Effect of Oral Contraceptive Use in Relation to Fertile Years on the Risk of Endometriosis in Women with Primary Infertility: A Ten-Year Single-Centre Retrospective Analysis.

Background and Objectives: Oral contraceptives (OCs) are usually used to treat endometriosis; however, the evidence is inconsistent about whether OC use in the past, when given to asymptomatic women, is protective against the development of future disease. We aimed to assess the relationship between the use of OCs and the likelihood of discovering endometriosis, considering the length of time under OCs during their fertile age. Materials and Methods: This was a monocentric retrospective cohort study in a tertiary-care University Hospital (Department of Human Reproduction, Division of Gynaecology and Obstetrics, University Medical Centre Ljubljana, Slovenia) carried out from January 2012 to December 2022. Reproductive-aged women scheduled for laparoscopic surgery for primary infertility and subsequent histopathological diagnosis of endometriosis were compared to women without an endometriosis diagnosis. They were classified based on the ratio of years of OC use to fertile years in four subgroups: never, <25%, between 25 and 50%, and >50. Results: In total, 1923 women (390 with and 1533 without endometriosis) were included. Previous OC use was higher in those with endometriosis than controls (72.31% vs. 58.64%; p = 0.001). Overall, previous OC usage was not related to histopathological diagnosis of endometriosis (aOR 1.06 [95% CI 0.87-1.29]). Women who used OCs for less than 25% of their fertile age had reduced risk of rASRM stage III endometriosis (aOR 0.50 [95% CI 0.26-0.95]; p = 0.036) or superficial implants (aOR 0.88 [95% CI 0.58-0.95]; p = 0.040). No significant results were retrieved for other rASRM stages. Using OCs for <25%, between 25 and 50%, or >50% of fertile age did not increase the risk of developing superficial endometriosis, endometriomas, or DIE. Conclusions: When OCs are used at least once, histological diagnoses of endometriosis are not increased. A protective effect of OCs when used for less than 25% of fertile age on superficial implants may be present. Prospective research is needed to corroborate the findings due to constraints related to the study's limitations.

Reproductive Outcome After GnRH Agonist Triggering With Co-Administration of 1500 IU hCG on the Day of Oocyte Retrieval in High Responders: A Long-Term Retrospective Cohort Study.

While triggering oocyte maturation with GnRH agonist (GnRHa) seems to be safe and effective in terms of the risk of developing OHSS and the number of metaphase II oocytes, it nevertheless results in luteal phase deficiency. To date, strategies have been developed in order to rescue defective luteal phase of GnRHa triggered cycles. Our study aimed to assess the reproductive outcome of GnRHa triggered cycles combined with modified luteal support (1500 IU hCG at the day of oocyte retrieval) in women with high ovarian response and to compare the outcome with hCG triggered cycles in GnRH antagonist IVF-ICSI procedures. A retrospective cohort database review of the results of GnRH antagonist IVF-ICSI cycles was conducted at a tertiary-care IVF center in Ljubljana, Slovenia. A total of 6126 cycles, performed from January 1, 2014, to December 31, 2020, were included in the final analysis. Final oocyte maturation was performed with either 5000, 6500, or 10,000 IU hCG (women with normal ovarian response) or 0.6 mg GnRHa (buserelin), supplemented with 1500 IU hCG on the day of oocyte retrieval (in women with high ovarian response). In cases of excessive ovarian response and/or high risk of OHSS luteal support was not introduced and all good quality blastocysts were frozen. According to significant differences in patients' age and the number of oocytes in the two groups, matching by age and number of oocytes was performed. No significant differences were observed regarding pregnancy rate per embryo transfer, rate of early pregnancy loss, and livebirth rate per pregnancy between the GnRHa and hCG trigger groups, respectively. A significant difference in the number of developed embryos and blastocysts, as well as the number of frozen blastocysts, was seen in favor of the GnRHa trigger. However, the birth weight in the GnRHa trigger group was significantly lower. Conclusion: The results of our study support the use of GnRHa for final oocyte maturation in GnRH antagonist IVF cycles in women with high ovarian response. Luteal phase rescue was performed by co-administration of 1500 IU hCG on the day of oocyte retrieval and estradiol and progesterone supplementation. In our experience, such an approach results in a comparable reproductive outcome with hCG trigger group.

Does Hysteroscopic Dissection of Partial Uterine Septum Represent a Risk Factor for Placental Abnormalities in Subsequent Pregnancy Compared with Controls Undergoing Other Hysteroscopic Surgery? Results from a Large Case-Control Analysis.

