Despite the demonstrated safety of human papillomavirus vaccines, concerns have arisen regarding potential associations of human papillomavirus vaccination on reproductive health. The objective of this registry-based study was to compare overtime association of vaccination and early pregnancy outcomes. Twenty thousand four hundred twenty-six women born in 1992-1995, who participated in a Finnish community-randomized human papillomavirus vaccination trial, and age- and community-aligned unvaccinated controls born in 1990-1991 (n = 19 473) were followed up for 11 years. Data was obtained from the nationwide Finnish Care Register for Health Care. Incidence rates of adverse early pregnancy outcomes were compared between the human papillomavirus vaccinated and unvaccinated group. The mean age at first abnormal pregnancy result was 23.5 years in the human papillomavirus vaccinated group and 22.2 years in the unvaccinated group. 1.6% of human papillomavirus vaccinated women experienced a miscarriage compared with 5.3% of unvaccinated controls (P < .0001). No miscarriages occurred in close temporal proximity to vaccination. Rates of ectopic pregnancies were low and comparable across all groups (0.6-1.0%). Among women with a history of abnormal pregnancy outcomes, 55.6% of human papillomavirus vaccinated individuals had at least one live birth, compared with 70.3% of unvaccinated women. Human papillomavirus vaccination was not associated with an increased risk of miscarriage or other adverse early pregnancy outcomes. These results provide reassurance that human papillomavirus vaccination is safe with respect to reproductive outcomes, supporting its continued use in adolescent and young adult populations.

Prophylactic HPV vaccines are effective against cervical cancer and its precursors, but data on their impact on fertility and pregnancy are limited. This registry-based study examined the association between HPV vaccination and childbirth rates. Study population comprised 6200 HPV- and 1667 hepatitis B-virus (HBV) vaccinated women born in 1992-1993 and an age- and community-aligned cohort of 19,473 unvaccinated women born in 1990-1991. Nearly half of the HPV-vaccinated women participated in a cervical screening trial between ages 22 and 28. Childbirth numbers and rates per 10,000 person-years with 95% confidence interval (CI) were compared across the groups. The mean age at first childbirth ranged between 22.9 and 23.4 years among the vaccinated and unvaccinated women. At the age of 28, the cumulative proportion of all childbirths among HPV-vaccinated and screened cohorts was 2277 (36.7%), among HBV-vaccinated 781 (46.9%) and among unvaccinated reference cohorts 8997 (46.2%). Childbirth rates per 10,000 person years were 306 (95% CI 294-319), 390 (95% CI 364-419) and 385 (95% CI 377-393), respectively. HPV-vaccinated and screened women had lower childbirth rates compared to unvaccinated women at young age, possibly due to sexual counseling that HPV-vaccinated participants got in an overlapping cervical screening trial conducted between ages 22 and 28. This may have postponed their family planning to later ages.

Research on the effectiveness of comprehensive sexuality education for 3-to-6-year-olds, especially outside the USA, is limited. This quasi-experimental ecological study assessed the impact of a comprehensive sexuality education programme provided to professionals on children's knowledge in five early education units across two municipalities in the capital region of Finland, compared to children's knowledge in two control settings. Professionals in the intervention units received continuing education and training and taught children using a structured plan. Children's sexuality-related knowledge was measured before (T1) and after (T2) the programme had been implemented for 1 year, involving 132 children at T1 and 205 at T2. The COVID-19 pandemic disrupted programme implementation, resulting in periods of home stays. Results indicated that children's knowledge remained stable in the intervention units but decreased in control units, suggesting pandemic-related learning losses. In one municipality, children's knowledge significantly increased compared to the control group. These findings support the efficacy of continuing education and training for professionals working in early childhood settings and suggest the inclusion of comprehensive sexuality education in the early childhood curriculum to enhance sexual health, safety, and wellbeing.

