The influence of frozen-thawed and fresh embryo transfer on utero-placental (vascular) development: the Rotterdam Periconception cohort
Authors: van Duijn Linette , Rousian Melek , Reijnders Igna F , Willemsen Sten P , Baart Esther B , Laven Joop S E , Steegers-Theunissen Régine P M 
Published: March 2021

Abstract

STUDY QUESTION
Does frozen-thawed or fresh embryo transfer (ET) influence utero-placental (vascular) development, when studied using three-dimensional (3D) ultrasound and virtual reality imaging techniques?

SUMMARY ANSWER
In the first trimester, placental developmental parameters, that is, placental volume (PV) and utero-placental vascular volume (uPVV), were comparable between pregnancies resulting from frozen-thawed ET, fresh ET and natural conception; and in the second and the third trimester, uterine artery Doppler indices were lower in pregnancies after frozen-thawed ET compared to pregnancies after fresh ET and natural conception.

WHAT IS KNOWN ALREADY
Pregnancies after frozen-thawed ET are at risk of developing placenta-related pregnancy complications. There is strong evidence that impaired first-trimester spiral artery remodelling is involved in the pathophysiology of these complications. Studies on longitudinal placental development in pregnancies with different modes of conception, that is, after frozen-thawed ET, fresh ET or natural conception, are lacking.

STUDY, DESIGN, SIZE, DURATION
Women with singleton pregnancies were included before 10 weeks of gestation, between January 2017 and July 2018, as a subcohort of the ongoing Rotterdam Periconception cohort. Results were partially validated in 722 women from the total cohort, which was conducted from November 2010 onwards.

PARTICIPANTS/MATERIALS, SETTING, METHODS
A total of 214 women, of whom 32 conceived after frozen-thawed ET, 56 conceived after fresh ET and 126 conceived naturally, were selected. PV and uPVV measurements were obtained at 7, 9 and 11 weeks of gestation by transvaginal 3D (power Doppler) ultrasound. The uterine artery pulsatility index (UtA-PI) and resistance index (UtA-RI) were measured transvaginally at 7, 9, 11 and 13 weeks and abdominally at 22 and 32 weeks of gestation by pulsed wave Doppler ultrasound. In the validation cohort, the PV was measured in 722 women. Associations between mode of conception and placental development were studied using linear mixed models.

MAIN RESULTS AND THE ROLE OF CHANCE
First-trimester parameters of placental development, that is, PV, uPVV, UtA-PI and UtA-RI, were comparable between pregnancies after frozen-thawed and fresh ET and naturally conceived pregnancies. In our validation cohort, comparable results were found for PV. However, the second- and third-trimester UtA-PI and UtA-RI in pregnancies after frozen-thawed ET were significantly lower than in pregnancies after fresh ET (βUtA-PI −0.158 (95% CI: −0.268, −0.048), P = 0.005; βUtA-RI −0.052 (95% CI: −0.089, −0.015), P = 0.006). The second- and third-trimester uterine artery indices in pregnancies after fresh ET were comparable to those in pregnancies after natural conception.

LIMITATIONS, REASONS FOR CAUTION
The main limitation of this study is the lack of power to optimally detect differences in placental development and placenta-related pregnancy outcomes between pregnancies after different modes of conception. Moreover, our population was selected from a tertiary hospital and included a relatively limited number of pregnancies. Therefore, external validity of the results should be confirmed in a larger sample size.

WIDER IMPLICATIONS OF THE FINDINGS
These findings indicate no significant impact of conception mode on early placental development and a beneficial impact for frozen-thawed ET on the second- and third-trimester Doppler indices. This suggests that frozen-thawed ET may not be as detrimental for placental perfusion as previous research has demonstrated. As the number of clinics applying the ‘freeze-all strategy’ increases, future research should focus on establishing the optimal uterine environment, with regards to hormonal preparation, prior to ET to reduce placental-related pregnancy complications after frozen-thawed ET.

STUDY FUNDING/COMPETING INTEREST(S)
This research was funded by the Erasmus MC Medical Research Advisor Committee’s ‘Health Care Efficiency Research’ program and the department of Obstetrics and Gynaecology of the Erasmus MC, University Medical Center, Rotterdam, The Netherlands. JSEL reports grants and personal fees from Ferring, personal fees from Titus Healthcare, grants and personal fees from Ansh Labs, grants from NIH, grants from Dutch Heart Association and grants from ZonMW outside the submitted work. None of the other authors have a conflict of interest.

TRIAL REGISTRATION NUMBER
Registered at the Dutch Trial Register (NTR6684).