Human papilloma virus (HPV) is the most common sexually transmitted infection worldwide causing a variety of benign and malignant conditions. A significant portion of the global population is infected with HPV, with the virus attributed to causing up to 5% of cancers worldwide. Bivalent, quadrivalent, and nine-valent vaccinations exist to aid in the prevention of these diseases and have been proven to be effective at preventing both benign and malignant disease. While vaccination is readily accessible in more developed countries, barriers exist to worldwide distribution and acceptance of vaccination. Vaccination and screening of HPV infection when used in combination are proven and predicted to decrease HPV related pathology. Improvements in vaccination formulations, for treatment as well as prevention, are actively being sought from a variety of mechanisms. Despite these advancements, and the data supporting their efficacy, there has been substantial delay in obtaining adequate vaccination coverage. In reviewing these challenges and looking forward to new vaccine development—especially within the current pandemic—it is clear from the challenges of HPV we require methods to more effectively encourage vaccination, ways to dispel vaccination myths as they occur, and implement better processes for vaccine distribution globally.

BACKGROUND Reported increases in maternal and perinatal morbidity (including macrosomia, large for gestational age (LGA), cesarean section, hemorrhage and hypertensive disorders of pregnancy) following frozen embryo transfer (FET) cycles may be associated with the lack of a corpus luteum seen in programmed FET. Given the growing number of studies comparing outcomes between natural FET and programmed FET cycles, a meta-analysis would prove useful to detect the presence of abnormalities in fetal birth weight in patients undergoing natural and programmed FET cycles. OBJECTIVE AND RATIONALE The aim of this study was to provide a systematic review and meta-analysis of the effects of natural versus programmed methods of endometrial preparation for FET cycles on fetal weight and the risks of LGA and macrosomia. SEARCH METHODS A literature search using MEDLINE, SCOPUS, EMBASE and clinicaltrials.gov was conducted for published research comparing neonatal outcomes in natural FET and programmed FET cycles. Primary outcomes of interest were fetal weight, macrosomia and LGA. Studies were included if the following criteria were met: study contained cohorts of NFET and programmed FET with outcome data of birth weight, large for gestational data and/or macrosomia. The data are presented as average weight and odds ratio (OR) with 95% confidence interval (CI) with fixed- or random-effects meta-analysis between cohorts of NFET and programmed FET cycles. Bias was assessed using Newcastle-Ottawa quality assessment scale for the 14 included studies. Multiple subgroup analyses were performed to assess for effect of the true natural cycle (defined as no ovulation trigger medication use) and the day of embryo transfer on fetal weight parameters compared with programmed cycle FET. OUTCOMES A total of 879 studies were identified, with 15 meeting inclusion the criteria. The studies varied with respect to country of origin, definition of natural cycle FET and type of progesterone supplementation used. The included studies had similar gestational ages at the time of birth. Programmed FET cycles resulted in a higher fetal weight compared with natural FET cycles (mean difference 47.38 gp = 0.04). Programmed FET cycles were also at higher risk for macrosomia (OR 1.15, 95% CI 1.06–1.26) and LGA (OR 1.10, 95% CI 1.02–1.19) compared with natural FET cycles. Subgroup analyses demonstrated that programmed FET cycles resulted in a higher fetal weight compared with true natural FET (mean difference 62.18 gp = 0.0001) cycles. Cleavage stage embryo transfers had an increased risk of LGA (OR 1.27, 95% CI 1.00–1.62) and an increased risk of macrosomia (OR 1.25, 95% CI 1.08–1.44) in programmed FET cycles compared with natural FET cycles. Blastocyst transfer in programmed FET cycles resulted in no difference in risk of macrosomia but an increased risk of LGA (OR 1.13, 95% CI 1.06–1.21) compared with natural FET cycles. WIDER IMPLICATIONS Programmed endometrial preparation for FET cycles had a significant effect, causing increased fetal birth weight and increased risks of LGA and macrosomia. The numbers of studies in the subgroup analyses were too low to determine reliable results. Further prospective randomized trials are needed to determine whether the changes seen in the observational trials are indeed accurate.

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and BMI >35 kg/m 2 (aRR 1.67, 95% CI 1.58-1.76)) and parity (1 prior birth (aRR 1.36, 95% CI 1.31-1.42) and >1 prior birth (aRR 1.39, 95% CI 1.31-1.47), compared to nulliparous patients). Use of gestational carrier (aRR 1.29, 95% CI 1.14-1.46) and use of donor sperm (aRR 1.20, 95% CI 1.12-1.29) were also positively associated with LGA after FET. In contrast, low BMI (<18.5 versus 18.5-24.9 kg/m 2 ), geographic region (NE and West compared to Midwest), low number of oocytes retrieved (5-9 versus 10-19 oocytes) and two or more fetal heartbeats were protective factors. In addition, compared to non-Hispanic (NH) White patients, NH Black, Hispanic, and Asian/Pacific Islander patients were at significantly lower risk of LGA infants born after FET.CONCLUSIONS: BMI, parity, and race/ethnicity were the strongest independent risk factors for LGA infants following FET cycles. The annual rate of LGA after FET cycles decreased over the fifteen-year period studied.IMPACT STATEMENT: Increased understanding of risk factors for LGA after FET can improve patient counseling and medical care for patients undergoing assisted reproductive technologies.