Immunomodulation for unexplained recurrent implantation failure: where are we now?

In brief: Immune dysfunction may contribute to or cause recurrent implantation failure. This article summarizes normal and pathologic immune responses at implantation and critically appraises currently used immunomodulatory therapies. Abstract: Recurrent implantation failure (RIF) may be defined as the absence of pregnancy despite the transfer of ≥3 good-quality blastocysts and is unexplained in up to 50% of cases. There are currently no effective treatments for patients with unexplained RIF. Since the maternal immune system is intricately involved in mediating endometrial receptivity and embryo implantation, both insufficient and excessive endometrial inflammatory responses during the window of implantation are proposed to lead to implantation failure. Recent strategies to improve conception rates in RIF patients have focused on modulating maternal immune responses at implantation, through either promoting or suppressing inflammation. Unfortunately, there are no validated, readily available diagnostic tests to confirm immune-mediated RIF. As such, immune therapies are often started empirically without robust evidence as to their efficacy. Like other chronic diseases, patient selection for immunomodulatory therapy is crucial, and personalized medicine for RIF patients is emerging. As the literature on the subject is heterogenous and rapidly evolving, we aim to summarize the potential efficacy, mechanisms of actions and side effects of select therapies for the practicing clinician.

How do bicornuate uteri alter pregnancy, intra-partum and neonatal risks? A population based study of more than three million deliveries and more than 6000 bicornuate uteri.

OBJECTIVES: To explore maternal and neonatal outcomes in pregnant women with bicornuate uteri. METHODS: Retrospective population-based cohort study utilizing data from the Healthcare-Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS) from 2010 to 2014. There were 3,846,342 births between 2010 and 2014, included in the study. Six thousand and 195 deliveries were to women with bicornuate uterus. The remaining deliveries without other uterine anomalies were categorized as the reference group (n=3,840,147). RESULTS: Pregnant women with bicornuate uterus were older and more likely to be obese (p=0.0001) with previous cesarean deliveries (CD) (31 vs. 17.1%, p=0.0001). After adjustment for confounders, they were more likely to experience pregnancy-induced hypertension (HTN) (aOR 1.21, 95%CI: 1.1-1.3), p=0.0001), preeclampsia (aOR 1.4, 95%CI: 1.2-1.6, p=0.0001) and placenta previa (aOR 1.7, 95%CI: 1.3-2.2, p=0.0001). Moreover, they were more likely to deliver preterm (aOR 2.8, 95%CI: 2.6-3.1, p=0.0001), deliver by CD (aOR 5, 95%CI: 3.1-4.1, p=0.0001), experience preterm pre-labor rupture of membranes (PPROM) (aOR 3.5, 95%CI: 2.6-3.1, p=0.0001), and have a placental abruption (aOR 3.0, 95%CI: 2.5-3.5, p=0.0001). There were increased risks of PPH (aOR 1.4, 95%CI: 1.2-1.6, p=0.0001), wound-complications (aOR 2.0, 95%CI: 1.5-2.7, p=0.0001), hysterectomy (aOR 2.6, 95%CI: 1.6-4.1, p=0.0001), blood-transfusion (aOR 1.7, 95%CI: 1.5-2.1, p=0.0001), and DIC (aOR 1.6, 95%CI: 1.1-2.5), p=0.014) in the group with bicornuate uteri. Also there was higher risk of SGA (aOR 2.9, 95%CI: 2.6-3.2, p=0.0001) and IUFD (aOR 2.5, 95%CI: 1.8-3.3, p=0.0001). CONCLUSIONS: Bicornuate uteri can increase risks in pregnancy by many folds. Particularly risks of: premature delivery, CD, PPROM, placental abruption, hysterectomy, SGA and IUFD were increased 250-500%.

Estimation of follicular growth-widely used, seldom studied.

We assessed whether estimation of follicular growth, rather than actual measurement of follicular size on the day of hCG trigger, affected pregnancy rates in intrauterine insemination (IUI) cycles. Patient and cycle characteristics were extracted from an existing database. Comparisons were made between the pregnant (defined as a positive beta hCG) and non-pregnant groups for the following variables: patient's age, number of previous IUI cycles, type of ovarian stimulation, endometrial thickness, number of follicles measuring 14 mm and above, pre and post wash sperm parameters, cycle day when IUI was done and number of days between last ultrasound scan and ovulation trigger. A total of 7302 cycles were included in the final analysis. In 4055 cycles (55.5%) the hCG trigger was on the day of the last ultrasound, in 2285 cycles (31.3%) the hCG trigger was 1 day after the last ultrasound, in 850 (11.6%) it was 2 days after the last ultrasound and in 112 (1.5%) it was 3 or more days after the last ultrasound. Sperm parameters, younger maternal age, and the number of follicles above 14 mm were all associated with pregnancy. No association was found between positive pregnancy test rates and the time from last ultrasound to hCG trigger. Planning IUI based on the estimation of follicular growth 1-4 days before trigger, does not affect pregnancy rates.