OBJECTIVE:Concerns have been raised that human papillomavirus (HPV)-vaccination programs may alter risk perceptions and increase risk-taking sexual behavior among adolescents. This study aimed to assess induced abortion rates (as a potential indicator of such behavior) between vaccinated and unvaccinated individuals. METHODS:This longitudinal, cluster-randomized cohort study included 6200 HPV-vaccinated women born in 1992-1993 who participated in a 2007 launched HPV-vaccination trial in Finland, and 19,473 unvaccinated women born in 1990-1991 from the same communities. Registry data from a 12-year follow-up period (between 2007 and 2020, depending on the group) up to the age of 28 years was obtained from The Finnish Register on Induced Abortions. RESULTS:Incidence rate of induced abortions per 10,000 person-years was significantly lower among HPV-vaccinated (145.6(95 %CI 137.1,154.5)) compared to unvaccinated individuals (161.4(95 %CI 156.4,166.7)). HPV-vaccinated individuals induced abortions in earlier gestational weeks (p = 0.049). Up to four-years post sexual health education given at HPV vaccination visits, induced abortion rates were significantly lower among individuals aged 15-19 (33.7(95 %CI 29.8,38.2)) than age-aligned unvaccinated controls (42.4(95 %CI 38.9,44.1)). CONCLUSIONS:HPV-vaccinated had lower induced abortion rates than unvaccinated individuals. When further developing HPV-vaccination programs, simultaneous sexual health education should be considered to comprehensively improve the reproductive health of adolescents.

Objectives: This study aims to evaluate the safety and tolerability of estetrol/drospirenone in adolescents. Methods: In this Phase 3 open-label study, postmenarchal adolescents (12-17 years) received estetrol (E4)/drospirenone (DRSP) 15 mg/3 mg orally for six cycles (24 active/4 placebo regimen). Safety was evaluated through adverse event (AE) reporting. Participants also recorded daily pill intake, bleeding/spotting, dysmenorrhea, and pain medication use in e-diaries. Descriptive statistics were used. Results: Of 112 enrolled participants, 105 received treatment (mean age: 15.2 years), and 84.8% were completers. No serious treatment-related AEs or safety concerns were observed. Nausea and dysmenorrhea (each 1.9%) were the most common treatment-related AEs. Over 71% of participants took all tablets in each cycle. The percentage of participants with unscheduled bleeding and/or spotting decreased from 45.8% (Cycle 1) to 14.5% (Cycle 5), and the number of days with unscheduled bleeding and/or spotting decreased from nine to six days per cycle. The scheduled bleeding and/or spotting rate ranged between 77.4% and 90.5%, with a duration decreasing from six to four days in Cycle 1 to Cycle 5. Absence of scheduled bleeding increased from 9.5% in Cycle 3 to 22.6% in Cycle 5. The proportion of participants reporting dysmenorrhea decreased by 34.8%, with a median visual analogue scale score dropping from 5.0 at baseline to 3.7 at Cycle 6. Pain medication use decreased from 63.9% to 31.6% in Cycle 6. Conclusions: The use of E4/DRSP in adolescents raised no safety concerns, was well tolerated, resulted in a clear and stable cyclic bleeding pattern, and reduced pain associated with dysmenorrhea.

Only a very few studies to date have comprehensively assessed children's knowledge of sexuality. In this study, we examined the level of sexual knowledge among children aged 3-6 years in Finland. We analysed children's explanations of what they saw in drawings related to genital naming, conception and childbirth, safety skills, and adult sexual activity. Levels of knowledge were generally low. The largest number of correct answers were given for genital naming and safety skills. Knowledge increased with age. Children's gender was not related to their total level of knowledge. There was a correlation between children's ability to name their genitals and their knowledge of safety skills. The results suggest that only what is known about can be protected. Building on the findings of this study, age-appropriate sexuality education should be provided to all children.

IntroductionWe report head-to-head comparison of the bivalent and quadrivalent HPV vaccine efficacies against immediate precursors of cervical cancer from 15 years’ country-wide cancer registry follow-up of phase III trial cohorts and an age-aligned cohort of unvaccinated women.MethodsThese individually and/or clusterrandomized cohorts of HPV6/11/16/18- and HPV16/18-vaccinated and unvaccinated women were enrolled, respectively, in 2002, 2004, and 2003/2005. The trial cohorts comprised initially 16- to 17-year-old HPV6/11/16/18-vaccinated FUTURE II (NCT00092534) participants (866) and HPV16/18-vaccinated PATRICIA (NCT00122681) and 012 trial (NCT00169494) participants (2,465), and 16,526 initially 16- to 19-year-old unvaccinated controls. After active 4-year clinical follow-up, passive, country-wide Finnish Cancer Registry (FCR) follow-up for cervical intraepithelial neoplasia grade 3 (CIN3) and adenocarcinoma in situ (AIS) was based on consented use of unique personal identifiers and started 6 months after the end of the FUTURE II and PATRICIA trials in 2007 and 2009, and ended at the end of 2019. The follow-up with altogether 229,020 follow-up years was age-aligned to ensure that similarly aged cohorts were passively followed up for 15 years post=vaccination for the intention-to-treat analyses of vaccine efficacy.ResultsOverall, we identified 5 and 16 CIN3 (no AIS) cases in the HPV6/11/16/18 and HPV16/18 cohorts, respectively, during the FCR-based follow-up. In the unvaccinated cohort, we identified 281 CIN3 cases, 20 AIS cases, and 13 cases with invasive cervical cancer. Vaccine efficacies against CIN3+ were 68.4% and 64.5% for the quadrivalent and the bivalent vaccines, respectively, with overlapping confidence intervals.DiscussionLong-term follow-up of randomized, initially adolescent HPV-vaccinated and unvaccinated cohorts shows, in this head-to-head setting, that the bivalent and quadrivalent HPV vaccines are equally effective against immediate precursors of cervical cancer.

