Multifetal Pregnancy After Implementation of a Publicly Funded Fertility Program.

Importance: A publicly funded fertility program was introduced in Ontario, Canada, in 2015 to increase access to fertility treatment. For in vitro fertilization (IVF), the program mandated an elective single-embryo transfer (eSET) policy. However, ovulation induction and intrauterine insemination (OI/IUI)-2 other common forms of fertility treatment-were more difficult to regulate in this manner. Furthermore, prior epidemiologic studies only assessed fetuses at birth and did not account for potential fetal reductions that may have been performed earlier in pregnancy. Objective: To examine the association between fertility treatment and the risk of multifetal pregnancy in a publicly funded fertility program, accounting for both fetal reductions and all live births and stillbirths. Design, Setting, and Participants: This population-based, retrospective cohort study used linked administrative health databases at ICES to examine all births and fetal reductions in Ontario, Canada, from April 1, 2006, to March 31, 2021. Exposure: Mode of conception: (1) unassisted conception, (2) OI/IUI, or (3) IVF. Main Outcomes and Measures: The main outcome was multifetal pregnancy (ie, a twin or higher-order pregnancy). Modified Poisson regression generated adjusted relative risks (ARRs) and derived population attributable fractions (PAFs) for multifetal pregnancies attributable to fertility treatment. Absolute rate differences (ARDs) were used to compare the era before eSET was promoted (2006-2011) with the era after the introduction of the eSET mandate (2016-2021). Results: Of all 1 724 899 pregnancies, 1 670 825 (96.9%) were by unassisted conception (mean [SD] maternal age, 30.6 [5.2] years), 24 395 (1.4%) by OI/IUI (mean [SD] maternal age, 33.1 [4.4] years), and 29 679 (1.7%) by IVF (mean [SD] maternal age, 35.8 [4.7] years). In contrast to unassisted conception, individuals who received OI/IUI or IVF tended to be older, reside in a high-income quintile neighborhood, or have preexisting health conditions. Multifetal pregnancy rates were 1.4% (95% CI, 1.4%-1.4%) for unassisted conception, 10.5% (95% CI, 10.2%-10.9%) after OI/IUI, and 15.5% (95% CI, 15.1%-15.9%) after IVF. Compared with unassisted conception, the ARR of any multifetal pregnancy was 7.0 (95% CI, 6.7-7.3) after OI/IUI and 9.9 (95% CI, 9.6-10.3) after IVF, with corresponding PAFs of 7.1% (95% CI, 7.1%-7.2%) and 13.4% (95% CI, 13.3%-13.4%). Between the eras of 2006 to 2011 and 2016 to 2021, multifetal pregnancy rates decreased from 12.9% to 9.1% with OI/IUI (ARD, -3.8%; 95% CI, -4.2% to -3.4%) and from 29.4% to 7.1% with IVF (ARD, -22.3%; 95% CI, -23.2% to -21.6%). Conclusions and Relevance: In this cohort study of more than 1.7 million pregnancies in Ontario, Canada, a publicly funded IVF program mandating an eSET policy was associated with a reduction in multifetal pregnancy rates. Nevertheless, ongoing strategies are needed to decrease multifetal pregnancy, especially in those undergoing OI/IUI.

The role of maternal age on the risk of preterm birth among singletons and multiples: a retrospective cohort study in Lombardy, Norther Italy.

BACKGROUND: All over the world, especially in the developed countries, maternal age at birth is rising. This study aimed to assess the role of maternal age on the occurrence of preterm birth (PTB) in a large birth cohort of Lombardy Region, Northern Italy. METHODS: This population-based study used data from regional healthcare utilization databases of Lombardy to identify women who delivered between 2007 and 2017. PTBs were defined as births before 37 completed weeks of gestation and considered according to the gestational age (two categories: < 32 weeks and 32 to 36 weeks). Six maternal age groups were defined (< 20, 20-24, 25-29, 30-34, 35-39, ≥40 years). Logistic regression models were fitted to estimate the crude and adjusted odds ratio (aOR) and the corresponding 95% confidence interval (CI) for PTB among different maternal age groups. Analyses were separately performed according to type of pregnancy (singletons and multiples). Reference group was the age group with the lowest frequency of PTB. RESULTS: Overall, 49,759 (6.6%) PTBs were observed, of which 41,807 were singletons and 7952 were multiples. Rates of PTB were lowest in the women aged 25-29 years among singletons and in the 30-34 years old group among multiples. Our results described a U-shaped association between maternal age and risk of PTB. In particular, the risk of a singleton PTB between 32 and 36 weeks was significantly higher for women aged less than 20 years (aOR = 1.16, CI 95%: 1.04-1.30) and more than 40 years (aOR = 1.62 CI 95%: 1.54-1.70). The highest risk of a multiple delivery between 32 and 36 weeks was observed among women aged less than 25 years and more than 40 years (aOR = 1.79, CI 95%: 1.01-3.17, aOR = 1.47, CI 95%: 1.16-1.85 and aOR = 1.36, CI 95%: 1.19-1.55 respectively for < 20, 20-24 and > 40 age categories). PTB before 32 completed weeks occurred more frequently in the same age categories, except that among multiples no association with advanced maternal age emerged. CONCLUSION: Our study suggested that, after adjustment for potential confounders, both advance and young maternal age were associated with an increased risk of PTB.

Risk factors for postpartum haemorrhage in the Northern Province of Rwanda: A case control study.