What type of uterine anomalies had an additional effect on pregnancy outcomes, compared to other uterine anomalies? An evaluation of a large population database.

OBJECTIVE: To compare pregnancy risks between different congenital uterine anomalies utilizing other congenital anomalies as a control group in a large population database. DESIGN, SETTING, AND SAMPLE: A retrospective population-based cohort study from the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS) included 3,846,342 births (2010-2014). Of them, 6195 deliveries were to women with bicornuate uteri, 798 with arcuate uteri, 2255 with didelphys uteri, 802 with unicornuate uteri and 1404 with septate uteri. MAIN OUTCOME MEASURES AND RESULTS: After adjustment for confounders, women with bicornuate uteri were more likely to deliver vaginally (aOR 1.4, 95%CI: 1.1-1.9), p = .01), less likely to deliver by cesarean (CD) and had lower risk of small for gestational age (SGA) (aOR 0.8, 95%CI: 0.7-0.9, p = .03) when compared to the other anomalies (aOR 0.6, 95%CI: 0.5-0.6, p = .0001). Pregnant women with arcuate uterus had lower risks of preterm delivery (PTD) (aOR 0.6, 95%CI: 0.5-0.8, p = .0001), less chance of operative vaginal delivery (aOR 0.5, 95%CI: 0.2-0.9, p = .04), and higher risk for CD (aOR 1.6, 95%CI: 1.4-2, p = .0001). Pregnant women with didelphys uteri had higher risk of preterm premature rupture of membranes (PPROM) (aOR 1.6, 95%CI: 1.3-1.9, p = .0001), PTD (aOR 1.5, 95%CI: 1.3-1.6, p = .0001), CD (aOR 1.4, 95%CI: 1.2-1.5, p = .0001) and wound complications (aOR 1.6, 95%CI: 1.1-2.4, p = .02). Pregnant unicornuate uteri had increased risks of PTD (aOR 1.4, 95%CI: 1.1-1.6, p = .0001), CD (aOR 2, 95%CI: 1.6-2.5, p = .0001) and of SGA (aOR 1.8, 95%CI: 1.4-2.3, p = .0001). Pregnant septate uteri had higher risk of chorioamnionitis (aOR 1.5, 95%CI: 1.1-2.1, p = .048) and CD (aOR 1.4, 95%CI: 1.2-1.6, p = .0001). CONCLUSIONS: We demonstrated that there are different risks for certain adverse pregnancy and neonatal outcomes in diverse uterine anomalies as compared to the other anomalies.

Among high responders, is oocyte development potential different in Rotterdam consensus PCOS vs non-PCOS patients undergoing IVF?

PURPOSE: To evaluate the oocyte potential to develop to blastocyst in Rotterdam consensus PCOS in women with hyper-responses requiring freeze-all embryos. METHODS: Retrospective, single-academic center, cohort study of 205 patients who underwent freeze-all antagonist IVF cycles for OHSS risk between 2013 and 2019. Women in the PCOS group (n = 88) were diagnosed per the 2003 Rotterdam criteria. Control patients (n = 122) had no evidence of hyperandrogenism or menstrual disturbance. Data was compared by t-tests, chi-squared tests, or multivariate logistic regression (SPSS). Frozen blastocysts were Gardner's grade BB or better. RESULTS: There was no difference in terms of number of oocytes collected (PCOS vs non-PCOS 27.7 ± 9.4 vs 25.9 ± 8.2, p = 0.157), number of MII (20.7 ± 8.0 vs 19.1 ± 6.6, p = 0.130), number of 2PN fertilized (15.6 ± 7.4 vs 14.4 ± 5.9, p = 0.220), and number of frozen blastocysts (7.8 ± 4.9 vs 7.1 ± 3.8, p = 0.272). In addition, fertilization rates (74 ± 17% vs 75 ± 17%, p = 0.730), blastulation rates per 2PN (51 ± 25% vs 51 ± 25%, p = 0.869), and blastulation rates per mature oocytes (37 ± 18% vs 37 ± 15%, p = 0.984) were all comparable between PCOS and controls, respectively. Moreover, there was no difference when comparing PCOS and controls in pregnancy rates (45/81 vs 77/122, p = 0.28) and clinical pregnancy rates (34/81 vs 54/122, p = 0.75), respectively. Multivariate logistic regression controlling for confounders failed to alter these results. CONCLUSION: PCOS subjects do not seem to have altered oocyte potential as measured by number of MII oocytes collected, fertilization, and blastulation rates when compared to high-responder controls, with similar magnitude of stimulation.

Geographic variation in semen parameters from data used for the World Health Organization semen analysis reference ranges.