Abstract Developing a vaccine to prevent congenital cytomegalovirus (CMV) infection and newborn disability requires an understanding of infection incidence. In a prospective cohort study of 363 adolescent girls (NCT01691820), CMV serostatus, primary infection, and secondary infection were determined in blood and urine samples collected at enrollment and every 4 months for 3 years. Baseline CMV seroprevalence was 58%. Primary infection occurred in 14.8% of seronegative girls. Among seropositive girls, 5.9% had ≥4-fold increase in anti-CMV antibody, and 23.9% shed CMV DNA in urine. Our findings provide insights on infection epidemiology and highlight the need for more standardized markers of secondary infection.

Objective We assessed the relationship between Chlamydia trachomatis infection, duration of oral contraceptive (OC) use and cervical atypia among young adult Finnish women. Design A longitudinal study. Setting and participants Women who were included in this study participated in a community-randomised trial on the effectiveness of human papillomavirus (HPV) vaccination and C. trachomatis screening at ages 18.5 and 22 years in Finland. They completed questionnaires on both visits about sexual behaviours. The cytology test results at age 18.5 and 22 years were also available for those women. The total number of participants in this study at 18.5 years of age were 11 701 and at 22 years of age were 6618. Main outcome measure ORs with 95% CIs using univariable and multivariable logistic regression were used to assess the association between C. trachomatis infection, duration of OC and squamous intraepithelial lesions (SIL). Results There were 940 cytological SIL cases at the first screening visit and 129 cytological SIL cases at the second screening visit. Among the 22 years old, more than fourfold adjusted risk of SIL was associated with C. trachomatis positivity. The HPV16/18, condom use, smoking and number of sexual partners adjusted joint effect of prolonged OC use and C. trachomatis was significantly increased (OR 4.7, 95% CI 1.7 to 12.8) in the 22-year-old women. This observed joint effect was 1.6 times higher than expected on a multiplicative scale. On additive scale, the observed relative excess risk from interaction was 1.8. Conclusion The risk of SIL in HPV vaccinated women is significantly increased if they are C. trachomatis positive and have used OC for 5 or more years. The biological basis may be lack of condom facilitated protection against sexually transmitted diseases. Trial registration number NCT00534638.

Puberty leads to the development of secondary sexual characteristics and reproductive ability. The development of the menstrual cycle is a slow gradual process.

Objectives To assess the contraceptive efficacy, bleeding pattern and safety of a combined oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg. Design Multicenter, open-label, phase 3 trial. Setting Sixty-nine sites in Europe and Russia. Population Sexually active women aged 18-50 years with regular menstrual cycles and body mass index <= 35 kg/m(2). Methods E4/DRSP was administered in a 24 active/4 placebo regimen for up to 13 cycles. Visits were scheduled during Cycles 2, 4, 7 and 10 and after completing treatment during which adverse events (AEs) were collected. Participants recorded medication intake, vaginal bleeding/spotting, use of other contraceptive methods and sexual intercourse on a daily diary. Main outcome measures Pearl Index (PI) for women 18-35 years (overall and method-failure), bleeding pattern and AEs. Results A total of 1553 women aged 18-50 years, including 1353 from 18 to 35 years old, received the study medication. PI was 0.47 pregnancies/100 woman-years (95% CI 0.15-1.11); method failure PI was 0.29 pregnancies/100 woman-years (95% CI 0.06-0.83). Scheduled bleeding/spotting occurred in 91.9-94.4% of women over Cycles 1 to 12 and lasted a median of 4-5 days per cycle. The percentage of women with unscheduled bleeding/spotting episodes decreased from 23.5% in Cycle 1 to <16% from Cycle 6 onwards. The most common AEs were headache (7.7%), metrorrhagia (5.5%), vaginal haemorrhage (4.8%) and acne (4.2%). One treatment-related serious AE was reported, a lower extremity venous thromboembolism. One-hundred and forty-one (9.1%) women discontinued study participation because of treatment-related adverse events. Conclusion E4/DRSP provides effective contraception, a predictable bleeding pattern and a favourable safety profile. Tweetable abstract A phase 3 trial with E4/DRSP shows high contraceptive efficacy, a predictable bleeding pattern and favourable safety profile.

