[IN VITRO FERTILIZATION (IVF) TREATMENTS IN MACCABI HEALTHCARE SERVICES 2015-2020].

BACKGROUND: Previously, we have summarized IVF treatment outcomes for the years 2007-2014. In 2014, the Ministry of Health (MOH) recommended that infertile patients above 39 years of age can be offered IVF as a first line treatment, given the natural age-related decrease in ovarian reserve. OBJECTIVES: The purpose of the current publication is to summarize IVF treatment outcomes for the years 2015-2020, and to explore possible changes in IVF treatments following the MOH statement. METHODS: IVF treatments and live birth data were collected from Maccabi Healthcare Services' fertility treatments registry. We have included only autologous fresh and frozen embryo transfer (FET) cycles. A successful treatment cycle was defined if a live birth was recorded between 6 to 10 months of its initiation. RESULTS: Mean patients' age increased from 36.2 years in 2011 to 37.5 years in the 6 years surveyed (2015-2020). While the number of fresh cycles was stable, the number of FET cycles increased from 4,507 in 2015 to 6,795 in 2020. The percentage of cycles performed in private hospitals increased gradually from 72% in 2015 to 77% in 2020. The number of patients over 40 years of age increased from 3,204 in 2011, to 3,648 in 2014, and to 3,915 in 2020. CONCLUSIONS: The total number of IVF cycles increased gradually from 2015 to 2020, mainly due to significant increase in FET cycles. The continued increase in mean patients' age may reflect the change in MOH recommendations.

An Outbreak of Parvovirus B19 in Israel.

Human parvovirus B19 (B19V) has a wide clinical spectrum, ranging from an asymptomatic infection to a life threatening one. During pregnancy, it can lead to fetal loss and hydrops fetalis. This retrospective study examined the incidence rates of B19V in Israel, analyzing anonymized electronic medical records of 2.7 million individuals between January 2015 and September 2023. A generalized linear model with a Poisson distribution was fit to the data, adjusting for potential confounders. A marked increase in B19V was observed in 2023, with an adjusted incidence rate ratio (IRR) of 6.6 (95% CI 6.33-6.89) when comparing 2023 to previous years. When specifically comparing 2023 to COVID-19 years (2020-2022), adjusted IRR climbs to 9.21 (8.66-9.80). Moreover, in 2023, previously existing seasonality has largely disappeared. High SES characterized most infected individuals with a marked discrepancy in social sectors; the Arab population was significantly less likely to be found B19V positive, even when adjusting for SES. Most infections occurred in school-aged children (6-11 years old). Pregnant women experienced the most significant rise in B19V, with an adjusted IRR of 11.47 (9.44-13.97) in 2023 compared to previous years; most cases were diagnosed in the first trimester. This study demonstrates that Israel is currently experiencing the largest and longest reported outbreak of B19V to date. Policymakers should consider setting screening policies in place, at least for populations at risk, while specifically studying and potentially targeting low socioeconomic populations and specific social sectors to avoid health inequalities.

Pregnancy outcomes after SARS-CoV-2 infection by trimester: A large, population-based cohort study.

OBJECTIVES: Data regarding women infected with SARS-CoV-2 during early trimesters are scarce. We aimed to assess preterm birth (PTB) and small-for-gestational-age (SGA) rates in a large and unselected cohort by trimester at infection and overall. DESIGN: A retrospective cohort study including all women with a positive SARS-CoV-2 RT-PCR test during a non-ectopic singleton pregnancy between February 21st 2020 and July 2nd 2021 (N = 2753). Each infected woman was matched to a non-infected pregnant woman by age, last menstruation date, sector, and socioeconomic status. METHODS: Logistic regression was conducted to assess the risks of PTB and SGA including an interaction between group and trimester of infection. Multivariable models included underlying diseases, previous abortions and null parity. Subgroup analyses were conducted on symptomatic infected women and matched non-infected women. RESULTS: A total of 2753 /2789 (98.7%) eligible women that were infected during pregnancy could be matched, among them, 17.4% and 48.4% were infected during the first and third trimesters, respectively. While first and second trimester infections were not associated with PTB (p>0.8), third trimester infections and in particular after 34 weeks of gestation had a greater risk of PTB with adjusted ORs of 2.76 (95% CI 1.63-4.67) and 7.10 (95% CI 2.44-20.61), respectively. PTB risk was further heightened in symptomatic third trimester infections (OR = 4.28, 95% CI 1.94-9.25). SGA risk was comparable between study groups across all trimesters of infection. Pregnancy loss incidence was similar in both groups (adjusted OR = 1.16; 95% CI 0.90-1.50). CONCLUSION: SARS-CoV-2 infection was associated with increased risk of PTB only among women infected during late pregnancy, particularly among symptomatic women.

Association of BNT162b2 COVID-19 Vaccination During Pregnancy With Neonatal and Early Infant Outcomes.