BACKGROUND: Postpartum haemorrhage (PPH) remains a major global burden contributing to high maternal mortality and morbidity rates. Assessment of PPH risk factors should be undertaken during antenatal, intrapartum and postpartum periods for timely prevention of maternal morbidity and mortality associated with PPH. The aim of this study is to investigate and model risk factors for primary PPH in Rwanda. METHODS: We conducted an observational case-control study of 430 (108 cases: 322 controls) pregnant women with gestational age of 32 weeks and above who gave birth in five selected health facilities of Rwanda between January and June 2020. By visual estimation of blood loss, cases of Primary PPH were women who changed the blood-soaked vaginal pads 2 times or more within the first hour after birth, or women requiring a blood transfusion for excessive bleeding after birth. Controls were randomly selected from all deliveries without primary PPH from the same source population. Poisson regression, a generalized linear model with a log link and a Poisson distribution was used to estimate the risk ratio of factors associated with PPH. RESULTS: The overall prevalence of primary PPH was 25.2%. Our findings for the following risk factors were: antepartum haemorrhage (RR 3.36, 95% CI 1.80-6.26, P<0.001); multiple pregnancy (RR 1.83; 95% CI 1.11-3.01, P = 0.02) and haemoglobin level <11 gr/dL (RR 1.51, 95% CI 1.00-2.30, P = 0.05). During the intrapartum and immediate postpartum period, the main causes of primary PPH were: uterine atony (RR 6.70, 95% CI 4.78-9.38, P<0.001), retained tissues (RR 4.32, 95% CI 2.87-6.51, P<0.001); and lacerations of genital organs after birth (RR 2.14, 95% CI 1.49-3.09, P<0.001). Coagulopathy was not prevalent in primary PPH. CONCLUSION: Based on our findings, uterine atony remains the foremost cause of primary PPH. As well as other established risk factors for PPH, antepartum haemorrhage and intra uterine fetal death should be included as risk factors in the development and validation of prediction models for PPH. Large scale studies are needed to investigate further potential PPH risk factors.

Dispensing of clomiphene citrate to treat infertility: medication supplied and population prevalence of assisted pregnancies and multiple births.

OBJECTIVE: To determine the proportion of pregnancies resulting in birth that were conceived with the use of clomiphene citrate (CC) and the frequency of multiple pregnancy. DESIGN: Whole-of-population cohort study, constructed through data linkage. Comprehensive Australian Government records of dispensed medications were linked to state Perinatal Registry records for all births of at least 20 weeks' gestation. SETTING: The state of South Australia. PATIENT(S): Women who maintained pregnancy for at least 20 weeks and gave birth between July 2003 and December 2015, a total of 150,713 women with 241,561 pregnancies. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Ongoing pregnancy occurring in proximity to CC, defined as dispensing from 90 days before to the end of a conception window derived from newborn date of birth and gestational age. RESULT(S): Linkage to dispensed prescription records was achieved for 97.9% of women. Women who conceived with CC tended to be older and socioeconomically advantaged and more likely than other women to have a history of miscarriage. Ongoing pregnancies associated with CC comprised 1.6% of the total; 5.7% were multiple births (mostly twins, 94.6%) compared with 1.5% in the remainder (98.5% twins). CONCLUSION(S): In South Australia, 1.6% of pregnancies (1 in 60) of at least 20 weeks' gestation were conceived proximal to CC dispensing. Of these, 5.7% were multiple pregnancies. This takes the proportion of women who achieved an ongoing pregnancy with medical assistance from 4.4%, based on reports from assisted reproductive technology clinics, to 6% in total.

Prevalence and performance of private equity-affiliated fertility practices in the United States.

OBJECTIVE: To quantify the proportion of annual assisted reproductive technology (ART) cycles performed at private equity-affiliated fertility practices and to test for differences in services and success rates between private equity-affiliated and nonaffiliated practices. DESIGN: Cross-sectional analysis of national data set. SETTING: Not applicable. PATIENT(S): None. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): The primary outcome measures were the volume of ART cycles performed, the percentage of retrievals resulting in live births, and the percentage of transfers resulting in live births. The secondary outcomes included the median income of the practice location, the use of preimplantation genetic testing, the clinical service availability, and the patient reasons for seeking treatment. RESULT(S): Of the practices listed on the Centers for Disease Control's 2018 Fertility Clinic Success Rates Report, 14.7% had a private equity affiliation. Of the 305,883 ART cycles performed in 2018, 29.3% (89,535) occurred at private equity-affiliated practices. Patients at private equity-affiliated practices were 6.75% (95% confidence interval [CI], -10.15%, -3.36%) less likely to initiate a cycle due to male factor infertility, and 10.60% (95% CI, 3.49, 17.76) more likely to use preimplantation genetic testing before embryo transfer. No statistically significant differences were found in success rates among women aged <35 years. The average median household income (standard error) in zip codes with private equity-affiliated practices compared with nonaffiliated practices was $83,610 ($35,990) and $72,161 ($32,314), respectively. CONCLUSION(S): A major portion of fertility practices in the United States are private equity-affiliated, and these practices perform an even greater portion of ART cycles in the United States each year. Fertility appears to be the medical specialty with the greatest market share owned by private equity. Our findings corroborate preliminary research, which forecasts the increasing involvement and consolidation by private equity in fertility. Future research should continue monitoring for differences in outcomes, financing, case mix, service use, and accessibility.

Impact of maternal education level on live birth rate after in vitro fertilization in China: a retrospective cohort study.

