Thin endometrial lining in single euploid embryo transfers: should we be concerned about adverse live birth outcomes?

Endometrial assessment is a standard aspect of monitoring protocols during fertility treatments. Characteristics such as the endometrial pattern and endometrial thickness have been regarded as prognostic factors for treatment success, with an endometrial thickness of less than 7 mm commonly associated with lower in vitro fertilization (IVF) pregnancy rates (1, 2). A major limitation of many of these studies is the inter/intraobserver variability in terms of endometrial thickness measurement and the heterogeneity of the study population included in various studies. Although the topics of endometrial thickness and pregnancy rates have already been addressed in several studies over the years, there is a paucity of data regarding the impact of a thin endometrial thickness on neonatal/obstetrical outcomes after an embryo transfer cycle.

Most pregnancies conceived via IVF are uncomplicated and result in healthy offspring. However, IVF-conceived pregnancies have been reported to be associated with slight increased risk of adverse perinatal outcomes such as preterm birth, low birthweight, small for gestational age, preeclampsia, and placental abnormalities. Furthermore, there is a growing body of literature investigating the effect of endometrial thickness on pregnancy and neonatal outcomes. Most of these studies are limited because of the small sample size, lack of data on the number of embryos transferred, and inconsistent day of embryo transfer (cleavage versus blastocyst stage).

In this issue of F&S Reports, Martel et al. (3) report the relationship between endometrial thickness and live birth outcomes in women undergoing a programmed frozen embryo transfer. In this retrospective cohort study from a single academic fertility center, live birth and obstetrical outcomes were reported in cycles with endometrial thickness measurements of <7 mm and ≥7 mm. The electronic medical records of all patients with a singleton live birth after a single euploid embryo transfer were reviewed. Patients with miscarriage after a euploid embryo transfer, multiple gestation (monozygotic twins), and missing data were excluded. Complete data from 492 patients were included in the analysis. The primary outcomes were neonatal birthweight and a composite obstetric complication rate defined by the presence of one of the following complications: preeclampsia or gestational hypertension, haemolysis, elevated liver enzymes, low platelet count syndrome, abnormal placentation and umbilical cord anomalies, premature rupture of membranes, oligohydramnios, or intrauterine growth restriction. The secondary outcomes were gestational age at delivery, preterm delivery rate, and rate of small for gestation age. When endometrial thickness was analyzed as a dichotomous variable with the endometrium measuring above or below 7 mm, neonates born from cycles with an endometrial thickness of <7 mm were more likely to be born at an earlier gestational age (37.3 weeks vs. 39.4 weeks, P=.01) and to have a lower birthweight (2,749.9 g vs. 3,345.2 g, P<.01). Endometrial thickness was not associated with an increased incidence of preterm birth and small for gestational age, or a composite obstetric complication outcome, even after adjusting for age and medical comorbidities.

The relationship between decreased neonatal birthweight and a thin endometrium (defined as below the 7–8-mm range) has been demonstrated in previous studies (4, 5). One previous study including 5,000 embryo transfer cycles reported that a thin endometrium (<7.5 mm) was associated with obstetric complications such as preeclampsia, placental abruption, placenta previa, small for gestational age, and preterm delivery in singleton live births with an adjusted odds ratio of 1.53 (95% confidence interval, 1.03–2.42; P=.04) even after excluding patients with previous pregnancy complications (4). In the study by Martel et al. (3), only 35 patients (7.1%) developed obstetrical complications, and only 7 patients (1.4%) had an endometrial thickness of <7 mm. With the small number of patients in the <7-mm group, this study was likely underpowered to detect a statistically significant difference, even if using nonparametric statistical analyses.

This study has inherent limitations of a retrospective study; it lacks available data on more detailed maternal characteristics such as body mass index, infertility diagnosis, and other factors that have been shown to affect neonatal weight, including smoking history and neonatal gender. Furthermore, the patients with miscarriage were excluded from this study. The relationship between endometrial thickness and miscarriage rate would be an outcome of interest to the readers and should be included in future studies. In this study, endometrial thickness was measured by different providers, and one could question the effect of interobserver variability on the endometrial measurements. However, as mentioned by the investigators, it is reassuring that their findings regarding birthweight and decreased gestational age are concordant with those of previous studies. Nonetheless, the study by Martel et al. (3) had the unique benefit of controlling for variables that hampered the interpretation of previous studies by including a homogenous group of single euploid cryopreserved and programmed embryo transfer cycles, which strengthens its conclusions.

In summary, endometrial thickness may be a valuable predictor of adverse live birth outcomes from a single euploid embryo transfer cycle. Neonates born from an endometrium of <7 mm are significantly more likely to have a lower birthweight and be born earlier than those born from an endometrium measuring 7 mm and above. This study highlights an important clinical goal of obtaining at least 7-mm endometrial thickness before transferring a frozen euploid embryo. The investigators have posed an important topic and elaborate on findings that can be helpful to counsel patients regarding possible obstetrical outcomes. However, these findings should be validated in future studies with a larger cohort of patients with a thin endometrium.