BACKGROUND: Hysteroscopic septum dissection (HSD) is thought to improve fertility and pregnancy outcomes. However, the available literature suggests that uterine surgery can cause placental abnormalities in subsequent pregnancies. METHODS: A case-control study was performed at the University Medical Center of Ljubljana, Department of Human Reproduction, from 1 January 2016 to 31 December 2018. The primary outcome was the association between HSD and the occurrence of placental abnormalities. We included women who underwent HSD due to infertility. Age-matched women who underwent hysteroscopic surgery for other issues were considered as controls. In addition, we divided the groups according to conception method. Only singleton pregnancies and first delivery were considered. RESULTS: A total of 1286 women (746 who underwent HSD and 540 controls) were included in the analysis. HSD had no influence on placental abnormalities since the ratio was comparable regardless of the method of conception (113/746 vs. 69/540; p = 0.515). Infertile women who conceived naturally after HSD had a normal placentation rate comparable to women who did not undergo HSD (380/427 vs. 280/312; p = 0.2104). The rate of placental abnormalities in women who achieved pregnancy with IVF/ICSI procedures following HSD was comparable to that of women who did not undergo HSD (52/319 vs. 33/228; p = 0.5478). Placenta previa occurred significantly more often in infertile women without HSD after IVF/ICSI compared to natural conception (2/312 vs. 7/228; p = 0.0401). CONCLUSIONS: HSD was not associated with higher rate of placental abnormalities in the first singleton pregnancy compared with other hysteroscopic procedures. A higher rate of placenta previa in pregnancies following IVF/ICSI procedures, which was shown by our research, is corroborated by previous research findings.

Preterm delivery risk in infertile women who conceived after reproductive surgery: natural conception versus IVF/ICSI.

STUDY QUESTION: Is preterm delivery an infertility treatment-related adverse outcome in infertile women who conceived after reproductive surgery? SUMMARY ANSWER: Compared with matched fertile women, preterm delivery appears to be a modest infertility treatment-related adverse outcome in infertile women who have reproductive surgery then conceived naturally or after IVF/ICSI. WHAT IS KNOWN ALREADY: Most observational studies have shown that women who receive any infertility treatment are more likely to deliver preterm than do fertile women. However, studies on the outcome of pregnancies in infertile women who conceive naturally after reproductive surgery are scarce. STUDY DESIGN, SIZE, DURATION: This was a single-centre historical two-part study: cohort and matched cohort study. Anonymized data of 761 infertile women who conceived after reproductive surgery and 758 fertile women were obtained by linking three computerized databases from 1 July 2012 to 31 December 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the cohort study, we evaluated the association between the mode of conception and preterm delivery <37 and <32 gestational weeks in 703 infertile women, with a singleton pregnancy who conceived after reproductive surgery, using logistic regression adjusted for relevant co-variates to calculate the adjusted odds ratio with a 95% CI. In the matched cohort study, we evaluated preterm delivery as infertility treatment-related adverse outcome using the propensity score (PS) method. The matched cohort comprised 758 infertile women and 758 fertile women with a twin or singleton pregnancy. Infertile women conceived after reproductive surgery either naturally or through IVF/ICSI. Infertile and fertile women were matched using PS matching. Infertile and fertile women were matched for pre-defined risk factors for preterm delivery. Three infertile women out of an original 761 were not included in the analysis because they lacked all required matching variables. We performed a 1:1 matching with an optimal matching algorithm with a caliper width of the linear predictor of 0.1 standard deviations. The effect of reproductive surgery on preterm delivery was evaluated in the PS-matched sample using Pearson's χ2 test and presented as the odds ratio (OR) with 95% CI. All women delivered at the Department of Perinatology, University Medical Centre Ljubljana, Slovenia. MAIN RESULTS AND THE ROLE OF CHANCE: Among 761 infertile women who conceived after reproductive surgery, 428 (56.2%) women conceived naturally and 333 (43.8%) conceived after IVF/ICSI. The incidence of twin pregnancies was significantly lower after natural conception (2.6% vs 14.1%). Among the 703 infertile women with a singleton pregnancy, 417 (59.3%) conceived naturally and 286 (40.7%) conceived after IVF/ICSI. Adjusted for maternal age and parity in infertile women with singleton pregnancies, IVF/ICSI showed a moderate association with preterm delivery <32 weeks. Compared with natural conception after reproductive surgery, the odds for preterm delivery after IVF/ICSI was 1.07 (95% CI 0.63-1.81) <37 weeks and 2.25 (95% CI 0.80-6.34) <32 weeks. Preterm delivery appears to be a modest infertility treatment-related adverse outcome. Compared with fertile women in the PS-matched sample, infertile women who conceived after reproductive surgery either naturally or after IVF/ICSI the odds of preterm delivery <37 weeks were 1.31 (95% CI 0.97-1.78) and odds of preterm delivery <32 weeks were 1.57 (95% CI 0.78-3.18). However, none of the estimations were statistically significant. LIMITATIONS, REASONS FOR CAUTION: The main limitations of the study were the retrospective design, the heterogeneity of the types of reproductive surgery performed and underlying reproductive pathologies. The low number of preterm deliveries in the present study might influence the precision of estimations. WIDER IMPLICATIONS OF THE FINDINGS: The present study aims to alter the prevailing opinion that reproductive surgery should only be considered preceding IVF to increase implantation and pregnancy rates after IVF. It implies that in selected infertile women who have had reproductive surgery, a high rate of natural conception, a low rate of multiple pregnancies, and a modest infertility treatment-related effect on preterm delivery should be the reasons to encourage natural conception after reproductive surgery. Furthermore, by allowing for natural conception, we can avoid a high-cost invasive medical procedure. STUDY FUNDING/COMPETING INTEREST(S): The study received no funding. We have no competing interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Perinatal outcome of in vitro fertilization pregnancies in women with polycystic ovary syndrome by pregravid BMI.