PURPOSE: To assess the association between maternal education level and live birth after in vitro fertilization (IVF). METHODS: We studied women who underwent the first cycle of fresh or frozen-thawed embryo transfer between 2014 and 2019. Women were divided into four educational categories according to the level of education received (elementary school graduate or less, middle school graduate, high school graduate, college graduate or higher). The live birth rate was compared between different education level groups. We used logistic regression to analyze the association between maternal education level and live birth after IVF. RESULTS: We studied 41,546 women, who were grouped by maternal educational level: elementary school graduate or less (n = 1590), middle school graduate (n = 10,996), high school graduate (n = 8354), and college graduate or higher (n = 20,606). In multivariable logistic regression analysis, we did not demonstrate a statistically significant relationship between educational level and live birth in middle school graduate (adjusted odds ratio [AOR] 0.96; 95% confidence interval [CI], 0.84-1.09), high school graduate (AOR 1.01; 95% CI, 0.87-1.14) or college graduate or higher (AOR 1.01; 95% CI, 0.88-1.14) patients, with elementary school graduate or less as the reference group. CONCLUSIONS: Maternal educational level was not associated with the likelihood of live birth in patients undergoing fresh or frozen embryo transfer.

Effects of the early phase of the COVID-19 pandemic on natural and ART-mediated birth rates in Lombardy Region, Northern Italy.

RESEARCH QUESTION: What effects did the early phase of the COVID-19 pandemic have on natural and assisted reproductive technology (ART)-mediated birth rates? DESIGN: Regional registries were consulted with permission from the Health Authorities of Lombardy Region, Northern Italy, an area particularly affected by the early phase of the epidemic. Deliveries occurring in the area between 1 January 2019 and 31 December 2020 from women beneficiaries of the National Health System and resident in Lombardy were identified. Comparisons mainly focused on December 2020, when women who conceived after 8 March (the start of the stringent lockdown imposed by the authorities) were expected to deliver. RESULTS: When comparing the periods January to November in 2019 and 2020, a 5.1% reduction of monthly general birth rate (from 5732 in 2019 to 5438 in 2020) was observed. The contribution of ART births was similar in 2019 and 2020, being 4.4% and 4.5%, respectively. In December 2020, a notable drop in natural (-17.8%), ART-mediated (-86.6%) and overall (-21.0%) births was observed compared with December 2019. After adjusting for the expected 5.1% reduction, the inferred effect of the COVID-19 crisis corresponded to a 16.7% reduction in birth rate, of which 76% was related to natural (707 births) and 24% to ART (218 births) conceptions. CONCLUSIONS: This is the first study providing population-based evidence on the effects of COVID-19 and its related stringent restrictions on birth rates. The birth rate was dramatically reduced following the critical period, and the closure of ART centres played only a marginal role (24%) in the overall detrimental effect.

Celebrating 30 years of ART in Latin America; and the 2018 report.

RESEARCH QUESTION: What are the trends in patient characteristics, effectiveness and safety of assisted reproductive technology (ART) performed in Latin America over the past three decades, as well as the detailed outcomes of procedures initiated in 2018? DESIGN: Retrospective collection of multinational data including epidemiology and outcomes of ART performed between 1990 and 2018. RESULTS: Over these 30 years we report 955,117 initiated cycles, 191,191 deliveries and 238,045 live births. In 1990, 66.5% of women were ≤34 years and 8.7% ≥40 years; in 2018, 26.4% of women were ≤34 years and 32.0% were ≥40 years. In 1990, 60.4% of transfers included ≥3 embryos, falling to 13.5% in 2018, and single embryo transfer (SET) increased from 13.8% to 30.4% between 1990 and 2018. Delivery rate per fresh transfer increased from approximately 17% in the 1990s to 25% in 2018, with a meaningful drop in high-order multiples, from 5-9% in the 1990s to 0.4% in 2018. This drop is associated with increasing use of frozen embryo transfer (FET) (57% in 2018) compared with 10% in 2000. In 2018, delivery rate in FET was 28.3%, reaching 31.2% in freeze-all cycles; and the cumulative live birth rate (fresh + FET) was 41.9%. Elective SET also increased, from 0.9% in 2010 to 10% in 2018. The delivery rate in elective SET (31.7%) was only 5.4% lower than elective double embryo transfer (DET) (37.1%); however, multiple births increased from 2.1% to 25.5% twins and 0.4% triplets in elective DET. CONCLUSION: The Latin American Registry of Assisted Reproduction (RLA) celebrates 30 years of voluntary reporting from a total of nearly 200 centres in 15 countries. This South-South Cooperation network has proven to be an efficient and safe system for technological transfer and regional growth.

Women with multiple gestations have an increased risk of development of hypertension in the future.

BACKGROUND: Multiple gestations are associated with an increased incidence of preeclampsia. However, there exists no evidence for an association between multiple gestations and development of hypertension(HTN) later in life. This study aimed to determine whether multiple gestations are associated with HTN beyond the peripartum period. METHODS: In this retrospective nationwide population-based study, women who delivered a baby between January 1, 2007, and December 31, 2008, and underwent a national health screening examination within one year prior to their pregnancy were included. Subsequently, we tracked the occurrence of HTN during follow-up until December 31, 2015, using International Classification of Diseases-10th Revision codes. RESULTS: Among 362,821 women who gave birth during the study period, 4,944 (1.36%) women had multiple gestations. The cumulative incidence of HTN was higher in multiple gestations group compared with singleton group (5.95% vs. 3.78%, p < 0.01, respectively). On the Cox proportional hazards models, the risk of HTN was increased in women with multiple gestations (HR 1.35, 95% CI 1.19, 1.54) compared with those with singleton after adjustment for age, primiparity, preeclampsia, atrial fibrillation, body mass index, blood pressure, diabetes mellitus, high total cholesterol, abnormal liver function test, regular exercise, and smoking status. CONCLUSIONS: Multiple gestations are associated with an increased risk of HTN later in life. Therefore, guidelines for the management of high-risk patients after delivery should be established.

