Early-pregnancy sex steroid and thyroid function hormones, thyroid autoimmunity, and maternal papillary thyroid cancer incidence in the Finnish Maternity Cohort.

Thyroid cancer more commonly affects women than men and is the third most frequently diagnosed cancer among women of reproductive age. We conducted a nested case-control study within the Finnish Maternity Cohort to evaluate pre-diagnostic sex steroid and thyroid function markers in relation to subsequent maternal papillary thyroid cancer. Cases (n = 605) were women ages 18-44 years, who provided an early-pregnancy (<20 weeks gestation) blood sample and were diagnosed with papillary thyroid cancer up to 11 years afterward. Controls (n = 1185) were matched to cases 2:1 by gestational age, mother's age, and date at blood draw. Odds ratios (ORs) for the associations of serum thyroid peroxidase antibodies (TPO-Ab), thyroglobulin antibodies (Tg-Ab), thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), progesterone, and estradiol with papillary thyroid cancer were estimated using conditional logistic regression. TPO-Ab and Tg-Ab positivity (>95th percentile among controls) were associated with more than 3-fold (OR = 3.32, 95% confidence interval [CI] 2.33-4.72) and 2-fold (OR = 2.03, 95% CI 1.41-2.93) increased odds of papillary thyroid cancer, respectively. These associations were similar by time since blood draw, parity, gestational age, smoking status, and age and stage at diagnosis. In models excluding TPO-Ab or Tg-Ab positivity, TPO-Ab (quartile 4 vs. 1: OR = 1.66, 95% CI 1.17-2.37, p-trend = .002) and Tg-Ab (quartile 4 vs. 1: OR = 1.74, 95% CI 1.22-2.49, p-trend = .01) levels were positively associated with papillary thyroid cancer. No associations were observed for estradiol, progesterone, TSH, fT3, or fT4 overall. Our results suggest that thyroid autoimmunity in early pregnancy may increase the risk of maternal papillary thyroid cancer.

Prediagnostic serum concentrations of per- and polyfluoroalkyl substances and risk of papillary thyroid cancer in the Finnish Maternity Cohort.

Human exposure to per- and polyfluoroalkyl substances (PFAS) occurs globally through contaminated food, dust, and drinking water. Studies of PFAS and thyroid cancer have been limited. We conducted a nested case-control study of prediagnostic serum levels of 19 PFAS and papillary thyroid cancer (400 cases, 400 controls) in the Finnish Maternity Cohort (pregnancies 1986-2010; follow-up through 2016), individually matched on sample year and age. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for log2 transformed and categorical exposures, overall and stratified by calendar period, birth cohort, and median age at diagnosis. We adjusted for other PFAS with Spearman correlation rho = 0.3-0.6. Seven PFAS, including perfluoroctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), N-ethyl-perfluorooctane sulfonamidoacetic acid (EtFOSAA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluorohexane sulfonic acid (PFHxS) were detected in >50% of women. These PFAS were not associated with risk of thyroid cancer, except for PFHxS, which was inversely associated (OR log2 = 0.82, 95% CI: 0.70-0.97). We observed suggestive but imprecise increased risks associated with PFOA, PFOS, and EtFOSAA for those diagnosed at ages <40 years, whereas associations were null or inverse among those diagnosed at 40+ years (P-interaction: .02, .08, .13, respectively). There was little evidence of other interactions. These results show no clear association between PFAS and papillary thyroid cancer risk. Future work would benefit from evaluation of these relationships among those with higher exposure levels and during periods of early development when the thyroid gland may be more susceptible to environmental harms.

Sexually Transmitted Infections and Risk of Epithelial Ovarian Cancer: Results From the Finnish Maternity Cohort.