OBJECTIVE: To study geographic variations in sperm parameters using data from the trials that defined the reference ranges of the World Health Organization 2021 manual. DESIGN: Retrospective evaluation of the data used to define the World Health Organization reference ranges. SETTING: Not applicable. PATIENT(S): Data from 11 studies, including 3,484 participants across 5 continents. INTERVENTION(S): The data were divided according to geographic locations. MAIN OUTCOME MEASURE(S): Differences in sperm parameters. RESULT(S): The semen volume was significantly lower in samples from Asia and Africa than in other regions. The sperm concentration was the lowest in Africa and highest in Australia. The total motile sperm count (TMSC) and total motile progressive sperm count (TMPS) were significantly lower in Africa than in other regions. The TMSC and TMPS in Asia and the United States were significantly lower than in Europe and Australia. The 5th percentile of the sperm concentration was lowest in the United States (12.5 × 106/mL). The 5th percentile for the normal sperm morphology was lowest in the United States (3%) and highest in Asia (5%). The 5th percentile for the TMSC and TMPS were lowest in Africa (TMSC, 15.08 million; TMPS, 12.06 million) and the United States (TMSC, 18.05 million; TMPS, 16.86 million) and highest in Australia (TMSC, 29.61 million; TMPS, 25.80 million). CONCLUSION(S): Significant geographic differences in sperm parameters exist, and regional fertility societies should consider adding their own reference ranges on the basis of local experience and treatment outcomes.

A comparison of frozen-thawed embryo transfer protocols in 2920 single-blastocyst transfers.

OBJECTIVE: To assess the effect of frozen-thawed embryo transfer (FET) protocol on live-birth rate (LBR) and clinical pregnancy rate (CPR), in single-vitrified-blastocyst transfer MATERIALS AND METHODS: Retrospective cohort study with FET of a single-blastocyst embryos (n = 2920 cycles) thawed 2013-2018. FET protocols were natural cycles (NC-FET) (n = 147), artificial hormone replacement treatment cycles (HRT-FET) (n = 2645), and modified NC (mNC) with hCG triggering (n = 128). Primary outcome was LBR. Adjustment for age, embryo grade, year of freezing\thawing, infertility cause, and endometrial thickness was performed. RESULTS: There were no significant differences between the groups with regard to female age, embryo grade, and endometrial thickness. LBR was higher in the mNC compared to HRT-FET cycles (38.3% vs. 20.9% P < 0.0001), and in the NC compared to HRT-FET cycles (34.7% vs. 20.9%, P = 0.0002). CPR was higher in the mNC compared to HRT-FET cycles (46.1% vs. 33.3% P = 0.0003), and in the NC compared to HRT-FET cycles (45.9% vs. 33.3%, P = 0.002). There was no significant difference in LBR or CPR between NC-FET and mNC-FET. Higher LBR with NC-FET and mNC-FET remained significant after adjusting for confounders (aOR 2.42, 95%CI 1.53-3.66, P < 0.0001). CONCLUSION: The use of the convenient artificial HRT-FET cycles must be cautiously reconsidered in light of the potential negative effect on LBR when compared with natural cycle FET.

Does increasing estrogen dose during frozen embryo transfer affect pregnancy rate?

OBJECTIVE: To assess the effect of increasing estrogen doses during hormone therapy frozen embryo transfer (HT-FET) cycles on endometrial thickness and success rates compared to patients who received fixed estrogen dose. MATERIALS AND METHODS: A retrospective study from a university-based fertility clinic during the years 2008-2021. We compared two groups: the fixed-dose group (i.e., received 6 mg estradiol dose daily until embryo transfer) and the increased-dose group (i.e., the initial estradiol dose was 6 mg daily, and was increased during the cycle). PRIMARY OUTCOME: clinical pregnancy rate. RESULTS: The study included 5452 cycles of HT-FET: 4774 cycles in the fixed-dose group and 678 cycles in the increased-dose group. Ultrasound scan on days 2-3 of the cycle showed endometrial thickness slightly different between the two groups (4.2 mm in the fixed-dose and 4.0 mm in the increased-dose group, P = 0.003). The total estrogen dose was higher, and the treatment duration was longer in the increased than the fixed-dose group (122 mg vs. 66 mg and 17 days vs. 11 days, respectively; P < 0.001). The last ultrasound scan done before the addition of progesterone showed that the endometrial thickness was significantly thicker in the fixed than the increased-dose group (9.5 mm vs. 8.3 mm; P < 0.001). The clinical pregnancy rates were 35.8% in the increased-group vs. 34.1% in the fixed-dose group; P = 0.401. CONCLUSIONS: The increased-dose group had thinner endometrium despite the higher doses of estrogen and longer treatment duration than the fixed-dose group. However, the pregnancy rates were similar between the two groups.