Importance: Pregnant women were excluded from the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine (Pfizer-BioNTech) preauthorization trial. Therefore, observational data on vaccine safety for prenatally exposed newborns are critical to inform recommendations on maternal immunization. Objective: To examine whether BNT162b2 mRNA vaccination during pregnancy is associated with adverse neonatal and early infant outcomes among the newborns. Design, Setting, and Participants: Population-based cohort study comprising all singleton live births in March through September 2021, within a large state-mandated health care organization in Israel, followed up until October 31, 2021. Exposure: Maternal BNT162b2 mRNA vaccination during pregnancy. Main Outcomes and Measures: Risk ratios (RR) of preterm birth, small birth weight for gestational age (SGA), congenital malformations, all-cause hospitalizations, and infant death. Stabilized inverse probability weighting was used to adjust for maternal age, timing of conception, parity, socioeconomic status, population subgroup, and maternal influenza immunization status. Results: The cohort included 24 288 eligible newborns (49% female, 96% born at ≥37 weeks' gestation), of whom 16 697 were exposed (n = 2134 and n = 9364 in the first and second trimesters, respectively) to maternal vaccination in utero. Median (IQR) follow-up after birth was 126 days (76-179) among exposed and 152 days (88-209) among unexposed newborns. No substantial differences were observed in preterm birth rates between exposed and unexposed newborns (RR = 0.95; 95% CI, 0.83-1.10) or SGA (RR = 0.97; 95% CI, 0.87-1.08). No significant differences were observed in the incidence of all-cause neonatal hospitalizations (RR = 0.99; 95% CI, 0.88-1.12), postneonatal hospitalizations after birth (RR = 0.95; 95% CI, 0.84-1.07), congenital anomalies (RR = 0.69; 95% CI, 0.44-1.04), or infant mortality over the study period (RR = 0.84; 95% CI, 0.43-1.72). Conclusions and Relevance: This large population-based study found no evident differences between newborns of women who received BNT162b2 mRNA vaccination during pregnancy, vs those of women who were not vaccinated, and contributes to current evidence in establishing the safety of prenatal vaccine exposure to the newborns. Interpretation of study findings is limited by the observational design.

Association Between BNT162b2 Vaccination and Incidence of SARS-CoV-2 Infection in Pregnant Women.

Importance: Data on BNT162b2 messenger RNA (mRNA) vaccine (Pfizer-BioNTech) effectiveness and safety in pregnancy are currently lacking because pregnant women were excluded from the phase 3 trial. Objective: To assess the association between receipt of BNT162b2 mRNA vaccine and risk of SARS-CoV-2 infection among pregnant women. Design, Setting, and Participants: This was a retrospective cohort study within the pregnancy registry of a large state-mandated health care organization in Israel. Pregnant women vaccinated with a first dose from December 19, 2020, through February 28, 2021, were 1:1 matched to unvaccinated women by age, gestational age, residential area, population subgroup, parity, and influenza immunization status. Follow-up ended on April 11, 2021. Exposures: Exposure was defined by receipt of the BNT162b2 mRNA vaccine. To maintain comparability, nonexposed women who were subsequently vaccinated were censored 10 days after their exposure, along with their matched pair. Main Outcomes and Measures: The primary outcome was polymerase chain reaction-validated SARS-CoV-2 infection at 28 days or more after the first vaccine dose. Results: The cohort included 7530 vaccinated and 7530 matched unvaccinated women, 46% and 33% in the second and third trimester, respectively, with a mean age of 31.1 years (SD, 4.9 years). The median follow-up for the primary outcome was 37 days (interquartile range, 21-54 days; range, 0-70). There were 118 SARS-CoV-2 infections in the vaccinated group and 202 in the unvaccinated group. Among infected women, 88 of 105 (83.8%) were symptomatic in the vaccinated group vs 149 of 179 (83.2%) in the unvaccinated group (P ≥ .99). During 28 to 70 days of follow-up, there were 10 infections in the vaccinated group and 46 in the unvaccinated group. The hazards of infection were 0.33% vs 1.64% in the vaccinated and unvaccinated groups, respectively, representing an absolute difference of 1.31% (95% CI, 0.89%-1.74%), with an adjusted hazard ratio of 0.22 (95% CI, 0.11-0.43). Vaccine-related adverse events were reported by 68 patients; none was severe. The most commonly reported symptoms were headache (n = 10, 0.1%), general weakness (n = 8, 0.1%), nonspecified pain (n = 6, <0.1%), and stomachache (n = 5, <0.1%). Conclusions and Relevance: In this retrospective cohort study of pregnant women, BNT162b2 mRNA vaccination compared with no vaccination was associated with a significantly lower risk of SARS-CoV-2 infection. Interpretation of study findings is limited by the observational design.

Does levonorgestrel-releasing intrauterine system increase breast cancer risk in peri-menopausal women? An HMO perspective.

