RESUMEN
STUDY QUESTION: How does a natural proliferative phase (NPP) strategy for frozen embryo transfer (FET) compare with the conventional artificial (AC) and natural (NC) endometrial preparation protocols in terms of live birth rates (LBR)? SUMMARY ANSWER: This study supports the hypothesis that, just as for NC, NPP-FET may be a superior alternative to AC in terms of LBR. WHAT IS KNOWN ALREADY: Although FETs are increasing worldwide, the optimal FET protocol is still largely controversial. Despite recent evidence supporting a possibly higher efficacy and safety of NC FETs, their widespread use is limited by the difficulties encountered during cycle monitoring and scheduling. STUDY DESIGN, SIZE, DURATION: In this single center retrospective cohort study, we describe the NPP-FET protocol, in which vaginal progesterone is initiated during the proliferative phase as soon as an endometrium with a thickness of at least 7 mm is identified and ovulation is ruled out, regardless of mean diameter of the dominant follicle. PARTICIPANTS/MATERIALS, SETTING, METHODS: For comparison, we considered all blastocyst stage FET cycles preformed at a private infertility center between January 2010 and June 2022, subdivided according to the following subgroups of endometrial preparation: AC, NPP, and NC. We performed multivariable generalized estimating equations regression analysis to account for the following potential confounding variables: oocyte age at retrieval, oocyte source (autologous without preimplantation genetic testing for aneuploidies (PGT-A) versus autologous with PGT-A versus donated), number of oocytes retrieved/donated, embryo developmental stage (Day 5 versus Day 6), number of embryos transferred, quality of the best embryo transferred, and year of treatment. The main outcome measure was LBR. The secondary outcomes included hCG positive, clinical pregnancy and miscarriage rates, and the following perinatal outcomes: first trimester bleeding, second/third trimester bleeding, preterm rupture of membranes, gestational diabetes, gestational hypertensive disorders (GHD), and gestational age at delivery. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 5791 FET cycles were included in this analysis (2226 AC, 349 NPP, and 3216 NC). The LBR for FET was lower in the AC subgroup when compared to the NPP and NC (38.4%, 49.1%, and 45.2%, respectively; P < 0.01 AC versus NPP and AC versus NC). The rates of miscarriage were also lower in the NPP and NC subgroups when compared to AC (19.7%, 25.0%, and 34.9%, respectively; P < 0.01 NPP versus AC and NC versus AC). Considering perinatal outcomes, NPP-FET and NC were associated with a significantly lower first trimester bleeding compared to AC (17.3%, 14.7%, and 37.6%, respectively; P < 0.01 NPP versus AC and NC versus AC). Additionally, NC was associated with a lower rate of GHD when compared with AC (8.6% versus 14.5%, P < 0.01), while the rate following NPP-FET was 9.4%. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective design. Moreover, there was also a low number of patients in the NPP subgroup, which may have led the study to be underpowered to detect clinically relevant differences between the subgroups. WIDER IMPLICATIONS OF THE FINDINGS: Our study posits that the NPP-FET protocol may be an effective and safe alternative to both NC and AC, while still allowing for enhanced practicality in patient follow-up and FET scheduling. Further investigation on NPP-FET is warranted, with prospective studies including a larger and more homogeneous subsets of patients. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the IVI-RMA-Lisbon (2008-LIS-053-CG). The authors did not receive any funding for this study. The authors have no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.
Asunto(s)
Criopreservación , Transferencia de Embrión , Resultado del Embarazo , Humanos , Femenino , Embarazo , Transferencia de Embrión/métodos , Estudios Retrospectivos , Adulto , Criopreservación/métodos , Índice de Embarazo , Tasa de Natalidad , Nacimiento Vivo , Endometrio , Progesterona , Inducción de la Ovulación/métodos , Fertilización In Vitro/métodosRESUMEN
STUDY QUESTION: Do children born after vitrified-thawed embryo transfers (ETs) using donated oocytes have worse perinatal outcomes when compared with fresh ET? SUMMARY ANSWER: No significant difference in birthweight and prematurity rates between fresh or frozen embryo transfers (FETs) in newborns after oocyte donation was found. WHAT IS KNOWN ALREADY: Autologous singletons born after fresh ET have been previously associated with higher rates of preterm birth and low birthweight, while FETs seem to confer a higher risk of hypertensive disorders during pregnancy and macrosomia. However, studies comparing these outcomes using autologous oocytes are unable to adequately disentangle the putative detrimental consequences of embryo vitrification from the possible effects that ovarian stimulation and endometrial preparation may have on endometrial receptivity prior to ET. The oocyte donation model is, for this reason, a more appropriate setting to study these hypotheses; however so far, the information available regarding neonatal outcomes in this patient population is limited to either small and/or heterogeneous studies. STUDY DESIGN, SIZE, DURATION: We performed a multicentre retrospective cohort study including 5848 singletons born between 2009 and February 2020 following oocyte donation and single blastocyst transfer, subdivided according to whether a fresh ET or FET was performed. We also performed two additional sensitivity analyses, subgrouping the sample according to the type of endometrial preparation (natural versus artificial) and whether the donated oocytes had previously been vitrified or not. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients with a first singleton livebirth after single blastocyst transfer were compared using multivariable regression analysis to account for potential confounding factors. The primary outcome was birthweight. Secondary outcomes were birthweight z-scores and percentiles, small/large for gestational age, gestational age at delivery, gender, prematurity (<37 weeks and <32 weeks), neonatal morbidity (Apgar scores and need for neonatal intensive care) and maternal morbidity (gestational hypertensive disorders, gestational diabetes and caesarean delivery). MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference between the fresh ET and FET groups in terms of mean birthweight (3215 g versus 3200 g) and birthweight z-scores (0.03 versus 0.1), in both the unadjusted and confounder-adjusted models. However, artificial endometrial preparation was associated with a higher birthweight (3220 g versus 3105 g) and birthweight z-scores (0.06 versus -0.13) when compared with a transfer in a natural cycle. Although a 1-day statistically significant difference in gestational age at birth (275 versus 274 days) was detected, premature birth rates (<37 weeks) did not vary significantly between groups (9.9% and 11.2% for fresh ET and FET, respectively). No other statistically significant differences were found in the remaining neonatal and maternal outcomes studies between the fresh ET and FET groups. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective design and lack of information regarding congenital malformations. Moreover, the sample selection criteria that were used may limit the generalizability of our results. WIDER IMPLICATIONS OF THE FINDINGS: Perinatal outcomes did not seem to be affected significantly by the embryo vitrification process in an oocyte donation model. Hence, other factors may contribute to the hindered perinatal outcomes described in ART, particularly the potential effect that ovarian stimulation and endometrial preparation may have on endometrial receptivity. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. All authors have no conflicts to declare. TRIAL REGISTRATION NUMBER: N/A.