Effects of embryo retention during embryo transfer on IVF outcomes.

PROPOSE: To investigate embryo retention (ER) rate in embryo transfer (ET) cycles and its effects on reproductive outcomes in a large database. METHODS: A matched retrospective cohort study in a tertiary academic hospital-based reproductive center. A total of 15,321 ET cycles were performed from January 2008 to December 2018. Each woman was matched with three separate control subjects of the same age (± 1 year), embryo condition, main causes of infertility, and type of protocol used for fresh or frozen ET cycles. The main outcomes were ER rate, and implantation, clinical pregnancy, ectopic pregnancy, and live birth rates. RESULTS: The overall incidence of ER was 1.4% (213/15,321). There was no difference in the rate of ER rate in fresh ET cycles compared with frozen transfer cycles (P = 0.54). We matched 188/213 (88%) of cases in the ER group to 564 non-ER cases. There were no cases of the blood in the catheter seen in the ER group. Pregnancy outcomes were similar between the ER and the non-ER cycles: clinical pregnancy rate (31.3% vs. 36.1%, P = 0.29), implantation rate (26.2% vs. 31.3%, P = 0.2), live birth rate (20.3% vs. 24%, P = 0.53), ectopic pregnancy rate (0.5% vs. 0.4%, P = 0.18), and miscarriage rate (10.7% vs. 11.3%, P = 0.53). CONCLUSION: Our results suggest that ER rate does not affect the reproductive outcomes including clinical pregnancy rate, implantation rate, and live birth rate. Patients and physicians should not be concerned about the retention of embryos during transfer since there is no effect on pregnancy outcome.

Is controlled ovarian stimulation and insemination an effective treatment in older women with male partners with decreased total motile sperm counts?

OBJECTIVE: To assess the effect of the total motile sperm counts (TMSC) on the success of controlled ovarian stimulation (COH) and intra-uterine insemination (IUI) in women 38-42 years of age. STUDY DESIGN: A database of all women aged 38-42 years who underwent IUI with stimulation at a University Reproductive Centre between 2009 and 2018 inclusive was developed. Including stimulation with clomiphene citrate, letrozole or gonadotropins and divided into TMSC 5.00-10.0 mil and < 5.00 mil. Statistics were compared with multivariate logistic regression, t tests or Chi-squared tests. RESULTS: A total of 397 cycles of IUI in 397 patients were included, of which, 190 cycles with TMSC 5.00-10.0 and 207 cycles with TMSC < 5.00. There were no statistical differences in the baseline characteristics between the two groups including: age (P = 0.2), gravidity (P = 0.7), parity (P = 0.6), basal FSH (P = 0.2), basal E2 (P = 0.4), antral follicular count (P = 0.5) and the number of mature follicles stimulated (P = 0.2). As expected, TMSC was 7.6 ± 1.5 mil in the first group and 2.4 ± 1.6 mil in the second group (P < 0.0001). The clinical pregnancy rate per cycle in the 5.01-10.00 TMSC group was 9.5 vs. 3.4% when TMSC < 5.00 (P = 0.01). When evaluating only women 40-42 years of age (99 women in the 5.00-10.00 TMSC group and 95 in the group of TMSC < 5.00); the pregnancy rates were not statistically different between the two groups (7 vs. 7.3%, P = 1), nor was the clinical pregnancy rate (5 vs. 6.3%, P = 0.7). CONCLUSIONS: Women 38-39 years of age have poorer outcomes at COH/IUI when TMSC < 5 million than if it is 5-10 million. Once a woman is 40 years of age, this effect is lost. With TMSC 5-10 million, women 38-39 years of age have respectable outcomes at COH/IUI. Clinical pregnancy rates are very low in women 40 years of age with TMSC ≤ 10 million or 38-39 years old with TMSC < 5 million and other treatments should be offered.

The Maternal Age Cut-Off for an Increase in Composite Adverse Outcomes.

OBJECTIVE: To investigate whether there is a specific maternal age cut-off at which there is an increase in maternal and neonatal adverse outcomes. METHODS: A retrospective study comparing maternal and neonatal outcomes between nulliparous women of different ages. The receiver operating characteristic model with the Youden index was used to find the best age cut-off using cesarean delivery (CD) and composite adverse outcomes. A multivariable logistic regression analysis was calculated after adjusting for smoking, induction of labour, epidural use, hypertensive disorders, gestational diabetes, and birth weight. RESULTS: The study included 11 343 nulliparous women. Age 28 years was found to be the cut-off age at which we found a significant increase in adverse outcomes. Women older than age 28 years had a higher risk of CD than women younger than 28 years (35.7% vs. 21.3%, P < 0.0001). They were also more likely to deliver prematurely (11.9% vs. 7.9%; P < 0.0001) and had higher rates hypertensive disorders (2.3% vs. 1.1%; P < 0.0001) and gestational diabetes mellitus (0.4% vs. 0.1%; P = 0.001). Furthermore, their babies were more likely to be growth restricted (1.1% vs. 0.3%; P < 0.0001). There were no differences in the rates of induction of labour or macrosomia. After adjusting for confounders, we found that women older than 28 years had higher risks of CD and adverse outcomes than younger women (aOR 1.9 [95% CI 1.744-2.1] and aOR 1.6 [95% CI 1.6-1.77], respectively). CONCLUSION: Increasing maternal age is independently associated with adverse maternal and neonatal outcomes with an age cut-off of 28 years. Women older than age 28 years are at higher risk for composite adverse outcomes than younger women.