PURPOSE: To evaluate the association between levonorgestrel-releasing intrauterine system (LNG-IUS) use and breast cancer (BC) risk. METHODS: A cohort of all Maccabi Healthcare Services (MHS) female members aged 40-50 years between 1/2003 and 12/2013 was used to identify LNG-IUS users as "cases," and 2 age-matched non-users as "controls." Exclusion criteria included: prior BC diagnosis, prior (5 years pre-study) and subsequent treatment with other female hormones or prophylactic tamoxifen. Invasive tumors were characterized by treatments received (chemotherapy, hormonal therapy, trastuzumab, or combination thereof). RESULTS: The analysis included 13,354 LNG-IUS users and 27,324 controls (mean age: 44.1 ± 2.6 vs. 44.9 ± 2.8 years; p < 0.0001). No significant differences in 5-year Kaplan-Meier (KM) estimates for overall BC risk or ductal carcinoma in situ occurrence were observed between groups. There was a trend towards higher risk for invasive BC in LNG-IUS users (5-year KM-estimate: 1.06% vs. 0.93%; p = 0.051). This difference stemmed primarily from the younger women (40-45 years; 0.88% vs. 0.69%, p = 0.014), whereas in older women (46-50 years), it was non-significant (1.44% vs. 1.21%; p = 0.26). Characterization of invasive BC by treatment demonstrated that LNG-IUS users had similar proportions of tumors treated with hormonal therapy, less tumors treated with trastuzumab, (7.5% vs. 14.5%) and more tumors treated with chemotherapy alone (25.8% vs. 14.9%; p = 0.041). CONCLUSIONS: In peri-menopausal women, LNG-IUS was not associated with an increased total risk of BC, although in the subgroup of women in their early 40's, it was associated with a slightly increased risk for invasive tumors.

In Vitro fertilization (IVF) treatments in Maccabi Healthcare Services 2007-2014.

BACKGROUND: Israel reports the world's highest IVF cycles per capita. However, clinical outcome data of these treatments are scarce. In a previous publication, we summarized IVF results among Maccabi Healthcare Services members for the years 2007-2010. The main findings included an increase in mean patients' age over the period studied, a 50 % increase in cycle numbers during this time, and a decrease in success rate (live birth) from 18.8 % in 2007 to 14.8 % in 2010. The purpose of the current publication is to summarize IVF outcome for the years 2011-2014, and to explore possible changes in the trends we reported previously. METHODS: IVF and live births data were collected from Maccabi Healthcare Services' fertility treatments registry. Analyses were conducted by treatment year and patients' age at the initiation of treatment cycles. Autologous cycles, were included (ovum donation cycles and frozen-thaw cycles were excluded). A successful cycle was defined if a live birth was recorded within 10 months of its initiation. RESULTS: In accordance with previous data for the years 2007-2010, mean patients' age continued to rise (from 36.2 in 2011 to 37.1 in 2014). In contrast to previous years, during which a continued increase in treatment cycles was recorded, we found that treatment number decreased from a peak of 9,751 in 2011 to 8,623 in 2014. Contrary to that trend, the number of patients over 40 years of age increased from 3,204 in 2011 to 3,648 in 2014. Success rate fluctuated between 14.4 % in 2014 to 16.4 % in 2013. The majority (78 %) of treatment cycles were conducted in four private medical centers. CONCLUSIONS: The decrease in treatment cycles in recent years notwithstanding, Israel is still leading the world with IVF treatments relative to population. Success rate is relatively low compared to international data. Given the steady increase in patients' mean age, and particularly, the increase in patients over 40 years of age, we maintain that the low success rate reflects a growing number of treatments that a priori have a low chance of success.

[In-vitro fertilization cycles and outcomes in Maccabi Healthcare Services in Israel 2007-2010].

INTRODUCTION: While Israel is by far number one in the world of in-vitro fertilization (IVF) treatments per capita, detailed information about the outcome of these treatments is not available. OBJECTIVES: To describe IVF activity during the years 2007-2010 in Maccabi Healthcare Services, an independent health provider that reimburses IVF treatments. METHODS: Data on IVF cycles and live births were collected from the Maccabi Healthcare Services infertility registry and analyzed by year and age at cycle start. RESULTS: During the four years surveyed, the average patients' age rose from 35.12 to 36.19 years. The number of IVF treatments increased by 50%, while the "live birth" rate fell from 18.8% in 2007, to 14.8% in 2010. A drop in success rate was noted in patients >35 years of age, and more so in patients >40 years of age. Beyond 43 years of age, the success rate was in the low one digit range. The estimated cost of a single live birth in this age group is NIS 399,000. SUMMARY: The clinical results are not encouraging relative to IVF outcomes in Europe and the U.S.A. SurprisingLy, and contrary to worldwide trends, the success rate in Israel decreased during the surveyed years. We speculate that the main reason is that many IVF treatments are conducted in patients that a priori have a very low chance of success. A nationwide prospective IVF registry should be implemented.