Objective: To evaluate overall and subgroup efficacy of an estetrol (E4) 15 mg drospirenone (DRSP) 3 mg oral contraceptive in a 24/4-day regimen. Study design: We pooled efficacy outcomes from 2 pivotal phase 3 contraceptive trials with E4/DRSP con-ducted in the United States/Canada and Europe/Russia. We assessed Pearl Index (PI; pregnancies per 100 participant-years) and 13-cycle life-table pregnancy rates in at-risk cycles (confirmed intercourse and no other contraceptive use) among participants 16 to 35 years. We calculated PI by age and further subcate-gorization (contraceptive history and body mass index [BMI]). We performed multivariable analysis using Cox regression to assess impact of potential confounding factors. Results: Analyses included 3027 participants, of whom 451 (14.9%) had a BMI >30 kg/m2. The pooled PI was 1.52 (95% confidence interval 1.04 -2.16) and the 13-cycle life-table pregnancy rate was 1.28% (0.83%- 1.73%). We calculated unadjusted pooled PI in participants 16 to 25 years and 26 to 35 years of 1.61 (0.94-2.57) and 1.43 (0.78-2.40), respectively; in new starters and switchers of 1.88 (1.09-3.00) and 1.24 (0.68-2.08), respectively; and by BMI < 25 kg/m2, 25 to 29.9 kg/m2, and >30 kg/m2 of 1.14 (0.64-1.88), 2.19 (1.05-4.03), and 2.27 (0.83-4.94), respectively. In multivariable analysis, we found associations of prior pregnancy (hazard ratio [HR] 3.61[1.56-8.38]), Black race (HR 4.61[1.97-10.80]), age 16 to 25 years (HR 2.37[1.09-5.15]) and compliance < 99% of expected pills (HR 4.21[2.04-8.66]) with conception. Conclusion: E4/DRSP is an effective oral contraceptive overall and across subgroups stratified by age, con-traceptive history, and BMI. Other than compliance, predictors of contraceptive failure are nonmodifiable. Implications Statement: Pooled results from two phase 3 trials demonstrate high contraceptive efficacy of the novel estetrol-drospirenone oral contraceptive. Several non-modifiable risk factors, including prior pregnancy, race, and age, are associated with higher pregnancy risk. Additional research is needed to better understand predictors of combined oral contraceptive failure. (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Abstract Background Respiratory syncytial virus (RSV) causes respiratory tract infections, which may require hospitalization especially in early infancy. Transplacental transfer of RSV antibodies could confer protection to infants in their first months of life. Methods In this first-in-human, placebo-controlled study, 502 healthy nonpregnant women were randomized 1:1:1:1 to receive a single dose of unadjuvanted vaccine containing 30/60/120 µg of RSV fusion (F) protein stabilized in the prefusion conformation (RSVPreF3) or placebo. Results Solicited local adverse events (AEs) were more frequently reported in the RSVPreF3 groups (4%–53.2%) versus placebo (0%–15.9%); most were mild/moderate. Unsolicited AEs were comparably reported among groups. Three serious AEs were reported; none was vaccination-related. Compared with prevaccination values, anti-RSV A neutralizing antibody geometric mean titers and anti-RSVPreF3 immunoglobulin G geometric mean concentrations increased 8- to 14-fold and 12- to 21-fold at day 8 and persisted 5- to 6-fold and 6- to 8-fold higher until day 91 in the RSVPreF3 groups versus 1-fold in placebo. Comparisons at day 8 and day 31 showed that the higher dose levels were significantly more immunogenic than the lowest one. Conclusions The RSVPreF3 vaccine was well tolerated and immunogenic. The 60 and 120 µg dose levels were selected for further investigation in pregnant women. Clinical Trials Registration NCT03674177.