Double versus single intrauterine insemination (IUI) in stimulated cycles for subfertile couples.

BACKGROUND: In subfertile couples, couples who have tried to conceive for at least one year, intrauterine insemination (IUI) with ovarian hyperstimulation (OH) is one of the treatment modalities that can be offered. When IUI is performed a second IUI in the same cycle might add to the chances of conceiving. In a previous update of this review in 2010 it was shown that double IUI increases pregnancy rates when compared to single IUI. Since 2010, different clinical trials have been published with differing conclusions about whether double IUI increases pregnancy rates compared to single IUI. OBJECTIVES: To determine the effectiveness and safety of double intrauterine insemination (IUI) compared to single IUI in stimulated cycles for subfertile couples. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase and CINAHL in July 2020 and LILACS, Google scholar and Epistemonikos in February 2021, together with reference checking and contact with study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled, parallel trials of double versus single IUIs in stimulated cycles in subfertile couples. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: We identified in nine studies involving subfertile women. The evidence was of low quality; the main limitations were unclear risk of bias, inconsistent results for some outcomes and imprecision, due to small trials with imprecise results. We are uncertain whether double IUI improves live birth rate compared to single IUI (odds ratio (OR) 1.15, 95% confidence interval (CI) 0.71 to 1.88; I2 = 29%; studies = 3, participants = 468; low quality evidence). The evidence suggests that if the chance of live birth following single IUI is 16%, the chance of live birth following double IUI would be between 12% and 27%. Performing a sensitivity analysis restricted to only randomised controlled trials (RCTs) with low risk of selection bias showed similar results. We are uncertain whether double IUI reduces miscarriage rate compared to single IUI (OR 1.78, 95% CI 0.98 to 3.24; I2 = 0%; studies = 6, participants = 2363; low quality evidence). The evidence suggests that chance of miscarriage following single IUI is 1.5% and the chance following double IUI would be between 1.5% and 5%. The reported clinical pregnancy rate per woman randomised may increase with double IUI group (OR 1.51, 95% CI 1.23 to 1.86; I2 = 34%; studies = 9, participants = 2716; low quality evidence). This result should be interpreted with caution due to the low quality of the evidence and the moderate inconsistency. The evidence suggests that the chance of a pregnancy following single IUI is 14% and the chance following double IUI would be between 16% and 23%. We are uncertain whether double IUI affects multiple pregnancy rate compared to single IUI (OR 2.04, 95% CI 0.91 to 4.56; I2 = 8%; studies = 5; participants = 2203; low quality evidence). The evidence suggests that chance of multiple pregnancy following single IUI is 0.7% and the chance following double IUI would be between 0.85% and 3.7%. We are uncertain whether double IUI has an effect on ectopic pregnancy rate compared to single IUI (OR 1.22, 95% CI 0.35 to 4.28; I2 = 0%; studies = 4, participants = 1048; low quality evidence). The evidence suggests that the chance of an ectopic pregnancy following single IUI is 0.8% and the chance following double IUI would be between 0.3% and 3.2%. AUTHORS' CONCLUSIONS: Our main analysis, of which the evidence is low quality, shows that we are uncertain if double IUI improves live birth and reduces miscarriage compared to single IUI. Our sensitivity analysis restricted to studies of low risk of selection bias for both outcomes is consistent with the main analysis. Clinical pregnancy rate may increase in the double IUI group, but this should be interpreted with caution due to the low quality evidence. We are uncertain whether double IUI has an effect on multiple pregnancy rate and ectopic pregnancy rate compared to single IUI.

Trends and predictors of eclampsia among singleton and multiple gestations in the United States, 1989-2018.

OBJECTIVE: To examine temporal trends of eclampsia by plurality in the US spanning three decades (1989-2018); and to investigate risk factors for eclampsia among singleton and multiple pregnancies in the US during the study period. STUDY DESIGN: We conducted a retrospective cohort study using the Natality data files, including information on all births within the gestational age of 20-42 weeks from 1989 through 2018. We used joinpoint regression analysis to evaluate trends in rates of eclampsia over the study period. We employed logistic regression models to examine the association between plurality and eclampsia after adjusting for socio-demographic and gestational factors. MAIN OUTCOME MEASURES: The primary outcome was eclampsia among singleton and multiple pregnancies. FINDINGS: There was a 2.8% (95% CI: -5.4, -0.1) average annual reduction in eclampsia rates among singletons, whereas among multiples there was a decline of about 3.7% (95% CI: -6.4, -1.0) annually. Mothers with multiple pregnancies had three-fold increased adjusted odds (OR = 95% CI: 2.95-3.21) of experiencing eclampsia when compared to those with singleton gestations. Non-Hispanic (NH) Black mothers with singletons had 37% greater adjusted odds of developing eclampsia than their NH-White peers (95%CI: 1.33-1.42). CONCLUSION: There was an overall decreasing trend in eclampsia incidence in the US from 1989 to 2018, regardless of plurality. The occurrence of eclampsia was associated with plurality, race/ethnicity, maternal age and maternal BMI. Given the heterogeneity in clinical presentations of eclampsia, personalized/standardized risk prediction models are needed to enable consistent diagnosis and timely intervention.

