Undetected, natural conception pregnancies in luteal phase stimulations-case series and review of literature.

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 >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.

Ongoing pregnancy rates in single euploid frozen embryo transfers remain unaffected by female age: a retrospective study.

RESEARCH QUESTION: Is female age a significant factor in the likelihood of an ongoing pregnancy in single euploid frozen embryo transfers (FET)? DESIGN: Retrospective study of 1923 single euploid FET cycles in 1464 women, either in a natural cycle or a hormone replacement therapy cycle. The primary outcome was the ongoing pregnancy rate (OPR). RESULTS: There were 990 (51.48%) ongoing pregnancies among 1923 included transfers. The OPR were 51.4%, 49.1%, 53.3% and 52.3% for women aged ≤35, >35-≤37, >37-≤40 and >40 years at oocyte retrieval (OCR), without a significant trend for decreasing OPR (P = 0.679). No significant differences in female age at embryo transfer (P = 0.609) and female age at OCR (P = 0.816) were found between the groups (ongoing pregnancy versus no pregnancy or miscarriage). Women who received good-quality embryos (P < 0.001), had a lower body mass index (BMI) (P < 0.001), had achieved at least one pregnancy previously (P < 0.001), and underwent natural cycle endometrial preparation (P < 0.001) were more likely to achieve an ongoing pregnancy. Multivariable regression analysis (adjusted for BMI, embryo quality and endometrial preparation) did not show a significant effect of female age at OCR on achieving an ongoing pregnancy. Compared with women aged ≤35 years, none of the age groups had significantly higher or lower OPR. A multinomial regression analysis showed that BMI, embryo quality and endometrial preparation were associated with miscarriage/no pregnancy versus ongoing pregnancy (P = 0.001, 0.001 and 0.001, respectively). Female age had no significant association with either outcome. CONCLUSIONS: Female age in itself does not have a substantial impact on the OPR in single euploid FET cycles, but the OPR is impacted significantly by embryo quality, BMI, previous parity, and a natural cycle endometrial preparation protocol.

Machine learning prediction of hypertension and diabetes in twin pregnancies using characteristics at prenatal care entry: a nationwide study.

OBJECTIVES: To develop a prediction model for hypertensive disorders in pregnancy (HDP) and gestational diabetes (GDM) in twin pregnancies utilizing characteristics at the prenatal care entry level. METHODS: Cross-sectional study using the US national live birth data between 2016 and 2021. The association of all prenatal candidate variables with HDP and GDM was tested with uni- and multi-variable logistic regression analyses. Prediction models were built with generalized linear models using the logit link function and classification and regression tree approach (XGboost) machine learning (ML) algorithm. Performance was assessed with repeated 2-fold cross-validation and performance metrics we considered were area under the curve (AUC). P value <0.001 was considered statistically significant. RESULTS: A total of 707,198 twin pregnancies were included in the HDP analysis and 723,882 twin pregnancies for the GDM analysis. The incidence of HDP and GDM significantly increased from 12.2% in 2016 to 15.4% in 2021 and from 8.1% in 2016 to 10.7% in 2021, respectively. Factors that increase the risk of HDP in twin gestations are maternal age <20, age≥35, infertility, prepregnancy DM, non-Hispanic Black population, obesity, and those with Medicaid insurance (p<0.001). Factors that more than doubled the risk are obesity class II and III (p<0.001). Factors that increase the risk of GDM in twin gestations are age <25, age≥30, history of infertility, prepregnancy hypertension, non-Hispanic Asian population, non-US nativity, and obesity (p<0.001). Factors that more than doubled the risk are maternal age ≥ 30 years, non-Hispanic Asian, and class I, II, and III maternal obesity ( p<0.001). For both HDP and GDM, the performance of the ML and logistic regression model was mostly similar with negligible difference in terms of all tested performance domains. The AUC of the final ML model for HDP and GDM were 0.62±0.004, and 0.67±0.004, respectively. CONCLUSIONS: The incidence of HDP and GDM in twin gestations is increasing. The predictive accuracy of the machine learning model for both HDP and GDM in twin gestations is similar to that of the logistic regression model. Both models had modest performance, well-calibrated, and neither had a poor fit. This article is protected by copyright. All rights reserved.

Association of fetal growth restriction and stillbirth in twin compared with singleton pregnancies.