BACKGROUND: Sexually transmitted infections, specifically Chlamydia trachomatis (CT), may be associated with epithelial ovarian cancer (EOC) risk. The association between CT and EOC subtypes is unclear. Our aim was to investigate whether history of CT and other infections (Mycoplasma genitalium [MG], herpes simplex virus type 2 [HSV-2], and human papillomavirus [HPV]) are associated with EOC risk by histotype. METHODS: We measured antibodies (Abs) to CT, MG, HSV-2, and HPV-16/18 in serum samples in a nested case-control study in the Finnish Maternity Cohort (N = 484 cases 1:1 matched to controls). Logistic regression was used to calculate relative risks (RRs) and 95% confidence intervals (CIs) in seropositive versus seronegative individuals in all cases, as well as serous (n = 249), clear cell and endometrioid (n = 91), and mucinous (n = 144) EOC. RESULTS: CT seropositivity was not associated with EOC risk (eg, CT pGP3-Ab: RR, 0.92 [95% CI, .72-1.19]), regardless of disease subtype. We observed a positive association between MG seropositivity and mucinous EOC (RR, 1.66 [95% CI, 1.09-2.54]; P for heterogeneity by histotype ≤ .001), but not other subtypes. No associations were observed with seropositivity to multiple STIs. CONCLUSIONS: CT infection was not associated with EOC risk, with associations observed only for MG and mucinous EOC. Mechanisms linking MG to mucinous EOC remain to be elucidated.

Associations of low sex hormone-binding globulin and androgen excess in early pregnancy with fasting and post-prandial hyperglycaemia, gestational diabetes, and its severity.

AIMS: We studied whether androgen excess and low sex hormone-binding globulin (SHBG) measured in early pregnancy are independently associated with fasting and post-prandial hyperglycaemia, gestational diabetes (GDM), and its severity. MATERIALS AND METHODS: This nationwide case-control study included 1045 women with GDM and 963 non-diabetic pregnant controls. We measured testosterone (T) and SHBG from biobanked serum samples (mean 10.7 gestational weeks) and calculated the free androgen index (FAI). We first studied their associations with GDM and secondly with the type of hyperglycaemia (fasting, 1 and 2 h glucose concentrations during the oral glucose tolerance test), early-onset GDM (<20 gestational weeks) and the need for anti-diabetic medication. RESULTS: After adjustments for gestational weeks at sampling, pre-pregnancy BMI, and age, women with GDM had 3.7% (95% CI 0.1%-7.3%) lower SHBG levels, 3.1% (95% CI 0.1%-6.2%) higher T levels, and 4.6% (95% CI 1.9%-7.3%) higher FAI levels than controls. SHBG was inversely associated with fasting glucose, whereas higher FAI and T were associated with higher post-prandial glucose concentrations. Women with early-onset GDM had 6.7% (95% CI 0.7%-12.7%) lower SHBG levels and women who needed insulin for fasting hyperglycaemia 8.7% (95% CI 1.8%-14.8%) lower SHBG levels than other women with GDM. CONCLUSIONS: Lower SHBG levels were associated especially with early-onset GDM, higher fasting glucose and insulin treatment, whereas androgen excess was associated with higher post-prandial glucose values. Thus, a low SHBG level may reflect the degree of existing insulin resistance, while androgen excess might impair post-prandial insulin secretion.

Maternal serum persistent organic pollutant exposure and offspring diagnosed ADHD in a national birth cohort.