The optimal number of embryo cells for effective pregnancy and decrease of multiple pregnancy rate in frozen-thawed embryo transfer.

To investigate the effect of the number of embryo cells on the clinical outcome of frozen-thawed embryo transfer and explore the optimal policy for decreases of multiple pregnancy rate, patients who experienced day 3 vitrified double frozen-thawed embryo transfer were retrospectively analyzed. According to the number of embryonic cells in each pre-frozen embryo, the patients were divided into six groups: 8C2 (two 8-cell embryos), 8C1- < 8C1 (one 8-cell embryo and one under-8-cell embryo), 8C1- > 8C1 (one 8-cell embryo and one over-8-cell embryo), < 8C2 (two under-8-cell embryos), < 8C1- > 8C1 (one under-8-cell embryo and one over-8-cell embryo), and > 8C2 (two over-8-cell embryos). The clinical data were analyzed. The classification decision tree was used to analyze the optimal transfer strategy. A total of 2184 cycles of day 3 vitrified double frozen-thawed embryo transfer were enrolled. In day 3 double frozen-thawed embryo cycles, the 8C2 group and 8C1- > 8C1 group had significantly (P < 0.05) higher pregnancy and multiple pregnancy rates than the other groups. No significant (P > 0.05) difference existed in the pregnancy rate and live birth rate between the 8C1- < 8C1 group, 8C2 group and 8C1- > 8C1 group, but the implantation rate and multiple pregnancy rate in the 8C1- < 8C1 group were significantly (P < 0.05) lower than in the other two groups. Compared with the multiple pregnancy rate of all cycles, the cycles in two branches showed significantly (P < 0.05) higher multiple pregnancy rates (≤ 29 years old: 8C2 / 8C1- > 8C1; 29 < age ≤ 36 years for the first transfer: 8C2 / 8C1- < 8C1 / 8C1- > 8C1, one branch showed similar rate (≤ 29 years old: 8C2 / 8C1- > 8C1) for the first transfer, and the remaining four branches demonstrated significantly (P < 0.05) lower rates. The clinical pregnancy rates before and after optimization were 51.0% vs 50.5%, and the multiple pregnancy rates were 38.5% vs 16.9%. In conclusion, the number of pre-frozen embryonic cells is an important factor affecting the clinical outcome of frozen-thawed embryo transfer in day 3 double good embryos frozen-thawed cycles. The age of patient, number of embryo cells, and the first time of transfer are the most valuable parameters for prediction. For women ≤ 29 years old, the single embryo transfer (SET) strategy was to choose an embryo ≥ 8 cells, and for women with < 29 age ≤ 36 years old, the SET strategy in the first transfer was to choose an embryo ≥ 8 cells.

Assisted hatching on assisted conception (in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI)).

BACKGROUND: Failure of implantation and conception may result from inability of the blastocyst to escape from its outer coat, which is known as the zona pellucida. Artificial disruption of this coat is known as assisted hatching and has been proposed as a method for improving the success of assisted conception by facilitating embryo implantation. OBJECTIVES: To determine effects of assisted hatching (AH) of embryos derived from assisted conception on live birth and multiple pregnancy rates.  SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register (until May 2020), the Cochrane Central Register of Controlled Trials (CENTRAL; until May 2020), in the Cochrane Library; MEDLINE (1966 to May 2020); and Embase (1980 to May 2020). We also searched trial registers for ongoing and registered trials (http://www.clinicaltrials.gov - a service of the US National Institutes of Health; http://www.who.int/trialsearch/Default.aspx - The World Health Organization International Trials Registry Platform search portal) (May 2020). SELECTION CRITERIA: Two review authors identified and independently screened trials. We included randomised controlled trials (RCTs) of AH (mechanical, chemical, or laser disruption of the zona pellucida before embryo replacement) versus no AH that reported live birth or clinical pregnancy data. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Two review authors independently performed quality assessments and data extraction. MAIN RESULTS: We included 39 RCTs (7249 women). All reported clinical pregnancy data, including 2486 clinical pregnancies. Only 14 studies reported live birth data, with 834 live birth events. The quality of evidence ranged from very low to low. The main limitations were serious risk of bias associated with poor reporting of study methods, inconsistency, imprecision, and publication bias. Five trials are currently ongoing. We are uncertain whether assisted hatching improved live birth rates compared to no assisted hatching (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.92 to 1.29; 14 RCTs, N = 2849; I² = 20%; low-quality evidence). This analysis suggests that if the live birth rate in women not using assisted hatching is about 28%, the rate in those using assisted hatching will be between 27% and 34%. Analysis of multiple pregnancy rates per woman showed that in women who were randomised to AH compared with women randomised to no AH, there may have been a slight increase in multiple pregnancy rates (OR 1.38, 95% CI 1.13 to 1.68; 18 RCTs, N = 4308; I² = 48%; low-quality evidence). This suggests that if the multiple pregnancy rate in women not using assisted hatching is about 9%, the rate in those using assisted hatching will be between 10% and 14%. When all of the included studies (39) are pooled, the clinical pregnancy rate in women who underwent AH may improve slightly in comparison to no AH (OR 1.20, 95% CI 1.09 to 1.33; 39 RCTs, N = 7249; I² = 55%; low-quality evidence). However, when a random-effects model is used due to high heterogeneity, there may be little to no difference in clinical pregnancy rate (P = 0.04). All 14 RCTs that reported live birth rates also reported clinical pregnancy rates, and analysis of these studies illustrates that AH may make little to no difference in clinical pregnancy rates when compared to no AH (OR 1.07, 95% CI 0.92 to 1.25; 14 RCTs, N = 2848; I² = 45%). We are uncertain about whether AH affects miscarriage rates due to the quality of the evidence (OR 1.13, 95% CI 0.82 to 1.56; 17 RCTs, N = 2810; I² = 0%; very low-quality evidence). AUTHORS' CONCLUSIONS: This update suggests that we are uncertain of the effects of assisted hatching (AH) on live birth rates. AH may lead to increased risk of multiple pregnancy. The risks of complications associated with multiple pregnancy may be increased without evidence to demonstrate an increase in live birth rate, warranting careful consideration of the routine use of AH for couples undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). AH may offer a slightly increased chance of achieving a clinical pregnancy, but data quality was of low grade. We are uncertain about whether AH influences miscarriage rates.

