET (6Roque 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: 2-14Crossref PubMed Scopus (185) Google Scholar, 11Wang A. Santistevan A. Hunter Cohn K. Copperman A. Nulsen J. Miller B.T. et al.Freeze-only versus fresh embryo transfer in a multicenter matched cohort study: contribution of progesterone and maternal age to success rates.Fertil Steril. 2017; 108: 254-261.e4Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). Compelling data indicate that cryopreserved embryos must be transferred to the uterus during a critical endometrial window for establishment of pregnancy (12Bergh P.A. Navot D. The impact of embryonic development and endometrial maturity on the timing of implantation.Fertil Steril. 1992; 58: 537-542Abstract Full Text PDF PubMed Google Scholar). Commonly used protocols for FET in ovulatory women are the natural cycle, modified natural cycle, stimulated cycle, and programmed cycle. With a natural cycle, a dominant follicle matures, producing E2 which leads to development and thickening of the uterine lining (endometrium). Ovulation occurs naturally, and the ovulation site becomes the corpus luteum (CL), a functional ovarian cyst producing P which allows the endometrium to become receptive to implantation of the embryo. A modified natural cycle is very similar to the natural cycle, except that ovulation is triggered by injection of hCG rather than by the spontaneous LH surge, and luteal phase support with the use of P may be prescribed (3Casper R.F. Yanushpolsky E.H. Optimal endometrial preparation for frozen embryo transfer cycles: window of implantation and progesterone support.Fertil Steril. 2016; 105: 867-872Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). In a stimulated cycle, ovulation is induced with either clomiphene citrate, letrozole, or gonadotropins, resulting in one or more CLs. In contrast, in a programmed cycle, exogenous E2 and P lead to development of the endometrium. The ovary is suppressed, and thus there is no development of a dominant follicle, ovulation does not occur, and there is no CL. The timing of the transfer is based on the number of days elapsed after initiation of exogenous P. Intramuscular P in oil is preferred to be administered because recent data support superiority of this route of administration over vaginal P in the absence of the CL (13Devine K. Richter K.S. Widra E.A. McKeeby J.L. Vitrified blastocyst transfer cycles with the use of only vaginal progesterone replacement with Endometrin have inferior ongoing pregnancy rates: results from the planned interim analysis of a three-arm randomized controlled noninferiority trial.Fertil Steril. 2018; 109: 266-275Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). In clinical practice, the programmed cycle is popular because it involves less monitoring and the ET can be scheduled on a convenient day for the patient and the practice. Despite the widespread use of FET, the optimal protocol with respect to live birth rate and pregnancy outcome has yet to be determined (14Ghobara T. Gelbaya T.A. Ayeleke R.O. Cycle regimens for frozen-thawed embryo transfer.Cochrane Database Syst Rev. 2017; : CD003414Google Scholar, 15Mackens S. Santos-Ribeiro S. van de Vijver A. Racca A. van Landuyt L. Tournaye H. et al.Frozen embryo transfer: a review on the optimal endometrial preparation and timing.Hum Reprod. 2017; 32: 2234-2242Crossref PubMed Scopus (117) Google Scholar). Multiple studies have demonstrated an increased risk for hypertensive disorders of pregnancy associated with in vitro fertilization (IVF) particularly with FET (6Roque 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: 2-14Crossref PubMed Scopus (185) Google Scholar, 10Sha 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.e9Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 16Wong K.M. van Wely M. Mol F. Repping S. Mastenbroek S. Fresh versus frozen embryo transfers in assisted reproduction.Cochrane Database Syst Rev. 2017; : CD011184Google Scholar, 17Sazonova A. Kallen 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: 1343-1350Crossref PubMed Scopus (170) Google Scholar, 18Maheshwari 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: 35-58Crossref PubMed Google Scholar, 19Sites C.K. Wilson D. Barsky M. Bernson D. Bernstein I.M. Boulet S. Zhang Y. Embryo cryopreservation and preeclampsia risk.Fertil Steril. 2017; 108: 784-790Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 20Opdahl S. Henningsen A.A. Tiitinen A. Bergh C. Pinborg A. Romundstad P.R. et al.Risk of hypertensive disorders in pregnancies following assisted reproductive technology: a cohort study from the CONARTAS group.Hum Reprod. 