OBJECTIVE: Twin pregnancies are at an increased risk of stillbirth compared to singletons. Fetal growth restriction (FGR) is a leading cause of perinatal mortality and morbidity, in both singleton and multiple pregnancies. Whether the contribution of FGR to stillbirth in twin pregnancies differs from that in singletons is yet to be determined. The main aim of this study was to determine the association between FGR and stillbirth in twin compared to singleton pregnancies. The secondary objectives include an assessment of the contribution of FGR to stillbirths, stratified by gestational age at delivery. Furthermore, we aimed to compare the association between FGR and stillbirth in twin pregnancies using the twin-specific versus singleton birthweight charts, stratified by chorionicity. METHODS: This was a cross-sectional study including pregnancies receiving obstetric care and birth at St George's Hospital, London. The exclusion criteria included triplet and higher order pregnancies, those resulting in miscarriage or livebirths at or prior to 23+6 weeks, or had a termination of pregnancy, or with missing data on the gestational age at birth. FGR and small for gestational age (SGA) were defined as birthweight <5th and <10th centile, respectively. While standard logistic regression was used for singleton pregnancies, the association of FGR and SGA designation with stillbirth in twin pregnancies was investigated with mixed-effects logistic regression models. For twin pregnancies, intercepts were allowed to vary for twin pairs to account for inter-twin dependency. Analyses were stratified by gestational age at delivery and chorionicity. RESULTS: The study included 95,342 singleton and 3,576 twin pregnancies. There were 494 (0.52%) stillbirths in singleton and 41 (1.15%) stillbirths in twin pregnancies (17 dichorionic and 24 monochorionic). FGR and SGA were significantly associated with stillbirth in singleton pregnancies, across all gestational ages at delivery (before 32 weeks- SGA: OR 2.36; 95% CI 1.78-3.13, p<0.001 and FGR: OR 2.67; 95% CI 2.02- 3.55, p<0.001; between 32-36 weeks- SGA: OR 2.70; 95% CI 1.71-4.31, p<0.001 and FGR: OR 2.82; 95% CI 1.78- 4.47, p<0.001; above 36 weeks- SGA: OR 3.85; 95% CI 2.83 - 5.21, p<0.001 and FGR: OR 4.43; 95% CI 3.16 - 6.12, p<0.001) A greater proportion of fetuses from twin pregnancies were diagnosed as SGA and FGR when singleton compared to the twin-specific chart was used (48.43% vs. 9.12%, and 36.73% vs. 6.23%, respectively). When stratified by gestational age at delivery, both SGA and FGR determined by the twin-specific charts were associated with significantly increased odds of having a stillbirth for those delivered before 32 weeks (SGA: OR 3.87; 95% CI 1.56-9.50, p=0.003 and FGR: OR 5.26; 95% CI 2.11-13.01, p<0.001), those delivered between 32-36 weeks (SGA: OR 6.67; 95% CI 2.11-20.41, p=0.001 and FGR: OR 9.54; 95% CI 3.01-29.40, p<0.001) and those delivered beyond 36 weeks (SGA: OR 12.68 95% CI 2.47-58,15, p=0.001 and FGR: OR 23.84; 95% CI 4.62-110.25, p<0.001), whereas the association of stillbirth with either SGA or FGR was inconsistent when analysed using singleton charts (before 32 weeks- SGA: p=0.014 and FGR: p=0.005; between 32-36 weeks- SGA: p=0.036 and FGR: p=0.008; above 36 weeks- SGA: p=0.080 and FGR: p=0.063). For dichorionic twins delivered before 32 weeks, the odds of an SGA or FGR fetus having a stillbirth was increased when analysed using twin-specific charts. In contrast, monochorionic twins delivered before 32 weeks showed lower and non-significant associations with stillbirth for both SGA and FGR cases using either twin-specific or singleton charts. In dichorionic twin pregnancies delivered between 32-36 weeks, the OR for stillbirth of SGA using twin birthweight chart was 6.70 (95% CI 0.80-56.46, p=0.059), and using singleton chart was 0.92 (95% CI 0.11-7.71, p=0.934) and statistically non-significant. Similarly, the OR for stillbirth of FGR using twin birthweight chart and singleton chart was 9.59 (95% CI 1.14-81.06, p=0.025), and 1.40 (95% CI 0.17-11.76, p=0.735), respectively. On the other hand, in monochorionic twin pregnancies delivered between 32-36 weeks, the OR for stillbirth of SGA and FGR using twin birthweight chart was 9.37 (95% CI 2.20- 37.72, p=0.001), and 13.55 (95% CI 3.12 - 55.94 p < 0.001) respectively. CONCLUSIONS: Our study demonstrates a significant association between SGA, particularly for FGR, with increased odds of stillbirths in singleton pregnancies across all gestational ages. For twin pregnancies, when twin-specific charts were used, SGA and in particular FGR were associated with a significantly increased risk of stillbirth, across all gestational ages at delivery. This article is protected by copyright. All rights reserved.

