Embryo development delayed in pregnancies that end in miscarriage

Embryos in pregnancies that end in miscarriage take longer to develop in the womb than those in pregnancies that result in live births, according to a study from Dutch researchers that has been published in the journal Human Reproduction.

The researchers collected data from women taking part in the ongoing Rotterdam Periconception Cohort (PREDICT study), a large prospective study embedded in patient care at Erasmus University Medical Center (Erasmus MC), Rotterdam. A total of 611 ongoing pregnancies and 33 pregnancies ending in a miscarriage were included from women recruited to the study between 2010 and 2018 when they were between seven and 10 weeks pregnant.

To study the internal and external characteristics and measurements of an embryo, known as embryo morphology, the ability to see the embryo in 3D is important. The researchers used state-of-the-art imaging technology, including 3D ultrasound with high-resolution transvaginal probes and virtual reality techniques, to create 3D holograms of the embryos. They then compared the morphology of these embryos against the established stages of embryo development for the first 10 weeks of gestation, known as the Carnegie stages.

“Without the aid of 3D and virtual reality, it is far more difficult to examine the development of the embryo,” said first author Dr Carsten Pietersma, a PhD candidate and ultrasonographer at Erasmus MC. “For instance, the 3D virtual reality technology makes it much easier to see the development of the arms and legs. In the Carnegie staging system, the curvature and position of the arms and legs have an important role. Many historic studies have examined the products of miscarriage, but this is the first time we have been able to look at the developing pregnancy while the pregnancy was still intact.”

Compared to an ongoing pregnancy, the researchers found that a pregnancy ending in a miscarriage was associated with a lower Carnegie stage and the embryo would reach the final Carnegie stage four days later than an embryo from a pregnancy that resulted in a healthy baby. A delay in Carnegie stage increased the likelihood of a miscarriage by 1.5% per delayed stage.

“We found that in the first 10 weeks of the pregnancy, embryos in pregnancies that end in a miscarriage took four days longer to develop than babies that did not miscarry,” said study leader Dr Melek Rousian, a gynaecologist at Erasmus MC. “We also found that the longer it takes for an embryo to develop, the more likely it is to miscarry.”

After the 10th week there is no staging system for embryo development, and so the researchers used foetal growth and birth weight to assess development thereafter. They found that a pregnancy ending in a miscarriage was linked to a shorter crown-rump length (distance between the crown of the head to the bottom of the embryo’s buttocks) and smaller embryonic volume.

“We are able to show a significant association between miscarriage and a delay in the early development of the embryo, even if the miscarriage was after 10 weeks of gestation,” Pietersma said.

The researchers adjusted their analyses to take account of factors that could affect pregnancy outcomes, such as whether or not the women had been pregnant previously, age, ethnicity, socio-economic status, alcohol use, smoking, and use of folic acid or other vitamin supplements. Limitations included the fact that the study featured a relatively small number of pregnancies that ended in miscarriage, and that the researchers do not know if the miscarried embryos had abnormal chromosome numbers that would have affected their non-viability.

Rousian concluded, “In the future, the ability to assess the shape and development of embryos could be used to estimate the likelihood of a pregnancy continuing to the delivery of a healthy baby. This would enable health professionals to provide counselling to women and their partners about the prospective outcome of the pregnancy and the timely identification of a miscarriage. This would be particularly useful for couples who have had previous pregnancies that have ended in miscarriage; we might be able to indicate the risk of another miscarriage or maybe offer some early reassurance.”

Image caption: Embryo developing in the womb at 10 weeks. Image credit: Dr Carsten Pietersma, Erasmus MC.