Are we preventing the primary cesarean delivery at the second stage of labor following ACOG-SMFM new guidelines? Retrospective cohort study.

OBJECTIVE: In 2014, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal Fetal Medicine (SMFM) published an Obstetric Care Consensus for safe prevention of primary cesarean delivery. We aimed to assess whether these guidelines decreased the primary CD rate during the second stage of labor, in our department. DESIGN, SETTING, AND POPULATION: A retrospective cohort study of all women reaching the second stage of labor, at term, in a single university-affiliated medical center between2010 and 2017. METHODS: We compared maternal and neonatal outcomes over three year's periods:-pre-guidelines (2010-2013) vs. 2nd period - post-guidelines (2014-2017). THE MAIN OUTCOME MEASURES: CD rate at 2ndstage of labor. RESULTS: The study included 11,464 women. The CD rate in the 2nd stage of labor has increased significantly from 4% to 5.9% in the post-guidelines period (OR 1.48, 95% CI 1.16-1.89, p = .001). After a sub-analysis of specific subgroups, and adjustment for confounders, the increase was solely observed in nulliparous women (aOR 1.418, 95% CI 1.067-1.885, p = .016). Furthermore, increased odds for vaginal operative delivery were observed in the multiparous women in the post-guidelines period (2.7% vs. 4.1%, p = .046). CONCLUSIONS: The implementation of the new ACOG and SMFM guidelines was not associated with a change in the CD rate performed at the 2nd stage of labor in the whole study population. However, there was a rise in the CD rate performed at the 2nd stage in nulliparous women. Furthermore, there was an increase in operative deliveries in the whole study population, especially in multiparous women, without an apparent increase in other immediate adverse neonatal or maternal outcomes.

An evaluation of changes over time in the semen parameters data used for the World Health Organization semen analysis reference ranges.

BACKGROUND: Previous meta-analyses concluded that there is a decline in sperm parameters over time. This conclusion might be incorrect due to inherent biases or focusing only on a single parameter - sperm concentration. OBJECTIVE: To study trends in sperm parameters over the past 20 years using data from the trials that defined the reference ranges of the World Health Organization manual. MATERIALS AND METHODS: Retrospective evaluation of the data used to define the World Health Organization reference ranges. The data from 11 studies, including 3589 participants between 1996 and 2016, were divided into three period groups based on the decade of study. Differences in semen parameters' distribution were presented in boxplot. p-values were calculated by the Kruskal-Wallis rank-sum test followed by Dunn post hoc test. Analyses were conducted using the R programming language. RESULTS: A small decrease was noted in mean sperm concentrations (88.1 million/ml, 87.6 million/ml, and 77.2 million/ml for the first, second, and third decades, respectively) (p < 0.01). However, the 5th percentile of sperm concentration for the third decade was higher than the first or second decades (18 million/ml versus 14.9 million/ml and 15 million/ml, respectively). No significant differences were noted in progressive motility over the years (p = 0.32). The percent of morphologically normal sperm decreased between the first (24.2%) and the second (12.6%) periods of the study (p < 0.001) and then increased in the third decade (14.2%) (p < 0.01). Total motile sperm count (TMC) declined between the second and third decades (189 million and 153.9 million, respectively, p < 0.001), at levels unlikely to decrease fertility. However, the 5th percentile of the TMC remained stable at 24.9, 20.8, and 20.6 million, for the first, second, and third decades respectively (p = 0.36). DISCUSSION AND CONCLUSION AND RELEVANCE: Trends in sperm parameters over the last three decades do not seem to be clinically significant.

Early exploration of COVID-19 vaccination safety and effectiveness during pregnancy: interim descriptive data from a prospective observational study.