Incidence of multiple births in relation to current regulations in Turkey regarding embryo transfer.

BACKGROUND: Before 2010, there were no regulations in Turkey regarding the number of embryos to be transferred in one cycle. In March 2010, regulations restricting this number were implemented by the Turkish Ministry of Health. These specify the transfer of a maximum of one embryo in the first and second cycles and a maximum of two embryos in subsequent cycles in women aged < 35, and a maximum of two embryos in women aged ≥35 in any one cycle. Our study evaluates the effect of these regulations. METHODS: This large retrospective single center study first evaluates the incidence of multiple pregnancies before and after the implementation of the 2010 regulations. Secondly, it compares the clinical outcomes of double blastocyst transfer (DBT) and single blastocyst transfer (SBT) performed in compliance with these regulations from 2014 onwards. RESULTS: After the introduction of the 2010 regulations, the multiple pregnancy rate decreased significantly from 37.9 to 15.7%. The singleton live birth rate increased significantly, whereas multiiple live birth rates significantly decreased (p = < 0.001). When the clinical outcomes of SBT and DBT performed in compliance with regulations from 2014 onwards were evaluated, in patients < 35 years, the multiple pregnancy rate decreased from 47.2% in the DBT group to 1.7% in the SBT group (p = < 0.001). In patients ≥35 years, in the DBT group, the twin birth rate was again high at 28.4%, whereas in the SBT group, it was only 1.8% (p = < 0.001). Importantly, there was no statistically significant difference in clinical pregnancy rates between these two groups. CONCLUSION: Turkish regulations have led to an encouragement of double embryo transfer (DET) as a routine practice, with many patients understanding it as an absolute right to have two embryos transferred. The results of our study suggest that, especially in the light of the success of blastocyst transfer, the Turkish regulations should be amended to limit the use of DET and encourage the use of single embryo transfer except in exceptional cases and particularly in women under 35 years old.

Fresh versus frozen embryo transfers in assisted reproduction.

BACKGROUND: In vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments conventionally consist of a fresh embryo transfer, possibly followed by one or more cryopreserved embryo transfers in subsequent cycles. An alternative option is to freeze all suitable embryos and transfer cryopreserved embryos in subsequent cycles only, which is known as the 'freeze all' strategy. This is the first update of the Cochrane Review on this comparison. OBJECTIVES: To evaluate the effectiveness and safety of the freeze all strategy compared to the conventional IVF/ICSI strategy in women undergoing assisted reproductive technology. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two registers of ongoing trials from inception until 23 September 2020 for relevant studies, checked references of publications found, and contacted study authors to obtain additional data. SELECTION CRITERIA: Two review authors (TZ and MZ) independently selected studies for inclusion, assessed risk of bias, and extracted study data. We included randomised controlled trials comparing a 'freeze all' strategy with a conventional IVF/ICSI strategy including a fresh embryo transfer in women undergoing IVF or ICSI treatment. DATA COLLECTION AND ANALYSIS: The primary outcomes were cumulative live birth rate and ovarian hyperstimulation syndrome (OHSS). Secondary outcomes included effectiveness outcomes (including ongoing pregnancy rate and clinical pregnancy rate), time to pregnancy and obstetric, perinatal and neonatal outcomes. MAIN RESULTS: We included 15 studies in the systematic review and eight studies with a total of 4712 women in the meta-analysis. The overall evidence was of moderate to low quality. We graded all the outcomes and downgraded due to serious risk of bias, serious imprecision and serious unexplained heterogeneity. Risk of bias was associated with unclear blinding of investigators for preliminary outcomes of the study during the interim analysis, unit of analysis error, and absence of adequate study termination rules. There was an absence of high-quality evidence according to GRADE assessments for our primary outcomes, which is reflected in the cautious language below. There is probably little or no difference in cumulative live birth rate between the 'freeze all' strategy and the conventional IVF/ICSI strategy (odds ratio (OR) 1.08, 95% CI 0.95 to 1.22; I2 = 0%; 8 RCTs, 4712 women; moderate-quality evidence). This suggests that for a cumulative live birth rate of 58% following the conventional strategy, the cumulative live birth rate following the 'freeze all' strategy would be between 57% and 63%. Women might develop less OHSS after the 'freeze all' strategy compared to the conventional IVF/ICSI strategy (OR 0.26, 95% CI 0.17 to 0.39; I2 = 0%; 6 RCTs, 4478 women; low-quality evidence). These data suggest that for an OHSS rate of 3% following the conventional strategy, the rate following the 'freeze all' strategy would be 1%. There is probably little or no difference between the two strategies in the cumulative ongoing pregnancy rate (OR 0.95, 95% CI 0.75 to 1.19; I2 = 31%; 4 RCTs, 1245 women; moderate-quality evidence).  We could not analyse time to pregnancy; by design, time to pregnancy is shorter in the conventional strategy than in the 'freeze all' strategy when the cumulative live birth rate is comparable, as embryo transfer is delayed in a 'freeze all' strategy. We are uncertain whether the two strategies differ in cumulative miscarriage rate because the evidence is very low quality (Peto OR 1.06, 95% CI 0.72 to 1.55; I2 = 55%; 2 RCTs, 986 women; very low-quality evidence) and cumulative multiple-pregnancy rate (Peto OR 0.88, 95% CI 0.61 to 1.25; I2 = 63%; 2 RCTs, 986 women; very low-quality evidence). The risk of hypertensive disorders of pregnancy (Peto OR 2.15, 95% CI 1.42 to 3.25; I2 = 29%; 3 RCTs, 3940 women; low-quality evidence), having a large-for-gestational-age baby (Peto OR 1.96, 95% CI 1.51 to 2.55; I2 = 0%; 3 RCTs, 3940 women; low-quality evidence) and a higher birth weight of the children born (mean difference (MD) 127 g, 95% CI 77.1 to 177.8; I2 = 0%; 5 RCTs, 1607 singletons; moderate-quality evidence) may be increased following the 'freeze all' strategy. We are uncertain whether the two strategies differ in the risk of having a small-for-gestational-age baby because the evidence is low quality (Peto OR 0.82, 95% CI 0.65 to 1.05; I2 = 64%; 3 RCTs, 3940 women; low-quality evidence). AUTHORS' CONCLUSIONS: We found moderate-quality evidence showing that one strategy is probably not superior to the other in terms of cumulative live birth rate and ongoing pregnancy rate. The risk of OHSS may be decreased in the 'freeze all' strategy. Based on the results of the included studies, we could not analyse time to pregnancy. It is likely to be shorter using a conventional IVF/ICSI strategy with fresh embryo transfer in the case of similar cumulative live birth rate, as embryo transfer is delayed in a 'freeze all' strategy. The risk of maternal hypertensive disorders of pregnancy, of having a large-for-gestational-age baby and a higher birth weight of the children born may be increased following the 'freeze all' strategy. We are uncertain if 'freeze all' strategy reduces the risk of miscarriage, multiple pregnancy rate or having a small-for-gestational-age baby compared to conventional IVF/ICSI.