BACKGROUND: Evidence implicates environmental factors in attention-deficit/hyperactivity disorder (ADHD) risk. Prenatal exposures to polychlorinated biphenyls (PCBs) and the pesticide metabolite p,p'-dichlorodiphenyl dichloroethylene (DDE) have been linked to lower cognitive ability, increased impulsivity, and attention related deficits in the offspring. However, information on the relationship of these exposures to the risk of clinically diagnosed ADHD is limited. OBJECTIVES: To determine whether prenatal maternal levels of PCBs or DDE are associated with ADHD diagnosis in the offspring. METHODS: The investigation was conducted in the Finnish Prenatal Study of ADHD (FIPS-ADHD), a case-control study nested in a national birth cohort. Cases were born in 1998 or 1999 and diagnosed with ADHD (ICD-9 314x or ICD-10 F90. x) according to the national Care Register for Health Care. Each case was individually matched to a control on sex, date, and place of birth. PCB congeners (PCB 74, 99, 118, 138, 153, 156, 170, 180, 183, 187) and DDE were quantified from archived prenatal maternal sera from 359 matched case-control pairs using gas chromatography - high triple quadrupole mass spectrometry. Maternal total PCBs were quantified as the sum of concentrations of the measured congeners. Associations with ADHD were examined using conditional logistic regression. RESULTS: Maternal PCB or DDE levels greater than the 75th percentiles of the control distributions showed no evidence of association with offspring ADHD (PCBs: adjusted odds ratio (aOR) = 1.01, 95% CI = 0.63, 1.60), p = 0.98; DDE: aOR = 1.13, 95% CI = 0.71, 1.81; p = 0.60). Maternal levels of either pollutant dichotomized at the 90th percentile or considered as a continuous variable also did not show evidence for association with offspring ADHD diagnosis. DISCUSSION: This study did not find evidence for association of maternal prenatal levels of PCBs or DDE with clinical diagnosis of offspring ADHD; however, this does not rule out the possibility of an impact on subclinical phenotypes.

Iodine and thyroid status during pregnancy and risk of stillbirth: A population-based nested case-control study.

Prior research suggests that severe iodine deficiency in pregnancy may be associated with stillbirth. However, the relationship between mild to moderate iodine insufficiency, which is prevalent even in developed countries, and risk of stillbirth is unclear. We thus examined associations of iodine status and risk of stillbirth in a prospective population-based nested case-control study in Finland, a mild to moderately iodine insufficient population. Stillbirth cases (n = 199) and unaffected controls (n = 249) were randomly selected from among all singleton births in Finland from 2012 to 2013. Serum samples were collected between 10 and 14 weeks gestation and analysed for iodide, thyroglobulin (Tg) and thyroid-stimulating hormone (TSH). Odds ratios (ORs) and 95% confidence intervals (CIs) for stillbirth were estimated using logistic regression. After adjusting for maternal age, prepregnancy body mass index, socio-economic status and other factors, neither high nor low serum iodide was associated with risk of stillbirth (Q1 vs. Q2-Q3 OR = 0.92, 95% CI = 0.78-1.09; Q4 vs. Q2-Q3 OR = 0.78; 95% CI = 0.45-1.33). Tg and TSH were also not associated with risk of stillbirth in adjusted models. Maternal iodine status was not associated with stillbirth risk in this mildly to moderately iodine-deficient population. Tg and TSH, which reflect functional iodine status, were also not associated with stillbirth risk. The lack of associations observed between serum iodide, TSH and Tg and risk of stillbirth is reassuring, given that iodine deficiency in pregnancy is prevalent in developed countries.

Sustained Cross-reactive Antibody Responses After Human Papillomavirus Vaccinations: Up to 12 Years Follow-up in the Finnish Maternity Cohort.

BACKGROUND: Human papillomaviruses (HPV) cause several human cancers. Bivalent (Cervarix) and quadrivalent (qGardasil) HPV vaccines both contain virus-like particles of the major oncogenic HPV types 16 and 18, but also cross-protect against some nonvaccine types. However, data on long-term sustainability of the cross-reactive antibody responses to HPV vaccines are scarce. METHODS: Serum samples donated 7-12 years after immunization at age 16-17 years with bivalent (n = 730) or quadrivalent (n = 337) HPV vaccine were retrieved from the population-based Finnish Maternity Cohort biobank. Serum antibody levels against HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, and 73 were determined using multiplex pseudovirion binding assay. Antibody avidity was assessed using ammonium thiocyanate treatment. RESULTS: Seropositivity for HPV31, 33, 35, 45, 51, 52, 58, 59, 68, and 73 was increasingly common (P ≤ .001; χ 2 test for trend for each of these types) when women had high anti-HPV16 antibody levels. For 8 nonvaccine HPV types seropositivity was more common among recipients of bivalent than quadrivalent vaccine, in particular for HPV31, 35, 45, 51, 52, and 58 (P < .001). Antibody avidity was higher in the quadrivalent vaccine recipients for HPV6, 11, and two of the nonvaccine types, but lower for HPV16 and 18 (P < .001). CONCLUSIONS: Both vaccines elicit cross-reactive antibodies detectable even 12 years after vaccination. Cross-reactive seropositivity is more common in women with high anti-HPV16 antibody response and in the bivalent vaccine recipients.