OBJECTIVE: During December 2020, a massive vaccination program was introduced in our country. The Pfizer-BioNTech, BNT162b2 vaccine was first offered exclusively to high-risk population, such as medical personnel (including pregnant women). In this study we compare short term outcomes in vaccinated vs. non-vaccinated pregnant women. METHODS: In this prospective observational cohort study, vaccinated and non-vaccinated pregnant women were recruited using an online Google forms questionnaire targeting medical groups on Facebook and WhatsApp. A second questionnaire was sent one month after the first one for interim analysis. Our primary outcome was composite complications in vaccinated and non-vaccinated groups, considered any of the following: vaginal bleeding, pregnancy loss, hypertension, gestational diabetes, and preterm birth. Secondary outcomes included: vaccine side effects, diagnosis of COVID-19 since the last questionnaire, prevalence of vaccinated participants, and reasons for refusal to be vaccinated. RESULTS: Overall, 432 women answered the first questionnaire, of which 326 responses were received to the second questionnaire. Vaccination rate increased from 25.5% to 62% within a month. Maternal age, gestational age at enrollment, nulliparity and number of children were similar in both groups. The rate of composite pregnancy complications was similar between vaccinated and non-vaccinated group (15.8% vs 20.1%, p = 0.37), respectively. The risk for COVID-19 infection was significantly lower in the vaccinated group (1.5% vs 6.5%, p = 0.024, Odds Ratio: 4.5, 95% confidence interval 1.19-17.6). CONCLUSIONS: mRNA vaccine during pregnancy does not seem to increase the rate of pregnancy complications and is effective in prevention of COVID-19 infection.

The effect of LH rise during artificial frozen-thawed embryo transfer (FET) cycles.

PURPOSE: To evaluate the association between a rise in serum luteinizing hormone (LH) levels during artificial frozen-thawed embryo transfer (FET) cycles and clinical pregnancy rate. METHODS: A retrospective cohort study of women undergoing artificial FET cycles. We compared cycles in which LH double itself from the early follicular phase and further (group A) to cycles without a rise in LH (group B). Endometrium preparation was achieved by administration of 2 mg three times per day estradiol valerate tablets. Embryo transfer (ET) was conducted after achieving endometrial thickness > 7 mm and vaginal progesterone was added according to the embryo's age. A beta-hCG was measured 13-14 days after ET. Clinical pregnancy was diagnosed on transvaginal ultrasound. RESULTS: Data from 984-FET cycles were retrieved. LH, exogenous estradiol (E2), progesterone values, endometrial thickness, and pregnancy outcomes were available in all patients. From 984-FET cycles, 629 (63.9%) had a doubling, and 355 (36.07%) had no rise in LH. Patients mean age was 30 years, similar in both groups. A multivariable logistic regression analysis was calculated to assess the effect of LH rise and pregnancy outcomes, after adjusting for confounders including a rise in E2 level and endometrial thickness. In this model, there was no association between doubling LH values and pregnancy rates (adjusted odds ratio: 1.06, 95% CI: 0.75-1.5, P = 0.74). CONCLUSION: LH rise during artificial FET cycles does not alter pregnancy rates. Apparently, hormonal monitoring of LH levels may not yield useful information in the artificial FET cycle and may be omitted. LAY SUMMARY: Supplementation of estradiol, a hormone produced by the ovaries, starting at the beginning of the menstrual cycle of an artificially frozen embryo transfer (FET) can lead to a rise in luteinizing hormone (LH), the hormone that induces ovulation. Such a rise in LH may interfere with embryo implantation, the process where the embryo attaches to the inner lining of the uterus and, therefore, could affect the chances of pregnancy. The current study is the first to assess the effect of a dynamic rise in LH levels during FET cycles on pregnancy rates. This study found no difference in pregnancy rates between FET cycles where the LH doubled compared to cycles without such a rise in LH. Larger, prospective studies should be conducted to assess the impact of LH elevation on pregnancy outcomes.

The impact of nurses' and physicians' shift change on obstetrical outcomes.