A Comparison of Respiratory Syncytial Viral Prophylaxis in Multiple Births versus Singletons in the Canadian Registry of Palivizumab.

OBJECTIVE: The aim of this study is to compare respiratory illness-related hospitalization (RIH) and respiratory syncytial virus (RSV)-related hospitalization (RSVH) in multiple births versus singletons, who received palivizumab during the RSV season and participated in the Canadian registry of palivizumab (CARESS). STUDY DESIGN: Prospective, observational study of infants aged <2 years recruited across 32 centers over 12 RSV seasons from 2005 to 2017. Demographic data were collected at enrolment and RIH events were recorded monthly. RESULTS: A total of 25,003 infants were enrolled of whom 6,949 (27.8%) were of multiple birth, and 18,054 (72.2%) were singletons. A significantly larger proportion of the multiple births were premature (80.2%) compared with the singleton group (56.8%). Multiples had a lower gestational age (mean ± standard deviation): 31.2 ± 3.2 versus 33.2 ± 5.5 weeks and birth weight (mean: 1,590 ± 606.8 vs. 2,069.4 ± 1068.5 g; both p < 0.0005). They were younger at enrolment (4.5 ± 5.0 vs. 6.1 ± 6.8 months), and fewer attended daycare (1.9 vs. 4.6%), and experienced exposure to smoking (24.5 vs. 29.9%), but more lived in a crowded household (36.7 vs. 19.4%); all p < 0.0005. Multiples had a longer length of neonatal stay (51.1 ± 65.9 vs. 47.9 ± 67.8 days), and more required respiratory support (65.7 vs. 57.7%), but for shorter duration (22.6 ± 32.9 vs. 24.7 ± 40.6 days); all p < 0.001. RIH and RSVH rates (%) in multiples versus singletons were 4.7; 7.7 and 1.4; and 1.6, respectively. Cox regression showed that multiples had a lower risk of RIH compared with singletons (hazard ratio [HR] = 0.616, 95% confidence interval [CI]: 0.543-0.698, p < 0.0005), but not RSVH (HR: 0.77, 95% CI: 0.57-1.02, p = 0.071). CONCLUSION: Multiple birth infants, who are known to be at greater risk for severe RSVH compared with singletons, are well protected by palivizumab, provided adherence to the monthly injection scheme is guaranteed.

Reproductive outcomes in women and men using complementary and alternative medicine treatment and not receiving artificial reproductive technology: a systematic review.

PURPOSE: Infertility is a global problem, but only a minority of couples access assisted reproductive technologies due to financial and sociocultural barriers. Complementary and alternative medicine are seen as another option. We aimed to determine the impact of complementary and alternative medicine on conception, miscarriage and live birth rates in couples not receiving assisted reproductive technology treatments. METHODS: The electronic databases EMBASE, PubMed, Web of Science and the Allied and Complementary Medicine Database were systematically searched before March 24th 2020. Reference lists of eligible studies were searched for relevant studies. Eligible studies included trials and observational studies that assessed a complementary or alternative medicine and conception, miscarriage or live births in men or women not undergoing fertility treatment. Data were extracted by two independent reviewers using a pre-designed data collection form. The study protocol was published in the PROSPERO database (CRD42018086980). RESULTS: Twenty randomized controlled trials were identified, including 2748 individuals. Most studies did not demonstrate any effect of a complementary or alternative medicine on pregnancy, live birth or miscarriage rates. Limited evidence was found for a positive effect of herbal therapies taken by women on conception rates. There was substantial diversity in quality across the studies. CONCLUSION: There is limited evidence of the effectiveness of complementary and alternative medicine on improving the chances of conception and live births, or increasing miscarriage risk. Owing to the generally sub-optimal quality and heterogeneous nature of the evidence, rigorous studies are needed to determine the impact of complementary and alternative medicine on fertility.