Human papillomavirus seroprevalence in pregnant women following gender-neutral and girls-only vaccination programs in Finland: A cross-sectional cohort analysis following a cluster randomized trial.

BACKGROUND: Cervical cancer elimination through human papillomavirus (HPV) vaccination programs requires the attainment of herd effect. Due to its uniquely high basic reproduction number, the vaccination coverage required to achieve herd effect against HPV type 16 exceeds what is attainable in most populations. We have compared how gender-neutral and girls-only vaccination strategies create herd effect against HPV16 under moderate vaccination coverage achieved in a population-based, community-randomized trial. METHODS AND FINDINGS: In 2007-2010, the 1992-1995 birth cohorts of 33 Finnish communities were randomized to receive gender-neutral HPV vaccination (Arm A), girls-only HPV vaccination (Arm B), or no HPV vaccination (Arm C) (11 communities per trial arm). HPV16/18/31/33/35/45 seroprevalence differences between the pre-vaccination era (2005-2010) and post-vaccination era (2011-2016) were compared between all 8,022 unvaccinated women <23 years old and resident in the 33 communities during 2005-2016 (2,657, 2,691, and 2,674 in Arms A, B, and C, respectively). Post- versus pre-vaccination-era HPV seroprevalence ratios (PRs) were compared by arm. Possible outcome misclassification was quantified via probabilistic bias analysis. An HPV16 and HPV18 seroprevalence reduction was observed post-vaccination in the gender-neutral vaccination arm in the entire study population (PR16 = 0.64, 95% CI 0.10-0.85; PR18 = 0.72, 95% CI 0.22-0.96) and for HPV16 also in the herpes simplex virus type 2 seropositive core group (PR16 = 0.64, 95% CI 0.50-0.81). Observed reductions in HPV31/33/35/45 seroprevalence (PR31/33/35/45 = 0.88, 95% CI 0.81-0.97) were replicated in Arm C (PR31/33/35/45 = 0.79, 95% CI 0.69-0.90). CONCLUSIONS: In this study we only observed herd effect against HPV16/18 after gender-neutral vaccination with moderate vaccination coverage. With only moderate vaccination coverage, a gender-neutral vaccination strategy can facilitate the control of even HPV16. Our findings may have limited transportability to other vaccination coverage levels. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00534638, https://clinicaltrials.gov/ct2/show/NCT00534638.

Maternal serum Vitamin B12 and offspring attention-deficit/hyperactivity disorder (ADHD).

Maternal Vitamin B12 deficiency during pregnancy is associated with offspring neuropsychiatric disorders. Few previous studies examining this association with attention-deficit/hyperactivity disorder (ADHD) report inconsistent findings. The study examines the association between maternal serum Vitamin B12 levels and offsprings' risk of ADHD. This study is based on the Finnish Prenatal Study of ADHD with a nested case-control design. All the singleton children born in Finland between January 1998 and December 1999 and diagnosed with ADHD were included in the study. A total of 1026 cases were matched with an equal number of controls on sex, date of birth and place of birth. Maternal Vitamin B12 levels were assessed using a chemiluminescence microparticle immunoassay and archived from maternal serum banks, collected during the first and early second trimester of pregnancy. Lower maternal Vitamin B12 levels when analyzed as a continuous variable was not associated with offspring ADHD (aOR 0.97, 95% CI 0.79-1.18, p = 0.75). No significant associations were seen in the lowest quintile of Vitamin B12 levels (aOR 0.96, 95% CI 0.73-1.27, p = 0.80). This is the first study examining maternal sera Vitamin B12 levels during early pregnancy and offspring ADHD. The result suggests that Vitamin B12 deficiency during early pregnancy has specificity for some disorders but not with offspring ADHD.