PURPOSE: To evaluate the effect around nurses' shift change and on-call physicians' shift change on obstetrical outcomes. METHODS: A retrospective study of women who had an attempt of labor in a single-medical center, January 2006-December 2017. Obstetrical outcomes were compared between the time around nurses' shift change (6:00-8:00, 14:00-16:00, and 22:00-00:00) to the rest of the day, and between the time around on-call physicians' shift change (6:00-8:00, 14:00-16:00) to the rest of the day. RESULTS: 32,861 women were included, 7826 deliveries occurred during nurses' shift-change, and 25,035 deliveries occurred during the rest of the day. The groups had similar general and obstetrical characteristics, with no statistical difference in cesarean delivery rate (10% vs. 9.8%, P = 0.45) (Table 1). Nurses' shift change had no measurable effect on obstetrical outcomes, including induction of labor, preterm labor, 5-min-Apgar score and cord pH value, except PPH which was less likely to occur during nurses' shift change period (3.8% vs. 4.4%, P = 0.045) (Table 2). From 32,861 deliveries, 5155 deliveries occurred during on-call physicians' shift-change, and 27,706 deliveries occurred during the rest of the day. Induction\augmentation of labor and epidural analgesia were less likely to happen during on-call physicians' shift change (34.4% vs. 38%, P < 0.0001, 59.6% vs. 61.8%, P = 0.003, respectively) (Table 3). The two groups had similar obstetrical outcomes, without statistical difference in cesarean delivery rate (10% vs. 9.8%, P = 0.63) (Table 4). Table 1 General and obstetric characteristics of women giving birth during the time of nurses shift change versus during the rest of the day Variable Change of nurses shifts (n = 7826) All other hours of the day (n = 25,035) P value Maternal age, y 30.3 ± 5.1 30.2 ± 5.2 0.09 Gestational age at birth (weeks) 39.7 ± 1.09 39.8 ± 1.10 0.55 Nulliparity 2077 (35%) 7067 (37%) 0.01 Induction\augmentation of labor 2905 (37) 9368 (38) 0.62 Epidural analgesia 4746 (61) 15,396 (62) 0.16 Neonatal birth weight, g 3340 ± 422 3330 ± 423 0.06 Data is presented as mean ± S.D or N (%) Table 2 Maternal and neonatal adverse outcomes of women giving birth during the time of nurses shift change versus during the rest of the day Variable (%) Change of nurses shifts (n = 7826) All other hours of the day (n = 25,035) P value Vacuum assisted delivery 615 (7.9) 2002 (8.0) 0.69 Cesarean delivery 788 (10) 2443 (9.8) 0.45 Postpartum hemorrhage 294 (3.8) 1089 (4.4) 0.045 Third- and fourth-degree perineal laceration 106 (1.4) 372 (1.5%) 0.51 5-min Apgar score < 7 39 (0.5) 139 (0.6) 0.65 Umbilical pH < 7.2 170 (23) 580 (23) 0.96 Prolonged second stage 190 (2.5) 559 (2.2) 0.22 Maternal and fetal composite adverse outcome* 1309 (16.7%) 4219 (16.9%) 1.00 Data is presented as N (%) *Maternal and fetal composite adverse outcome was defined as the presence of any of the following: vacuum delivery, CD, prolonged second stage, postpartum hemorrhage, third and fourth degree perineal laceration, 5-min Apgar score < 7 and umbilical cord pH < 7.2 Table 3 General and obstetric characteristics of women giving birth during the time of the on-call physicians shift change versus during the rest of the day Variable Change of physicians shifts (n = 5155) All other hours of the day (n = 27,706) P value Maternal age, years 30.3 ± 5.1 30.2 ± 5.2 0.38 Gestational age at birth (weeks) 39.8 ± 1.09 39.8 ± 1.10 0.95 Nulliparity (%) 1303 (33.4) 7841 (37) < 0.0001 Induction\augmentation of labor (%) 1769 (34.3) 10,504 (38) < 0.0001 Epidural analgesia (%) 3067 (59.6) 17,075 (61.8) 0.003 Neonatal birth weight (gr) 3345 ± 416 3330 ± 424 0.019 Data is presented as mean ± S.D or N (%) Table 4 Maternal and neonatal adverse outcomes of women giving birth during the time of physicians on-call shift change versus during the rest of the day Variable (%) Change of physicians shifts (n = 5155) All other hours of the day (n = 27,706) P value Vacuum assisted delivery 397 (7.7) 2220 (8.0) 0.45 Cesarean delivery 517 (10.0) 2714 (9.8) 0.63 Postpartum hemorrhage 209 (4.1) 1174 (4.3) 0.54 Third- and fourth-degree perineal laceration 67 (1.3) 411 (1.5) 0.31 5-min Apgar score < 7 22 (0.5) 156 (0.6) 0.30 Umbilical pH < 7.2 94 (20.3) 656 (23.3) 0.15 Prolonged second stage 127 (2.5%) 622 (2.3%) 0.36 Maternal and fetal composite adverse outcome* 852 (16.5%) 4676 (16.9%) 1.00 Data is presented as N (%) *Maternal and fetal composite adverse outcome was defined as the presence of any of the following: vacuum delivery, CD, prolonged second stage, postpartum hemorrhage, third and fourth degree perineal laceration, 5-min Apgar score < 7 and umbilical cord pH < 7.2 CONCLUSION: Nurses' shift change and on-call physicians' shift change does not appear to be associated with an increase in adverse maternal or neonatal outcomes.

Induction of labor versus expectant management among women with macrosomic neonates: a retrospective study.