OBJECTIVES: Given the adverse effects of either polycystic ovary syndrome (PCOS) or overweight/obesity, one could speculate that patients with both would fare worse than others. We sought to evaluate the relationship between pregravid BMI and pregnancy complications in PCOS patients conceived by assisted reproductive techniques (ART). METHODS: Maternal and fetal/neonatal outcomes of singleton pregnancies after assisted reproduction in women with and without PCOS were compared by pregravid body mass index (BMI, <24.9 vs. ≥25 kg/cm2). RESULTS: The study population comprised 185 with a BMI <24.9 kg/cm2 including 39 (21%) with PCOS and 146 (79%) without. We also included 84 patients with BMI ≥25 kg/cm2, involving 34 (40.5%) with PCOS and 50 (59.5%) without. PCOS (total 73 patients) was significantly more common among overweight/obese patients, OR 2.5 (95% CI 1.4, 4.4). Neonates >4,000 g were born only to the overweight/obese mothers in the PCOS group. A higher incidence of gestational diabetes, chronic hypertension, and gestational hypertension was related to pregravid overweight/obesity rather than PCOS. CONCLUSIONS: In this specific subgroup of patients conceived after assisted reproduction, pregravid BMI>25 kg/cm2 rather than PCOS itself appears to be associated with GDM and hypertensive disorders.

Effect of hysteroscopic septum resection on preterm delivery rate in singleton pregnancies.

INTRODUCTION: Uterine septum is the most common uterine anomaly and is often found during the work-up in primary infertile women. In this study, we aimed to evaluate the potential effect of hysteroscopic septum resection (HSR) on preterm delivery (PTD) in primary infertile women who had singleton pregnancies. MATERIAL AND METHODS: We analyzed 420 singleton pregnancies after primary infertility treatment and compared the PTD rates in women who underwent previous HSR (cases) and women who did not undergo previous operative hysteroscopy or cervical dilation (controls), regardless of the modality of conception (spontaneous or by in vitro fertilization). RESULTS: We did not find significant differences between cases and controls for the incidence of overall PTD rate (p = .237), PTD before 32 gestational weeks (p = .848), and between 32 and 37 gestational weeks (p = .324), premature rupture of membranes (p = .419), and neonatal birth weight (p = .129). Overall, the risk of spontaneous PTD <37 gestational weeks after HSR was not found to be significantly higher compared to controls (RR 1.29, 0.61-2.73 95% CI; p = .561). CONCLUSION: According to our results, previous HSR could be not considered a risk factor for PTD in singleton pregnancies, regardless of the modality of conception (spontaneous or by in vitro fertilization).

Is IVF/ICSI [corrected] an Independent Risk Factor for Spontaneous Preterm Birth in Singletons? A Population-Based Cohort Study.

