Maternal and obstetric outcomes are influenced by developmental stage and cryopreservation of transferred embryos after clomiphene citrate-based minimal stimulation IVF
Authors: Onogi Sachie , Ezoe Kenji , Kawasaki Nami , Hayashi Hiroko , Kuroda Tomoko , Takeshima Kazumi , Tanoue Kaou , Nishii Shogo , Kato Keiichi 
Published: April 2022

Abstract

STUDY QUESTION
Is the embryo transfer (ET) method associated with maternal and perinatal outcomes after minimal stimulation IVF using clomiphene citrate (CC)?

SUMMARY ANSWER
The incidence of pregnancy complications and adverse perinatal outcomes was influenced by the developmental stage (cleavage versus blastocyst stages) and cryopreservation (fresh versus vitrified) of the transferred embryos.

WHAT IS KNOWN ALREADY
Pregnancies resulting from IVF are associated with higher risks of adverse perinatal outcomes compared to natural conceptions; therefore, the next focus in reproductive medicine should be to assess whether these increased risks are attributable to IVF. Pregnancy complications and perinatal outcomes should be considered in addition to pregnancy outcomes when selecting the ET method, however, studies that describe the influence of transfer methods on perinatal and maternal outcomes are limited.

STUDY DESIGN, SIZE, DURATION
This study retrospectively analysed a large single-centre cohort. The clinical records of 36 827 women who underwent oocyte retrieval (during a CC-based minimal stimulation cycle) followed by their first ET at the fertility treatment centre between January 2008 and December 2017 were retrospectively analysed. The patients underwent a single fresh cleavage-stage ET (SFCT), single vitrified-warmed cleavage-stage ET (SVCT) or single vitrified-warmed blastocyst transfer (SVBT). This study only included one cycle per patient.

PARTICIPANTS/MATERIALS, SETTING, METHODS
Oocyte retrieval was performed following CC-based minimal ovarian stimulation. The embryos were transferred 2–3 days after retrieval or vitrified at the cleavage or blastocyst stage. The vitrified embryos were then warmed and transferred within the natural cycles. Pregnancy complications and perinatal outcomes were stratified according to the transfer methods used. Multivariate logistic regression analysis was performed to evaluate the effect of ET methods on the prevalence of pregnancy complications and congenital anomalies.

MAIN RESULTS AND THE ROLE OF CHANCE
The rates of clinical pregnancy and delivery were significantly different among the groups. We analysed pregnancy complications in 7502 singleton births (SFCT, 3395 cycles; SVCT, 586 cycles; and SVBT, 3521 cycles). Multivariate logistic regression analysis revealed that the adjusted odds ratio (AOR) for hypertensive disorders in pregnancy was significantly lower in the SVBT group than in the SFCT group [AOR, 0.72; 95% CI, 0.56–0.92]. The AOR for low-lying placenta was lower in the SVBT group than in the SFCT group (AOR, 0.34; 95% CI, 0.19–0.60). The AOR for placenta previa was lower in the SVCT and SVBT groups than in the SFCT group (AOR, 0.21; 95% CI, 0.07–0.58 versus AOR, 0.53; 95% CI, 0.38–0.75, respectively). A total of 7460 follow-up data on neonatal outcomes was analysed. The AOR for preterm delivery was lower in the SVBT group than in the SFCT group (AOR, 0.78; 95% CI, 0.64–0.94). The AOR for low birthweight was significantly lower after SVCT and SVBT than after SFCT (AOR, 0.68; 95% CI, 0.46–0.98 versus AOR, 0.57; 95% CI, 0.48–0.66, respectively). The AOR for small for gestational age was lower in the SVCT and SVBT groups than in the SFCT group (AOR, 0.68; 95% CI, 0.46–0.98 versus AOR, 0.44; 95% CI, 0.36–0.55, respectively). The AOR for large for gestational age babies was higher in the SVBT group than in the SFCT group (AOR, 1.88; 95% CI, 1.62–2.18). The incidence of each congenital anomaly was similar among the groups.

LIMITATIONS, REASONS FOR CAUTION
The study data were collected through self-reported parental questionnaires on maternal and neonatal outcomes. Our findings were not compared with the incidence of pregnancy complications and congenital anomalies in natural pregnancies. Furthermore, this study was retrospective in nature; therefore, further studies are required to ascertain the generalizability of these findings to other clinics with different protocols and/or different patient demographics.

WIDER IMPLICATIONS OF THE FINDINGS
This study demonstrated reassuring outcomes for SVBT (in terms of a lower incidence of pregnancy complications) compared to SFCT. Our findings provide valuable knowledge that will help improve perinatal and maternal outcomes in CC-based stimulation and inform couples of the possible benefits and risks of each type of ET method.

STUDY FUNDING/COMPETING INTEREST(S)
This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. The authors have no conflicts of interest to declare.

TRIAL REGISTRATION NUMBER
N/A.