2015; 30: 1724-1731Crossref PubMed Scopus (108) Google Scholar, 21Chen Z.J. Shi Y. Sun Y. Zhang B. Liang X. Cao Y. et al.Fresh versus frozen embryos for infertility in the polycystic ovary syndrome.N Engl J Med. 2016; 375: 523-533Crossref PubMed Scopus (387) Google Scholar, 22Ishihara 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: 128-133Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). Some of the studies reporting an increased risk of preeclampsia with IVF grouped both fresh (multiple CLs) and frozen-thawed (frequently absent CL) transfers together within the category of IVF (23Pandey S. Shetty A. Hamilton M. Bhattacharya S. Maheshwari A. Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis.Hum Reprod Update. 2012; 18: 485-503Crossref PubMed Scopus (449) Google Scholar, 24Qin J. Liu X. Sheng X. Wang H. Gao S. Assisted reproductive technology and the risk of pregnancy-related complications and adverse pregnancy outcomes in singleton pregnancies: a meta-analysis of cohort studies.Fertil Steril. 2016; 105: 73-85.e1–6Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, 25Tandberg A. Klungsoyr K. Romundstad L.B. Skjaerven R. Pre-eclampsia and assisted reproductive technologies: consequences of advanced maternal age, interbirth intervals, new partner and smoking habits.BJOG. 2015; 122: 915-922Crossref PubMed Scopus (38) Google Scholar, 26Thomopoulos C. Salamalekis G. Kintis K. Andrianopoulou I. Michalopoulou H. Skalis G. et al.Risk of hypertensive disorders in pregnancy following assisted reproductive technology: overview and meta-analysis.J Clin Hypertens. 2017; 19: 173-183Crossref Scopus (25) Google Scholar). Most studies that directly compared fresh ET versus FET reported higher risk with FET for hypertensive disorders of pregnancy (10Sha 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.e9Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 18Maheshwari 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: 35-58Crossref PubMed Google Scholar, 19Sites C.K. Wilson D. Barsky M. Bernson D. Bernstein I.M. Boulet S. Zhang Y. Embryo cryopreservation and preeclampsia risk.Fertil Steril. 2017; 108: 784-790Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 20Opdahl S. Henningsen A.A. Tiitinen A. Bergh C. Pinborg A. Romundstad P.R. et al.Risk of hypertensive disorders in pregnancies following assisted reproductive technology: a cohort study from the CONARTAS group.Hum Reprod. 2015; 30: 1724-1731Crossref PubMed Scopus (108) Google Scholar, 21Chen Z.J. Shi Y. Sun Y. Zhang B. Liang X. Cao Y. et al.Fresh versus frozen embryos for infertility in the polycystic ovary syndrome.N Engl J Med. 2016; 375: 523-533Crossref PubMed Scopus (387) Google Scholar, 22Ishihara 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: 128-133Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). Perhaps one could hypothesize that there is something different about transferring “second-string” embryos in an FET. Maybe in the available datasets, the better embryos were transferred first in a fresh cycle and those that remain for FET were more likely to lead to abnormal placentation. This “second-string” hypothesis is unlikely to be correct, given that hypertensive disorders were still noted to be higher with FET even when considering freeze-only cycles in which all embryos (including the best ones) were frozen. A meta-analysis performed by Roque et al. (6Roque 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: 2-14Crossref PubMed Scopus (185) Google Scholar) including 11 studies with 5,379 patients reported a significant overall increase in elective FET compared with fresh frozen transfer (risk ratio [RR] 1.12, 95% confidence interval [CI] 1.01–1.24). The RR of preeclampsia was 1.79 (1.03–3.09) for elective FET versus fresh ET. One may also hypothesize that perhaps FET has a higher risk of preeclampsia because of some differences among women who conceive via FET versus those who conceive via fresh ET. However, an elegantly designed Nordic study suggests that this is not the case (20Opdahl S. Henningsen A.A. Tiitinen A. Bergh C. Pinborg A. Romundstad P.R. et al.Risk of hypertensive disorders in pregnancies following assisted reproductive technology: a cohort study from the CONARTAS group.Hum Reprod. 2015; 30: 1724-1731Crossref PubMed Scopus (108) Google Scholar). In that study, the investigators examined the risk of hypertensive disorders of pregnancy for women who conceived twice with the use of assisted reproductive technology (ART), with each woman essentially serving as her own control. The FET was always associated with a trend for a higher risk for hypertensive disorders, regardless of whether the FET led to the first or the second pregnancy. If both pregnancies for an individual woman were conceived with FET, the risk for hypertensive disorders remained elevated in both the first and the second pregnancy. Overall, the literature strongly suggests that FET increases the risk of preeclampsia. But the reasons for this increased risk are not clear. Over a