Oxford Luteal Dysfunction and Placental Insufficiency Study

The corpus luteum (CL), formed in the ovary after ovulation, secretes a range of molecules (e.g., oestradiol, progesterone, vascular endothelial growth factor [VEGF], relaxin-2) that regulate embryo implantation and placentation.1 Without a CL, early pregnancy invariably fails, unless women receive exogenous hormone replacement.2 After 8 weeks of pregnancy, the placenta takes over endogenous hormone synthesis from the CL, ensuring pregnancy maintenance until birth; this is termed the luteo-placental shift.2 3 Placental maladaptation is the principal driver of preeclampsia, a pregnancy complication that kills >70,000 women and 500,000 babies annually worldwide.4 Despite its catastrophic effects, there remains a paucity of interventions to prevent or treat preeclampsia. The best tool currently available to predict preeclampsia in the index pregnancy is a validated algorithm which can only be used at 10-14 weeks (the Fetal Medicine Foundation [FMF] Preeclampsia prediction tool, whose positive predictive value is 90%).5

The role of the CL in orchestrating placentation has recently gained prominence following a huge rise in frozen embryo transfer (FET) treatment in assisted conception.6 There are different methods of preparing the endometrium for FET. These include unmedicated regimens, relying on the woman's menstrual cycle to time embryo transfer; and medicated protocols, involving the administration of oestradiol and progesterone before embryo transfer.7 The latter suppresses the pituitary gland, preventing ovulation and the formation of a CL. Uniquely, pregnancies resulting from medicated FET cycles are the only gestations capable of reaching viability without a CL, and are only able to progress because of early hormone replacement.8

Pregnancies without a functioning CL exhibit more than double the odds of preeclampsia (odds ratio [OR] 2.13, 95% confidence interval [CI] 1.89-2.38; 4 studies; n = 22,856 women) versus pregnancies with a functioning CL,8 highlighting a crucial role of the CL in preventing placental maladaptation. Our previous work has elucidated this role by showing a strong association between low luteal serum progesterone and reduced odds of live birth (adjusted OR 0.41, 95% CI 0.18-0.91).9 10 We have also demonstrated that administering exogenous progesterone in early pregnancy significantly reduces the incidence of preeclampsia (risk ratio [RR] 0.61, 95% CI 0.41-0.92; 3 randomised controlled trials [RCTs]; I2 = 0%; n = 5,267 women).11 These findings provide a strong signal that luteal phase insufficiency plays a fundamental role in placental maladaptation, yet crucially it appears amenable to exogenous rescue.

Case-control evidence suggests an association between low serum levels of corpus luteal products, including progesterone and relaxin-2, and the risk of preeclampsia, although data remain scarce and of low quality.12 13 In addition, current practice involves screening women in early pregnancy for their risk of preeclampsia based on their history, yielding a detection rate that is at most 30%.14 Identifying blood and ultrasound markers in early pregnancy associated with the risk of developing preeclampsia later on would allow to develop diagnostic tests and therapeutic targets to prevent preeclampsia.

Therefore, this study aims to establish the association between early serum and ultrasound markers of corpus luteal function and pregnant women's risk of developing preeclampsia. By focusing on recruiting women in very early gestation (<8 weeks), we aim to develop a set of prognostic markers which will help to better identify women at high risk of developing preeclampsia as early as possible. This will allow for better risk stratification in this population, and for future trials investigating interventions to prevent preeclampsia from early gestation rather than at 12 weeks (e.g., when aspirin is currently commenced) which may be too late to effectively correct placental maladaptation.

Inclusion criteria

• Participant is willing and able to give written informed consent for participation in the study.
• Female, aged 16 years or above. As in vitro fertilisation is not undertaken in women younger than 18 years, those with pregnancies resulting from natural cycle frozen embryo transfer will be aged 18 years or above.
• Pregnancy <8 completed weeks of gestation (i.e., up to 7 weeks and 6 days' gestation).
• Conception through any of the following means: unassisted ("natural"), ovulation induction (with clomifene citrate, letrozole or gonadotropin injections, including trigger injection), intrauterine insemination (with or without ovulation induction, including trigger injection), or natural cycle frozen embryo transfer.
• Intrauterine viable pregnancy confirmed on research ultrasound scan.
• Intention to deliver at Oxford University Hospitals.

Exclusion criteria

• Unable to read, or to understand written or spoken English.
• Vaginal bleeding at first visit.
• Miscarriage at first visit, defined as fetal crown-rump length of 7 mm or longer with no visible heartbeat, OR gestational sac with a mean of 25 mm or greater in diameter with no visible fetal pole on ultrasonography.
• Evidence of ectopic pregnancy at first visit.
• Multiple pregnancy.
• Uterine pathology (e.g., uterine polyp, fibroid, septate uterus, uterus didelphys, bicornuate uterus, unicornuate uterus).
• Fresh in vitro fertilisation.
• Donor oocyte in vitro fertilisation.
• Frozen embryo transfer using hormone replacement therapy for endometrial preparation.
• Participation in any concurrent trials of medicinal products in pregnancy.