Abstract Objectives Estetrol (E4), a native estrogen produced by the fetal human liver, has four hydroxyl-groups, making it structurally distinct from other estrogens. We determined the human metabolic profile of E4, which is recently marketed combined with drospirenone as a novel contraceptive and is currently in development for the relief of menopausal symptoms. Method: We studied the in vitro metabolism of E4 using human hepatocytes, human liver microsomes and recombinant CYP enzymes in reaction phenotyping studies to evaluate the role of human cytochrome P450 enzymes, UDP-glucuronosyltransferases (UGT) and sulfotransferases (SULT). Furthermore, we evaluated the in vivo metabolism of E4 in an open-label, non-randomised phase 1 human absorption, distribution, metabolism, and excretion study, in which six healthy postmenopausal participants received a single oral solution containing 15 mg [14C]-E4. We analysed blood (up to 240h), urine and faecal samples (up to 312h). Metabolite profiling and identification was performed using liquid chromatography with tandem mass spectrometry. Results The in vitro studies showed that E4 undergoes extensive phase 2 metabolism to form glucuronide and sulphate conjugates. UGT2B7 is the key enzyme catalysing the direct glucuronidation of E4 and SULT1E1 is the dominant sulfotransferase for sulphate conjugation in vitro. Unlike for other estrogens, oxidative phase 1 metabolism by P450 enzymes does not play a major role in the metabolism of E4. Following oral administration of E4 to humans, the major metabolites observed in human plasma were E4-16-glucuronide, E4-3-glucuronide and E4-glucuronide-sulfate (respectively 62%, 17% and 9% of radioactivity at the time of maximum plasma concentration [Tmax]). At Tmax, unchanged E4 accounts for only 7.5% of plasma radioactivity. Main metabolites quantified in urine during the first 6 hours after administration were E4-16-glucuronide and E4-3-glucuronide (respectively 77.4% and 16.5% of urine radioactivity). Approximately 69% of the total administered radioactivity was recovered in urine and 22% in faeces. Mass spectrometry showed that E4 was not present in urine but was detected in faeces and that E4 is not converted back into one of the other natural estrogens (estriol, estradiol, estrone). Conclusions Altogether, these data suggest that E4 has a unique metabolic profile. E4 is a terminal end-product of estrogen metabolism, which is not converted back, in vivo, into active metabolites like estriol, estradiol or estrone. Unlike for other estrogens, CYP450 enzymes do not play a major role in the metabolic pathway of E4. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:48 p.m. - 12:53 p.m.

Background Human papillomavirus (HPV) vaccination protects against HPV, a necessary risk factor for cervical cancer. We now report results from population-based follow-up of randomised cohorts that vaccination provides HPV-type-specific protection against invasive cancer. Methods Individually and/or cluster randomised cohorts of HPV-vaccinated and non-vaccinated women were enrolled in 2002–2005. HPV vaccine cohorts comprised originally 16–17 year-old HPV 16/18-vaccinated PATRICIA ( NCT00122681 ) and 012 trial ( NCT00169494 ) participants (2465) and HPV6/11/16/18-vaccinated FUTURE II ( NCT00092534 ) participants (866). Altogether, 3341 vaccines were followed by the Finnish Cancer Registry in the same way as 16 526 non-HPV-vaccinated controls. The control cohort stemmed from 15 665 originally 18–19 years-old women enrolled in 2003 (6499) or 2005 (9166) and 861 placebo recipients of the FUTURE II trial. The follow-up started 6 months after the clinical trials in 2007 and 2009 and ended in 2019. It was age aligned for the cohorts. Findings During a follow-up time of up to 11 years, we identified 17 HPV-positive invasive cancer cases (14 cervical cancers, 1 vaginal cancer, 1 vulvar cancer and 1 tongue cancer) in the non-HPV-vaccinated cohorts and no cases in the HPV-vaccinated cohorts. HPV typing of diagnostic tumour blocks found HPV16 in nine cervical cancer cases, HPV18, HPV33 and HPV52 each in two cases and HPV45 in one cervical cancer case. The vaginal, vulvar and tongue cancer cases were, respectively, positive for HPV16, HPV52/66 and HPV213. Intention-to-treat vaccine efficacy against all HPV-positive cancers was 100% (95% CI 2 to 100, p<0.05). Interpretation Vaccination is effective against invasive HPV-positive cancer. Trial registration number NCT00122681 , Post-results; NCT00169494 , Post-results; NCT00092534 , Post-results.

