Embryonic morphological development is delayed in pregnancies ending in a spontaneous miscarriage
Authors: Pietersma C S , Mulders A G M G J , Willemsen S P , Graafland N , Altena A C , Koning A H J , de Bakker B S , Steegers E A P , Steegers-Theunissen R P M , Rousian M 
Published: March 2023

Abstract

STUDY QUESTION
Is there a difference in embryonic morphological development between ongoing pregnancies and live pregnancies ending in a miscarriage?

SUMMARY ANSWER
Embryonic morphological development, assessed by the Carnegie stages, is delayed in live pregnancies ending in a miscarriage compared to ongoing pregnancies.

WHAT IS KNOWN ALREADY
Pregnancies ending in a miscarriage tend to have smaller embryos and slower heart rates.

STUDY DESIGN, SIZE, DURATION
Between 2010 and 2018, 644 women with singleton pregnancies, in the periconception period, were enrolled in a prospective cohort study with follow up until 1 year after delivery. A miscarriage was registered as a non-viable pregnancy before 22 weeks gestational age, defined by an absent heartbeat by ultrasound for a previously reported live pregnancy.

PARTICIPANTS/MATERIALS, SETTING, METHODS
Pregnant women with live singleton pregnancies were included and serial three-dimensional transvaginal ultrasound scans were performed. Embryonic morphological development was assessed by the Carnegie developmental stages and evaluated using virtual reality techniques. The embryonic morphology was compared to clinically used growth parameters (i.e. crown-rump length (CRL) and embryonic volume (EV)). Linear mixed models were used to evaluate the association between miscarriage and the Carnegie stages. Logistic regression with generalized estimating equations was used to calculate the odds of a miscarriage after a delay in Carnegie stages. Adjustments were made for potential confounders or covariates and include age, parity, and smoking status.

MAIN RESULTS AND THE ROLE OF CHANCE
A total of 611 ongoing pregnancies and 33 pregnancies ending in a miscarriage were included between 7 + 0 and 10 + 3 weeks gestational age, resulting in 1127 assigned Carnegie stages for evaluation. Compared to an ongoing pregnancy, a pregnancy ending in a miscarriage is associated with a lower Carnegie stage (βCarnegie = −0.824, 95% CI −1.190; −0.458, P &lt; 0.001). A live embryo of a pregnancy ending in a miscarriage will reach the final Carnegie stage with a delay of 4.0 days compared to an ongoing pregnancy. A pregnancy ending in a miscarriage is associated with a smaller CRL (βCRL = −0.120, 95% CI −0.240; −0.001, P = 0.049) and EV (βEV = −0.060, 95% CI −0.112; −0.007, P = 0.027). The delay in Carnegie stage increases the odds of a miscarriage by 1.5% per delayed Carnegie stage (ORCarnegie = 1.015, 95% CI 1.002; 1.028, P = 0.028).

LIMITATIONS, REASONS FOR CAUTION
We included a relatively small number of pregnancies ending in a miscarriage from a study population that is recruited from a tertiary referral centre. Furthermore, results of genetic testing on the products of the miscarriages or information on the karyotype of the parents were not available.

WIDER IMPLICATIONS OF THE FINDINGS
Embryonic morphological development, assessed by the Carnegie stages, is delayed in live pregnancies ending in a miscarriage. In the future, embryonic morphology may be used to estimate the likelihood of a pregnancy continuing to the delivery of a healthy baby. This is of crucial importance for all women but in particular for those at risk of a recurrent pregnancy loss. As part of supportive care, both women and their partners may benefit from information on the prospective outcome of the pregnancy and the timely identification of a miscarriage.

STUDY FUNDING/COMPETING INTEREST(S)
The work was funded by the Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. The authors declare no conflicts of interest.

TRIAL REGISTRATION NUMBER
N/A.