A study of pregnancy after endometrial ablation using linked population data.

INTRODUCTION: Endometrial ablation encapsulates a range of procedures undertaken to destroy the endometrial lining of the uterus as a treatment for heavy menstrual bleeding in women who no longer wish to bear children. Pregnancy following ablation, while unlikely, can occur and may carry higher rates of complications. The aim of this study was to identify factors associated with post-endometrial ablation pregnancy and to describe pregnancy and birth outcomes for post-endometrial ablation pregnancies. MATERIAL AND METHODS: This population-based data linkage study included all female residents of New South Wales, Australia, aged 15-50 years with a hospital admission between July 2001 to June 2014 who birthed between July 2001 and June 2015. Cox proportional hazard regression was used to estimate associations between women's characteristics and post-endometrial ablation pregnancy of at least 20 weeks' gestation. Descriptive statistics were used to characterize pregnancy and birth outcomes. RESULTS: Of 18 559 women with an endometrial ablation, 575 (3.1%) had a post-ablation pregnancy of at least 20 weeks' gestation. Nulliparity (adjusted hazard ratio [aHR] 12.2, 95% confidence interval [CI] 9.1-16.2), older age (35-39 years: aHR 0.39, 95% CI 0.29-0.51; 40-44 years: aHR 0.06, 95% CI 0.04-0.11), marital status (single: aHR 0.67, 95% CI 0.55-0.83; widowed/divorced/separated: aHR 0.58, 95% CI 0.36-0.94) and a diagnosis of heavy menstrual bleeding (aHR 0.09, 95% CI 0.07-0.13) were associated with post-ablation pregnancy. There were high rates of cesarean delivery (43%), preterm birth (13%), twin or higher order pregnancies (9%) and stillbirth (13.3/1000 births) among these post-ablation pregnancies. CONCLUSIONS: Nulliparity at the time of endometrial ablation is associated with increased risk of post-ablation pregnancy, highlighting the importance of careful discussion and consideration of treatment options for heavy menstrual bleeding.

Transabdominal fetal reduction: a report of 124 cases.

To prevent fetal loss, preterm delivery, and perinatal morbidity of multifetal pregnancies (MPs), fetal reduction (FR) is offered to some patients. We retrospectively analysed the data of 124 MPs that underwent transabdominal FR to twin (n = 63) and singleton (n = 61) pregnancies at a mean gestational age of 12 + 6 weeks between December 2006 and January 2018. FR was performed transabdominally with the injection of potassium chloride into the intracardiac or intrathoracic space of the fetus or fetuses after ultrasound screening for nuchal translucency and anatomical defects. The initial number of embryos were 48 twins, 63 triplets, 11 quadruplets, and 2 quintuplets. The procedure-related pregnancy loss rate was 0.8% (1/124), the overall pregnancy loss rate was 2.4% (3/124), the fetal loss rate was 1.6% (2/124), and the neonatal death rate was 0.8% (1/124). The baby take-home rates were 96% for twin pregnancies and 96.7% for singletons. This study shows that transabdominal FR is an effective and safe procedure with a pregnancy loss rate of 2.4%.Impact statementWhat is already known on this subject? The incidence of multifetal pregnancies has increased over the years. Because multifetal pregnancies increase perinatal morbidity and mortality due to prematurity, fetal reduction is offed to some patients.What the results of this study add? The results of this study add to the growing body of research on fetal reduction. The study showed that transabdominal fetal reduction is a safe procedure with a pregnancy loss rate of 2.4%.What the implications are of these findings for clinical practice and/or further research? The results of this study can be used in counselling couples with multifetal pregnancies who are considering fetal reduction. Further research is needed to confirm the current findings.

Indications and factors associated with cesarean section in Bhutan: A hospital-based study.

OBJECTIVE: To investigate the factors associated with cesarean section (CS) in Bhutan. METHODS: This was a cross-sectional study, using the retrospective data from the birth registers maintained in comprehensive emergency obstetric care centers for the year 2018. The data were entered in excel 2013 and analyzed using STATA 13. Multiple logistic regression was used to understand the factors associated with CS in Bhutan. RESULTS: The rate of CS in Bhutan was 18.7%. The indications for CS were previous CS, fetal distress, prolonged labor, and failed induction. The factors associated with CS were maternal age over 25 years, male child, women with smaller number of living children, multiple pregnancy, and gestation over 40 weeks. In addition, mothers delivering in Samtse Hospital and Central Regional Referral Hospital had higher odds of CS. CONCLUSION: In Bhutan, CS was commonly performed for mothers with previous CS, fetal distress, and prolonged labor. Increasing maternal age, multiple pregnancy, and postdated pregnancy and those with one child, or none, were more likely to undergo CS. To reduce the CS rate, Bhutan should focus on decreasing the primary CS rate as well as preventing over-diagnosis of prolonged labor by focusing on the partograph.