The aim of our study was to explore the risk factors for very preterm (gestation under 32 weeks) and moderate preterm birth (gestation weeks 32-36 6/7) in singleton pregnancies in a national retrospective cohort study. We also wanted to establish whether IVF/ICSI is an independent risk factor for preterm birth after adjusting for already known confounders. We used data for 267 718 singleton births from 2002-2015 from the National Perinatal Information System of Slovenia, containing data on woman, pregnancy, birth, the postpartum period, and the neonate for each mother-infant pair. Mode of conception, maternal age, education, BMI, parity, smoking, history of cervical excision procedure, history of hysteroscopic resection of uterine septum, presence of other congenital uterine malformations, bleeding in pregnancy, preeclampsia or HELLP and maternal heart, and pulmonary or renal illness were included in the analyses. Unadjusted OR for very preterm birth after IVF-ICSI [corrected] was 2.8 and for moderate preterm birth was 1.7. After adjusting for known confounders, the OR was still significantly elevated (1.6 and 1.3, respectively). Risk factors for very preterm birth with OR higher than 2.4 were history of cervical excision procedure, resection of uterine septum, operation or having other congenital uterine malformations, and bleeding in pregnancy. Risk factors for very preterm birth with OR between 1.4 and 2.1 were age >35 years, being underweight or obese, not having professional education, smoking, first birth, preeclampsia/HELLP, and IVF/ICSI. Risk factors for moderate preterm birth with OR higher than 2.4 were history of cold knife conization and other congenital uterine malformations. We found that even after adjustment, IVF/ICSI represents a single risk factor for early and late preterm birth even after adjustment with other risks such as maternal age, smoking, or a history of invasive procedures for either cervical intraepithelial neoplasia or infertility treatment.

Spontaneous pregnancy rates after reproductive surgery.

With the development of IVF procedures, the role of reproductive surgery in the management of infertile couples has been questioned. Pregnancy rates (PR) after IVF procedures are well known, but recent data on spontaneous PR after reproductive surgery are scarce. This study aimed to prospectively evaluate how often fertility is restored by reproductive surgery and to identify which independent factors influence spontaneous pregnancy after reproductive surgery. Eight hundred eighty-eight infertile women who underwent surgery for infertility were prospectively included. Women who were referred to IVF after surgery, ceased to plan pregnancy and were lost to follow-up were excluded. Spontaneous PR was analysed for 519 women. A total of 252 (48.6%) women, including 30 treated with clomiphene citrate, conceived spontaneously in the 12-18 months observation period following surgery. Multivariate logistic regression showed that woman's age (OR 0.95, 95% CI 0.90-0.99) and duration of infertility (OR 0.86, 95% CI 0.74-0.99) significantly influence spontaneous PR. Each year of infertility lowers spontaneous PR following surgery by 14% and each year of woman's age by 5%. The study shows a relatively high percentage of women conceived spontaneously after reproductive surgery. The role of reproductive surgery in the management of infertility should be re-evaluated.

Independent factors influencing large-for-gestation birth weight in singletons born after in vitro fertilization.

PURPOSE: Higher risk for birth of singletons being large for gestational age (LGA) has been revealed after in vitro fertilization (IVF) frozen-thawed embryo-transfer (FET). This phenomenon is now being investigated, since there is a speculation that these neonates could suffer from underlying epigenetic disturbances. The aim of the study was to expose independent LGA risk factors and to identify those connected to the IVF techniques. METHODS: Altogether, 4508 singleton pregnancies and births were included in the cohort case-matched study. Two hundred eleven singleton pregnancies and births after FET and 916 after fresh embryo transfer (ET) were included into two study groups. The IVF procedures were performed at the University Medical Centre Ljubljana between 2004 and 2011. For each IVF pregnancy, three matched consecutive controls after natural conception were included. Using logistic regression models, we observed LGA connection to maternal parameters (smoking, hypertension, parity, BMI, gestational diabetes, IVF conception, FET, double ET, and ICSI procedure). RESULTS: Singletons born after FET had a significantly higher risk for being LGA (p = 0.032; OR 1.697; 95 % CI 1.047-2.752). BMI 25-30 was a significant independent risk factor for LGA in the IVF groups (FET p = 0.041, OR 2.460, 95 % CI 1.030-5.857 and fresh ET p = 0.003; OR 2.188, 95 % CI 1.297-3.691). ICSI and double ET had no significant effect on LGA occurrence. CONCLUSIONS: Besides maternal BMI, FET is a significant independent LGA risk factor in IVF patients. Other observed factors (smoking, hypertension, multiparity, GDM, ICSI procedure, or number of embryos transferred) do not influence LGA risk significantly.