Background: The macrosomic fetus predisposes a variety of adverse maternal and perinatal outcomes. Although older studies have shown no benefit in inducing women of suspected macrosomic fetuses, more updated studies show different information.Objectives: The aim of our study was to compare induction of labor versus expectant management among women with macrosomic neonates weighing more than 4000 g at term (between 37°/7 and 416/7 weeks' gestation).Study design: This was a retrospective cohort study of all live-born singleton pregnancies with macrosomic newborns who were delivered at our institution between 1 January 2000 and 1 June 2015. We compared the outcomes of induction of labor, at each gestational age (GA), between 37 and 41 weeks (study group) with ongoing pregnancy. The primary outcome was cesarean section (CS) rate. Secondary outcomes were composite maternal and neonatal outcome and birth injuries.Results: Overall, out of 3095 patients with macrosomic newborns who were included in the study, 795 women (25.7%) underwent induction of labor. The cesarean section rate was not found to be significantly different between the groups at all gestational ages, nor was the vaginal delivery rate. After adjusting for confounders, induction of labor at 40 and 41 weeks' gestation was associated with composite maternal outcome (adjusted odds ratio (aOR) 1.6, 95% confidence interval (CI): 1.3-2.1; aOR 1.7, 95% CI: 1.3-2.2, respectively) and composite neonatal outcome (aOR 1.6, 95% CI: 1.1-2.4; aOR 1.8, 95% CI: 1.1-2.9). Induction of labor at 40 weeks' gestation was also associated with increased risk of birth injuries (aOR 2.9, 95% CI: 1.4-6).Conclusions: Compared with ongoing pregnancy, induction of labor of women with macrosomic neonates between 37 and 41 weeks of gestation does not reduce the CS rate, nor does it increase the vaginal delivery rate. Moreover, induction of labor of those women beyond 39 weeks' gestation is associated with composite adverse maternal/neonatal outcome, specifically birth injuries.

Who may accompany the parturient to the delivery room?

OBJECTIVE: To assess the association of the attendant of the parturient (husband or mother or both), on labor duration, mode of delivery, maternal and neonatal complications. STUDY DESIGN: A retrospective cohort study, over a 4-year period, of women admitted to the delivery room accompanied by their husband, their mother or both. Medical records were reviewed for demographic, medical and obstetrical history. RESULTS: Overall, 3029 patients were included, 2192 were accompanied by their husband; 127 were accompanied by their mother and 710 were accompanied by both. Women accompanied by their husbands were significantly older and more likely to be multiparous than women accompanied by their mother (30.2 years vs. 27.8 years, P < 0.001 and 60% vs. 48.8%, P = 0.02, respectively). Compared to women supported during labor by their mothers, women supported only by their husbands spent less hours in the delivery room (from admission to delivery) (11.1 h vs. 13.7 h, P = 0.02). While the nature of the attendant had no influence on the mode of delivery among nulliparous women (p = 0.13), multiparous women supported by the mothers had a significantly higher rate of cesarean delivery compared to those supported only by their husband or by both (OR = 2.07, 95% CI = [1.317-3.246], P = 0.002, OR = 3.33, 95% CI = [1.623-6.849], P = 0.001, respectively). CONCLUSIONS: Women supported by their mothers during labor have a longer second stage of labor, a decreased rate of vaginal delivery and an increased risk for cesarean delivery compared to women supported by their husbands. Future large prospective studies are needed to confirm our observation and to find causative affect.

Differences in outcomes between cesarean section in the second versus the first stages of labor.

OBJECTIVE: We aimed to compare maternal morbidity and mortality of cesarean sections (CS) in the second versus first stage of labor. STUDY DESIGN: Retrospective study of all CS at a single, university-affiliated medical center, between January 2010 and December 2014. Eligibility was limited to term, singleton pregnancies with cephalic presentation. Maternal outcomes of second-stage CS were compared to those of first-stage CS. The primary outcome was defined as estimated blood loss >1000 ml. RESULTS: Overall, 1004 women met the inclusion criteria, of which 290 (29%) had a second-stage CS and 714 (71%) had a first-stage CS. Women in the second-stage CS group had a higher nulliparity and hypertensive disorders rates and a lower rate of previous CS. Second-stage CS was associated with more than double the rate of estimated blood loss >1000 ml (9.7% versus 3.8%, p<.001), and more prone to unintentional uterine incision extension, uterine atony, hemoglobin decrease >2 g/l and antibiotic treatment for suspected endometritis. In a multivariable logistic regression model, second-stage CS was found to be independently associated with unintentional uterine incision extension (OR 6.8, 95% CI 4.1-11.2), uterine atony (OR 3.3, 95% CI 1.4-8.0) and antibiotic treatment for suspected endometritis (OR 2.6, 95% CI 1.4-5.1), but not with excessive blood loss (OR 1.5, 95% CI 0.8-2.8). Additionally, failed assisted vaginal delivery prior to second-stage CS was not associated with a higher rate of complications. CONCLUSION: Second-stage CS is associated with higher rates of adverse maternal outcomes, mainly unintentional uterine incision extension, uterine atony, and suspected endometritis.