Long-term follow-up of human papillomavirus type replacement among young pregnant Finnish females before and after a community-randomised HPV vaccination trial with moderate coverage.

Large scale human papillomavirus (HPV) vaccination against the most oncogenic high-risk human papillomavirus (HPV) types 16/18 is rapidly reducing their incidence. However, attempts at assessing if this leads to an increase of nonvaccine targeted HPV types have been hampered by several limitations, such as the inability to differentiate secular trends. We performed a population-based serological survey of unvaccinated young women over 12 years. The women were under 23-years-old, residents from 33 communities which participated in a community-randomised trial (CRT) with approximately 50% vaccination coverage. Serum samples were retrieved pre-CRT and post-CRT implementation. Seropositivity to 17 HPV types was assessed. HPV seroprevalence ratios (PR) comparing the postvaccination to prevaccination era were estimated by trial arm. This was also assessed among the sexual risk-taking core group, where type replacement may occur more rapidly. In total, 8022 serum samples from the population-based Finnish Maternity Cohort were retrieved. HPV types 16/18 showed decreased seroprevalence among the unvaccinated in communities only after gender-neutral vaccination (PR16/18A = 0.8, 95% CI 0.7-0.9). HPV6/11 and HPV73 were decreased after gender-neutral vaccination (PR6/11A = 0.8, 95% CI 0.7-0.9, PR73A = 0.7, 95% CI 0.6-0.9, respectively) and girls-only vaccination (PR6/11B = 0.8, 95% CI 0.7-0.9, PR73B = 0.9, 95% CI 0.8-1.0). HPV68 alone was increased but only after girls-only vaccination (PR68B = 1.3, 95% CI 1.0-1.7, PRcore68B = 2.8, 95% CI 1.2-6.3). A large-scale, long-term follow-up found no type replacement in the communities with the strongest reduction of vaccine HPV types. Limited evidence for an increase in HPV68 was restricted to girls-only vaccinated communities and may have been due to secular trends (ClinicalTrials.gov number: NCT00534638).

Epstein-barr virus and multiple sclerosis risk in the finnish maternity cohort.

OBJECTIVE: To determine whether maternal Epstein-Barr virus (EBV) IgG antibody levels are associated with risk of multiple sclerosis (MS) in the offspring. METHODS: We conducted a prospective nested case-control study in the Finnish Maternity Cohort (FMC) with serum samples from >800,000 women collected during pregnancy since 1983. Cases of MS among offspring born between 1983 and 1991 were identified via hospital and prescription registries; 176 cases were matched to up to 3 controls (n = 326) on region and dates of birth, sample collection, and mother's birth. We used conditional logistic regression to estimate relative risks (RRs) and adjusted models for sex of the child, gestational age at sample collection, and maternal serum 25-hydroxyvitamin D and cotinine levels. Similar analyses were conducted among 1,049 women with MS and 1,867 matched controls in the FMC. RESULTS: Maternal viral capsid antigen IgG levels during pregnancy were associated with an increased MS risk among offspring (RRtop vs bottom quintile = 2.44, 95% confidence interval [CI] = 1.20-5.00, p trend = 0.004); no associations were found between maternal EBV nuclear antigen 1 (EBNA-1), diffuse early antigen, or cytomegalovirus IgG levels and offspring MS risk. Among women in the FMC, those in the highest versus lowest quintile of EBNA-1 IgG levels had a 3-fold higher risk of MS (RR = 3.21, 95% CI = 2.37-4.35, p trend <1.11e-16). These associations were not confounded or modified by 25-hydroxyvitamin D. INTERPRETATION: Offspring of mothers with high viral capsid antigen IgG during pregnancy appear to have an increased risk of MS. The increase in MS risk among women with elevated prediagnostic EBNA-1 IgG levels is consistent with previous results. ANN NEUROL 2019;86:436-442.

