Undetected, natural conception pregnancies in luteal phase stimulations—case series and review of literature
Authors: Lawrenz B , Ata B , Kalafat E , Del Gallego R , Selim S , Edades J , Fatemi H 
Published: July 2024

Abstract

STUDY QUESTION
What is the risk of an undetected natural conception pregnancy during luteal phase ovarian stimulation, and how does it impact the pregnancy's course?

SUMMARY ANSWER
The risk for an undetected, natural conception pregnancy in luteal phase ovarian stimulation is low and it appears that ovarian stimulation is unlikely to harm the pregnancy.

WHAT IS KNOWN ALREADY
Random start ovarian stimulation appears to be similarly effective as early follicular stimulation start; and it allows ovarian stimulation to be started independent of the cycle day and throughout the cycle, in accordance with the patients’ and clinics’ schedule as long as there is no intention of a fresh embryo transfer in the same cycle. Starting ovarian stimulation in the luteal phase bears the possibility of an—at the timepoint of stimulation start—undetected, natural conception pregnancy that has already occurred. There is scarce data on the incidence of this event as well as on the possible implications of ovarian stimulation on the course of an existing pregnancy.

STUDY DESIGN, SIZE, DURATION
This retrospective observational study, performed between June 2017 and January 2024, analyzed luteal phase stimulations, in which a natural conception pregnancy was detected during the ovarian stimulation treatment for IVF/ICSI. Luteal phase stimulation was defined as ovarian stimulation started after ovulation and before the next expected menstrual bleeding, with a serum progesterone (P4) level of &gt;1.5 ng/ml on the day of stimulation start or 1 day before.

PARTICIPANTS/MATERIALS, SETTING, METHODS
Women who underwent a luteal phase ovarian stimulation in a tertiary referral ART center.

MAIN RESULTS AND THE ROLE OF CHANCE
A total of 488 luteal phase stimulation cycles were included in the analysis. Luteal phase stimulation was only started after a negative serum hCG measurement on the day or 1 day before commencement of ovarian stimulation. Ten patients (2.1%) had an undetected natural conception pregnancy at the time of luteal phase stimulation start. Eight of these patients underwent an ovarian stimulation in a GnRH-antagonist protocol and two in a progestin-primed stimulation protocol (PPOS). Recombinant FSH was used as stimulation medication for all patients, the patients with a PPOS protocol received additional recombinant LH. One pregnancy (0.2%) was detected after the oocyte retrieval, the other nine pregnancies were detected either due to persistent high serum progesterone levels or due to an increasing progesterone level after an initial decrease before oocyte retrieval. In the cycles with an undetected natural conception pregnancy, the median number of stimulation days was 8 days (range: 6–11 days) and median serum hCG at detection of pregnancy was 59 IU hCG (range: 14.91–183.1). From 10 patients with a pregnancy, three patients delivered a healthy baby, two patients had ongoing pregnancies at the time of summarizing the data, three patients had biochemical pregnancies (patient age: 30, 39, and 42 years), one patient had an ectopic pregnancy which required a salpingectomy, and one patient (age: 34 years) had an early pregnancy loss.

LIMITATIONS, REASONS FOR CAUTION
The retrospective study design and the small sample size can limit the accuracy of the estimates.

WIDER IMPLICATIONS OF THE FINDINGS
Overall, there is a small risk of undetected natural conception pregnancies when luteal phase stimulation is undertaken. It appears that there are no adverse effects through either direct effect on the embryo or indirectly through a detrimental effect on the corpus luteum function on the pregnancy in our cohort.

STUDY FUNDING/COMPETING INTEREST(S)
This study did not receive funding. The authors declare that there is no conflict of interest.

TRIAL REGISTRATION NUMBER
N/A.