decade ago, Kirk Conrad proposed the hypothesis that absence of the CL in the programmed cycles that are commonly used for FET may lead to an increased risk of abnormal maternal cardiovascular adaptation to pregnancy and subsequent increased risk of preeclampsia (27Conrad 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: 69-72Crossref PubMed Scopus (75) Google Scholar). Why might absence of the CL in programmed cycles increase the risk for hypertensive disorders of pregnancy? This hypothesis is biologically plausible because the CL produces not only E2 and P, but also vasoactive products such as relaxin, vascular endothelial growth factor (VEGF), and angiogenic metabolites of estrogen (28Sherwood O.D. Relaxin.in: Knobil E. Neill J.D. Greenwald G.S. Markert C.L. Pfaff D.W. The physiology of reproduction. 2nd ed. Raven Press, New York1994: 861-1008Google Scholar, 29Johnson M.R. Abdalla H. Allman A.C. Wren M.E. Kirkland A. Lightman S.L. Relaxin levels in ovum donation pregnancies.Fertil Steril. 1991; 56: 59-61Abstract Full Text PDF PubMed Google Scholar, 30von Versen–Höynck F. Strauch N.K. Fleischmann R. Chi Y.Y. Keller-Wood M. Conrad K.P. Baker V.L. Effect of corpora lutea number on renal electrolyte levels in early pregnancy.Reprod Sci. 2019; 26: 412-419Crossref PubMed Scopus (44) Google Scholar). Before the establishment of the placenta as a source of pregnancy-maintaining reproductive hormones, such as P and estrogen, the CL serves as an important source of reproductive hormones. Specifically, the vasoactive products of the CL are hypothesized to be important for initial placentation, and abnormal early placentation has been proposed to be a critical step in the development of preeclampsia (31de Paco C. Kametas N. Rencoret G. Strobl I. Nicolaides K.H. Maternal cardiac output between 11 and 13 weeks of gestation in the prediction of preeclampsia and small for gestational age.Obstet Gynecol. 2008; 111: 292-300Crossref PubMed Scopus (81) Google Scholar, 32Khalil A. Garcia-Mandujano R. Maiz N. Elkhouli M. Nicolaides K.H. Longitudinal changes in maternal hemodynamics in a population at risk for pre-eclampsia.Ultrasound Obstet Gynecol. 2014; 44: 197-204Crossref PubMed Scopus (35) Google Scholar, 33Katsipi I. Stylianou K. Petrakis I. Passam A. Vardaki E. Parthenakis F. et al.The use of pulse wave velocity in predicting pre-eclampsia in high-risk women.Hypertens Res. 2014; 37: 733-740Crossref Scopus (21) Google Scholar, 34Khaw 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: 369-376Crossref PubMed Scopus (62) Google Scholar, 35Weissgerber T.L. Milic N.M. Milin-Lazovic J.S. Garovic V.D. Impaired flow-mediated dilation before, during, and after preeclampsia: a systematic review and meta-analysis.Hypertension. 2016; 67: 415-423Crossref PubMed Scopus (71) Google Scholar). Because the relaxin and VEGF are not replaced, the programmed cycle is associated with a deficiency of these vasoactive products compared with natural, modified natural, and stimulated cycles. Findings from studies in nonhuman animal models and early studies in humans supported the hypothesis that absence of the CL could be important for maternal cardiovascular adaptation to pregnancy. Circulating relaxin is one biologically plausible mediator for any effect of absent CL (36Conrad K.P. Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia.Semin Nephrol. 2011; 31: 15-32Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 37Conrad K.P. Maternal vasodilation in pregnancy: the emerging role of relaxin.Am J Physiol Regul Integr Comp Physiol. 2011; 301: R267-R275Crossref PubMed Scopus (128) Google Scholar). Relaxin is secreted solely from the CL during human pregnancy (28Sherwood O.D. Relaxin.in: Knobil E. Neill J.D. Greenwald G.S. Markert C.L. Pfaff D.W. The physiology of reproduction. 2nd ed. Raven Press, New York1994: 861-1008Google Scholar, 29Johnson M.R. Abdalla H. Allman A.C. Wren M.E. Kirkland A. Lightman S.L. Relaxin levels in ovum donation pregnancies.Fertil Steril. 1991; 56: 59-61Abstract Full Text PDF PubMed Google Scholar). Relaxin is a potent vasodilator (38Danielson L.A. Sherwood O.D. Conrad K.P. Relaxin is a potent renal vasodilator in conscious rats.J Clin Invest. 1999; 103: 525-533Crossref PubMed Scopus (224) Google Scholar, 39Smith M.C. Danielson L.A. Conrad K.P. Davison J.M. Influence of recombinant human relaxin on renal hemodynamics in healthy volunteers.J Am Soc Nephrol. 2006; 17: 3192-3197Crossref PubMed Scopus (77) Google Scholar, 40Conrad K.P. Davison J.M. The renal circulation in normal pregnancy and preeclampsia.Am J Physiol Renal Physiol. 2014; 306: F1121-F1135Crossref PubMed Scopus (50) Google Scholar) that mediates circulatory changes, including increases in glomerular filtration rate (GFR) and effective renal plasma flow (eRPF), cardiac output, and arterial compliance in the gravid rat model (41Novak J. Danielson L.A. Kerchner L.J. Sherwood O.D. Ramirez R.J. Moalli P.A. Conrad K.P. Relaxin is essential for renal vasodilation during pregnancy in conscious rats.J Clin Invest. 