The combination of dydrogesterone and micronized vaginal progesterone can render serum progesterone level measurements on the day of embryo transfer and rescue attempts unnecessary in an HRT FET cycle.

PURPOSE: To evaluate the role of serum progesterone (P4) on the day of embryo transfer (ET) when dydrogesterone (DYD) and micronized vaginal progesterone (MVP) are combined as luteal phase support (LPS) in a hormone replacement therapy (HRT) frozen ET (FET) cycles. METHODS: Retrospective study, including single euploid HRT FET cycles with DYD and MVP as LPS and P4 measurement on ET day. Initially, patients with P4 levels < 10 ng/ml increased MVP to 400 mg/day; this "rescue" was abandoned later. RESULTS: 560 cycles of 507 couples were included. In 275 women, serum P4 level was < 10 ng/ml on the ET day. Among those with low P4 levels, MVP dose remained unchanged in 65 women (11.6%) and was increased in 210 women (37.5%). Women with P4 levels ≥ 10 ng/ml continued LPS without modification. Overall pregnancy rates in these groups were 61.5% (40/65), 54.8% (115/210), and 48.4% (138/285), respectively (p = n.s.). Association of serum P4 levels with ongoing pregnancy rates was analyzed in women without any additional MVP regardless of serum P4 levels (n = 350); multivariable analysis (adjusted for age, BMI, embryo quality (EQ)) did not show a significant association of serum P4 levels with OPR (OR 0.96, 95% CI 0.90-1.02; p = 0.185). Using inverse probability treatment weights, regression analysis in the weighted sample showed no significant association between P4 treatment groups and OP. Compared to fair EQ, the transfer of good EQ increased (OR 1.61, 95% CI 1.22-2.15; p = 0.001) and the transfer of a poor EQ decreased the odds of OP (OR 0.73, 95% CI 0.55-0.97; p = 0.029). CONCLUSION: In HRT FET cycle, using LPS with 300 mg/day MVP and 30 mg/day DYD, it appears that serum P4 measurement and increase of MVP in patients with P4 < 10 ng/ml are not necessary.

Do women with severely diminished ovarian reserve undergoing modified natural-cycle in-vitro fertilization benefit from earlier trigger at smaller follicle size?

OBJECTIVE: To evaluate whether trigger and oocyte collection at a smaller follicle size decreases the risk of premature ovulation while maintaining the reproductive potential of oocytes in women with a severely diminished ovarian reserve undergoing modified natural-cycle in-vitro fertilization. METHODS: This was a retrospective cohort study including women who had at least one unsuccessful cycle (due to no response) of conventional ovarian stimulation with a high dosage of gonadotropins and subsequently underwent a modified natural cycle with a solitary growing follicle (i.e. only one follicle > 10 mm at the time of trigger). The association between follicle size at trigger and various cycle outcomes was tested using regression analyses. RESULTS: A total of 160 ovarian stimulation cycles from 110 patients were included in the analysis. Oocyte pick-up (OPU) was performed in 153 cycles and 7 cycles were canceled due to premature ovulation. Patients who received their trigger at smaller follicle sizes (≤ 15 mm) had significantly lower rates of premature ovulation and thus higher rates of OPU (98.9% vs 90.8%; odds ratio, 9.56 (95% CI, 1.58-182.9); P = 0.039) compared with those who received their trigger at larger follicle sizes (> 15 mm). On multivariable analysis, smaller follicle sizes at trigger (> 10 to 13 mm, > 13 to 15 mm, > 15 mm to 17 mm) were not associated significantly with a lower rate of cumulus-oocyte complex (COC) retrieval, metaphase-II (MII) oocytes or blastulation when compared to the > 17-mm group. On sensitivity analysis including only the first cycle of each couple, the maturity rate among those with COC retrieval was highest in follicle sizes > 15 to 17 mm (92.3%) and > 13 to 15 mm (91.7%), followed by > 10 to 13 mm (85.7%) and lowest in the > 17-mm group (58.8%). During the study period, five euploid blastocysts developed from 48 fertilized MII oocytes with follicle sizes of 12 mm (n = 3), 14 mm (n = 1) and 16 mm (n = 1) at trigger. Of those, four were transferred and resulted in two live births, both of which developed from follicles with a size at trigger of 12 mm. CONCLUSIONS: The ideal follicle size for triggering oocyte maturation may be smaller in women with a severely diminished ovarian reserve managed on a modified natural cycle when compared to conventional cut-offs. The risk of OPU cancellation was significantly higher in women triggered at follicle size > 15 mm and the yield of mature oocytes was not adversely affected in women triggered at follicle size > 13 to 15 mm compared with > 15 to 17 mm. Waiting for follicles to reach sizes > 17mm may be detrimental to achieving optimal outcome. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.