Introduction We conducted a community-randomized trial (NCTBLINDED) in Finland to assess gender-neutral and girls-only vaccination strategies with the AS04-adjuvanted human papillomavirus (HPV)-16/18 (AS04-HPV-16/18)vaccine. Methods Girls and boys (12-15 years) were invited. We randomized 33 communities (1:1:1 ratio): Arm A: 90% of randomly selected girls and boys received AS04-HPV-16/18 vaccine and 10% received hepatitis B vaccine (HBV); Arm B: 90% of randomly selected girls received AS04-HPV-16/18 vaccine, 10% of girls received HBV, and all boys received HBV; Arm C: all participants received HBV. Effectiveness measurements against prevalence of HPV-16/18 cervical infection were estimated in girls at 18.5 years. The main measures were: (1) overall effectiveness comparing Arms A or B, regardless of vaccination status, vs Arm C; (2) total effectiveness comparing AS04-HPV-16/18 vaccinated girls in pooled Arms A/B vs Arm C; (3) indirect effectiveness (herd effect) comparing girls receiving HBV or unvaccinated in Arm A vs Arm C. Co-primary objectives were overall effectiveness following gender-neutral or girls-only vaccination. Results Of 80,272 adolescents invited, 34,412 were enrolled. Overall effectiveness was 23.8% (95% confidence interval: -19.0, 51.1; P = 0.232) with gender-neutral vaccination. Following girls-only vaccination, overall effectiveness was 49.6% (20.1, 68.2; P = 0.004). Total effectiveness was over 90% regardless of vaccination strategy. No herd effect was found. Immunogenicity of the AS04-HPV-16/18 vaccine was high in both sexes. Conclusions This study illustrates the difficulty in conducting community randomized trials. It is not plausible that vaccinating boys would reduce overall effectiveness, and the apparent lack of herd effect was unexpected given findings from other studies. This analysis was likely confounded by several factors but confirms the vaccine's high total effectiveness as in clinical trials.

Background Quadrivalent and bivalent vaccines against oncogenic human papillomavirus (HPV) are used worldwide with different reported overall efficacies against HPV infections. Although protective concentrations of vaccine-induced antibodies are still not formally defined, we evaluated the sustainability of neutralising antibodies in vaccine trial participants 2-12 years after vaccination and the correlation with reported vaccine efficacy. Methods We did a follow-up analysis of data from the Finnish cohorts of two international, randomised, double -blind, phase 3 trials of HPV vaccines, PATRICIA (bivalent, HPV16 and 18) and FUTURE II (quadrivalent, HPV6, 11, 16, and 18). In 2002 and 2004-05, respectively, Finnish girls aged 16-17 years participated in one of these two trials and consented to health registry follow-up with the Finnish Cancer Registry. The cohorts were also linked with the Finnish Maternity Cohort (FMC) that collects first-trimester serum samples from nearly all pregnant Finnish women, resulting in 2046 post-vaccination serum samples obtained during up to 12 years of follow-up. We obtained serum samples from the FMC-based follow-up of the FUTURE II trial (from the quadrivalent vaccine recipients) and the PATRICIA trial (from corresponding bivalent vaccine recipients who were aligned by follow-up time, and matched by the number of pregnancies). We assessed neutralising antibody concentrations (type-specific seroprevalence) to HPV6, 16, and 18, and cross-neutralising antibody responses to non-vaccine HPV types 31, 33, 45, 52, and 58 from 2 to 12 years after vaccination. Findings Up to Dec 31, 2016, we obtained and analysed 577 serum samples from the quadrivalent vaccine recipients and 568 from the bivalent vaccine recipients. In 681 first-pregnancy serum samples, neutralising antibodies to HPV6, 16, and 18 were generally found up to 12 years after vaccination. However, 51 (15%) of 339 quadrivalent vaccine recipients had no detectable HPV18 neutralising antibodies 2-12 years after vaccination, whereas all 342 corresponding bivalent vaccine recipients had HPV18 neutralising antibodies.. In seropositive quadrivalent vaccine recipients, HPV16 geometric mean titres (GMT) halved by years 5-7 (GMT 3679, 95% CI 2377 to 4708) compared with years 2-4 (6642, 2371 to 13 717). Between 5 and 12 years after vaccination, GMT of neutralising antibodies to HPV16 and 18 were 5middot7 times and 12middot4 times higher, respectively, in seropositive bivalent vaccine recipients than in the quadrivalent vaccine recipients. Cross-neutralising antibodies to HPV31, 33, 45, 52, and 58 were more prevalent in the bivalent vaccine recipients but, when measurable, sustainable up to 12 years after vaccination with similar GMTs in both vaccine cohorts. Seroprevalence for HPV16, 31, 33, 52, and 58 significantly correlated with vaccine efficacy against persistent HPV infections in the bivalent vaccine recipients only (rs=0middot90, 95% CI 0middot09 to 0middot99, p=0middot037, compared with rs=0middot62, 95% CI -0middot58 to 0middot97, p=0middot27 for the quadrivalent vaccine recipients). Correlation of protection with prevalence of neutralising or cross-neutralising HPV antibodies was not significant in the quadrivalent vaccine recipients. Interpretation The observed significant differences in the immunogenicity of the two vaccines are in line with the differences in their cross-protective efficacy. Protective HPV vaccine-induced antibody titres can be detected up to 12 years after vaccination. Funding Academy of Finland and Finnish Cancer Foundation. Copyright (c) 2021 Elsevier Ltd. All rights reserved.