Prevalence and persistence of Chlamydia trachomatis-specific antibodies after occasional and recurrent infections.

OBJECTIVES: Population-based Chlamydia trachomatis seroepidemiological studies help to identify trends in chlamydia infection. However, an improved understanding of the antibody response to infection is required when using serology to estimate cumulative incidence. Thus, the objectives of this longitudinal, retrospective, biobank-based study were to assess the appearance and persistence of C. trachomatis major outer membrane protein (MOMP)-specific serum IgG antibodies after infection and to evaluate the role of antibodies in providing protective immunity against recurrent infection. METHODS: Data of notified C. trachomatis infections in Finland were obtained from the National Infectious Diseases Register. Serum samples were acquired from the Finnish Maternity Cohort. 411 women with single chlamydia infection and 62 women with recurrent infections, and for whom suitable paired serum samples were available, were included in the study. Antibody appearance, persistence after infection and the impact of recurrent infections were evaluated. IgG antibodies specific for MOMP were measured from serum using an ELISA method. RESULTS: Anti-C. trachomatis MOMP-specific IgG antibodies were detected in 65.5% (269/411) of women within 3 months of notification of infection. In the absence of recurrent infection, seroprevalence declined to 34.5% (142/411) 3-10 years after the initial infection. The serum antibody levels at baseline correlated positively with seroprevalence at follow-up. Reinfection boosted the humoral immune response by increasing seroprevalence and the serum antibody levels. Seroprevalence within 3 months after first notification of infection was 65.5% (19/29) in women who were later diagnosed with recurrent infection, comparable with women with single notification of infection (65.5%, 269/411). CONCLUSIONS: Approximately one-third of women with single notification of chlamydia infection remain seropositive 3-10 years after the initial infection. The concentration of antibodies remained stable during the follow-up. Recurrent infection boosted the humoral immune response, but reinfection occurred despite the presence of pre-existing antibodies.

Smoking during pregnancy reduces vitamin D levels in a Finnish birth register cohort.

OBJECTIVE: Maternal vitamin D level in pregnancy may have implications for both the mother and fetus. Deficiency of vitamin D has been linked to several pregnancy complications and fetal skeletal health. Smoking has been associated with reduced serum level of the vitamin D metabolite, 25-hydroxyvitamin D (25(OH)D). DESIGN: A nested case-control study within the Finnish Maternity Cohort, a population-based cohort which includes first-trimester sera from 98 % of pregnancies in Finland since 1987. The selection consisted of women with uncomplicated pregnancies. We studied serum concentration of 25(OH)D in 313 non-smoking and forty-six self-reported smoking pregnant women. SETTING: We hypothesize that pregnant smokers may have an increased risk of low 25(OH)D levels especially during winter months. PARTICIPANTS: A control group from an unpublished pregnancy complication study consisting of 359 uncomplicated pregnancies. Individuals who reported that they do not smoke were considered 'non-smokers' (n 313) and those who reported continued smoking after the first trimester of pregnancy were considered 'smokers' (n 46). RESULTS: Smokers had significantly lower levels of 25(OH)D irrespective of sampling time (P<0·0001). Furthermore, during the low sun-exposure season, only 14 % of smokers met the guideline level of 40 nmol/l for serum 25(OH)D in comparison with 31 % of non-smokers. CONCLUSIONS: Expectant mothers who smoke have an increased risk of vitamin D deficiency during low sun-exposure months in northern regions. Further studies are needed to assess the associated risks for maternal and fetal health as well as possible long-term implications for the infant.