2001; 107: 1469-1475Crossref PubMed Scopus (183) Google Scholar, 42Debrah 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.Endocrinol. 2006; 147: 5126-5131Crossref PubMed Scopus (102) Google Scholar) and possibly in pregnant women too, as shown in one pilot study (43Smith 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: 253-255Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). In a gravid rat model, rat relaxin-neutralizing antibody (MCA1) and control antibody (MCAF) was used in virgin and day 11 pregnant rats. The neutralizing antibody completely inhibited the gestational increase in GFR and eRPF, as well as the reduction in effective renal vascular resistance, on gestational days 11 and 14 (MCA1 vs. MCAF: P < 0.01; P < 0.05 vs. MCA1 and MCAF virgin.). This was coupled with abolishment of the reduction in myogenic reactivity in small renal arteries from pregnant rats ex vivo (27Conrad 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: 69-72Crossref PubMed Scopus (75) Google Scholar). Other vasoactive products of the CL, such as VEGF, are also not replaced during a programmed FET, and their absence could have consequences. In fact, we know little about which factors are secreted into the circulation by the CL in women that may be important for pregnancy health and are not replaced in FET protocols with absent CL. Increasing arterial compliance is a major physiologic adaptation in normal human pregnancy. Therefore, carotid-femoral pulse-wave velocity and transit time were assessed by investigators at the University of Florida (44von Versen–Höynck F. Schaub A.M. Chi Y.-Y. Chiu K.-H. Liu J. Lingis M. et al.Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum.Hypertension. 2019; 73: 640-649Crossref PubMed Scopus (123) Google Scholar).The investigators reported an attenuation of the expected decline in carotid-femoral pulse-wave velocity and rise in the carotid femoral pulse-wave transit time during the first trimester between 0-CL and combined single/multiple-CL cohorts (group-time interaction: P=.06 and P=.03, respectively). The same changes from before pregnancy in the 0-CL cohort were most striking at 10–12 weeks of gestation (P=.01 and P=.006 vs. 1 and >1 CL, respectively). In a parallel study (45von Versen–Höynck F. Narasimhan P. Selamet Tierney E.S. Martinez N. Conrad K.P. Baker V.L. Winn V.D. Absent or excessive corpus luteum number is associated with altered maternal vascular health in early pregnancy.Hypertension. 2019; 73: 680-690Crossref PubMed Scopus (63) Google Scholar) conducted with a different population of women at Stanford University (n = 85), women with absent CL (programmed cycle) did not have the expected drop in mean arterial blood pressure compared with those with 1 CL. In FET cycles, a lower reactive hyperemia index and a higher augmentation index was noted in FETs without a CL compared with FETs in a natural cycle with a CL (both P=.03). In FETs, the numbers of angiogenic and nonangiogenic circulating endothelial progenitor cell numbers were lower in the absence of a CL (P=.01 and P=.03). In another study of 184 infertile women at Stanford University (30von Versen–Höynck F. Strauch N.K. Fleischmann R. Chi Y.Y. Keller-Wood M. Conrad K.P. Baker V.L. Effect of corpora lutea number on renal electrolyte levels in early pregnancy.Reprod Sci. 2019; 26: 412-419Crossref PubMed Scopus (44) Google Scholar), levels of relaxin-2, creatinine, and electrolytes were assessed in early pregnancy. Relaxin-2 levels were undetectable in patients who had undergone programmed FET with absence of the CL. Creatinine, sodium, and total CO2 levels were significantly higher in the 0-CL group (relaxin absent) compared with all other groups (relaxin present), which was consistent with the findings by Smith et al. (43Smith 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: 253-255Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). These findings suggest potential compromise of the normal renal and osmoregulatory changes of pregnancy in the absence of a CL that could contribute to the higher risk of adverse pregnancy outcomes such as preeclampsia. Overall, these studies support the premise that absence of the CL is associated with deficient circulatory adaptations during early gestation. Such findings are of concern because multiple studies demonstrated that abnormal maternal vascular adaptation to pregnancy is linked to adverse pregnancy outcomes, including preeclampsia (31de Paco C. Kametas N. Rencoret G. Strobl I. Nicolaides K.H. Maternal cardiac output between 11 and 13 weeks of gestation in
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