Abstract Objective To compare systemic exposure to levonorgestrel (LNG) released from commercially available intrauterine systems (IUSs), a subdermal implant, and oral contraceptives. Methods An integrated population pharmacokinetic (popPK) analysis of data from over 3400 individuals in ten clinical studies with six different LNG-releasing contraceptives (four long-acting reversible contraceptives [LARCs: LNG-IUS 8, 12, and 20, initially releasing LNG 14, 17.5, and 20 μg/day, a subdermal implant initially releasing LNG 100 μg/day according to label]; progestin-only pill [POP: LNG 30 μg/day]; and combined oral contraceptive [COC] pill [LNG 100 μg/day and ethinylestradiol 20 μg/day]), was conducted to generate a popPK model. LNG release rates, and total and unbound serum/plasma LNG concentrations with LARCs were estimated over the indicated period of use; maximum (Cmax) and average (Cav) serum LNG concentrations were estimated at steady state for oral contraceptives. Influence of body weight on LNG PK was also investigated. Results Serum LNG concentration with LARCs increased with increasing daily LNG release rate, being lowest with LNG-IUS 8, higher with LNG-IUS 12 and LNG-IUS 20, and highest with the subdermal implant (1.7–2.1-times that with LNG-IUS 20). Compared with early serum LNG concentrations with LNG-IUS 20, Cav and Cmax were 1.7- and 4.5-fold higher with POP, and 8.6- and 18-fold higher with COC. Total LNG bioavailability was >97% for the LNG-IUSs and 66–80% with other contraceptives. Serum/plasma LNG concentrations decreased with increasing body weight. Conclusions Among the contraceptives examined, COC had the highest and LNG-IUSs the lowest systemic exposure to LNG. Systemic LNG concentration was inversely correlated to body weight.

A safe childhood respecting sexual rights forms the foundation of an individual’s sexual health. However, the understanding, support, and protection of early sexuality are seldom discussed. Children already express their sexuality verbally and behaviorally in daycare, often requiring a response from staff. These day-to-day situations may have an influence on children’s later sexuality. The World Health Organization Regional Office for Europe and BZgA (2010) published a framework for professionals on age-appropriate, holistic sexuality education. Using this framework, we evaluated children’s sexuality-related expressions in Finnish daycare. Our nationwide questionnaire among professionals in early childhood education and care (n = 507) focused on how 1–6-year-old children expressed their sexuality in their speech and behavior. All eight topics in the WHO framework emerged regularly. The two most prevalent topics were the body and emotions. Also, 71% of professionals had a child in their group who masturbated openly. Early sexual development manifested as curiosity about one’s own body, exploring its functions, traits, and attributes, while on an emotional level it manifested as abundant feelings of infatuation and tenderness, shown openly toward those—peers and adults alike—whom the child cares for. Childhood sexuality is broadly and diversely present in children’s verbal and behavioral expressions in daycare settings. Children need and have the right to receive explicit responses related to issues concerning their sexual development and to receive age-appropriate information, skills, and attitudes fostering healthy development.