Maternal serum C-reactive protein (CRP) and offspring attention deficit hyperactivity disorder (ADHD).

Exposure to infection and inflammation during the fetal period are associated with offspring neuropsychiatric disorders. Few previous studies have examined this association with ADHD with mixed findings. This study aims to examine the association between early gestational maternal C-reactive protein (CRP), prospectively assayed in stored maternal sera and the risk of ADHD in offspring. This study is based on the Finnish Prenatal studies of ADHD (FIPS-ADHD) with a nested case-control design. It includes all singleton-born children in Finland between January 1, 1998 and December 31, 1999 and diagnosed with ADHD. A total of 1079 cases and equal number of controls were matched on date of birth, sex and place of birth. Maternal CRP levels were assessed using a latex immunoassay from archived maternal serum specimens, collected during the first and early second trimester of pregnancy. Elevated maternal CRP when analyzed as a continuous variable was not associated with offspring ADHD (OR 1.05, 95% CI 0.96-1.15). No significant associations were seen in the highest quintile of CRP (OR 1.18, 95% CI 0.88-1.58). The results were similar in both sexes as well as among ADHD cases with or without comorbid ASD or conduct disorder. In this first study examining CRP, a biomarker for inflammation, during early pregnancy in relation to offspring ADHD, we report no significant associations. The lack of any association, when considered with positive findings seen in ASD and schizophrenia, and negative findings in bipolar disorder suggests different pathways linking maternal immune activation and development of various neuropsychiatric disorders.

Long-term Antibody Response to Human Papillomavirus Vaccines: Up to 12 Years of Follow-up in the Finnish Maternity Cohort.

Background: Most cervical cancers are caused by vaccine-preventable infections with human papillomaviruses (HPV). The HPV prophylactic vaccines Gardasil and Cervarix have been widely used for >10 years and are reported to induce high antibody levels. A head-to-head comparison of the antibody responses induced by the 2 vaccines has been performed only up to 5 years. Methods: Among 3300 Finnish females aged 16-17 years who got 1 of the 2 HPV vaccines in phase 3 licensure trials, virtually all consented to registry-based long-term follow-up. Linkage with the Finnish Maternity Cohort found that they donated >2500 serum samples up to 12 years later. Sera of 337 (38.6%) Gardasil and 730 (30.3%) Cervarix vaccine recipients were retrieved from the Finnish Maternity Cohort biobank and type-specific anti-HPV antibody levels were determined using in-house multiplexed heparin-HPV pseudovirion Luminex assay. Results: Anti-HPV-16 and anti-HPV-18 antibody levels remained stable and above natural infection-related antibody levels for up to 12 years for most vaccine recipients. The median antibody levels were higher among Cervarix recipients 7-12 years post vaccination (P < .0001). Conclusions: The stability of vaccine-induced antibody levels is in accordance with the high long-term protection reported previously. The differences in antibody levels induced by the 2 vaccines imply that continued follow-up to identify possible breakthrough cases and estimation of the minimal protective levels of serum antibodies is a research priority.

The joint role of thyroid function and iodine concentration on gestational diabetes risk in a population-based study.

INTRODUCTION: Iodine is essential for thyroid function, and iodine deficiency during pregnancy is common in Europe and the USA. However, no published studies have examined the role of iodine deficiency in the relation between thyroid function and gestational diabetes mellitus (GDM). MATERIAL AND METHODS: We conducted a population-based, nested case-control study within the Finnish Maternity Cohort using pregnancy and perinatal outcome data from the Finnish Maternal Birth Register. We randomly selected 224 GDM cases with singleton pregnancies and 224 controls without GDM from all singleton births occurring in Finland during 2012-2013. Blood was drawn at 10-14 weeks' gestation and analyzed for serum iodide, thyroglobulin, and thyroid-stimulating hormone (TSH) concentrations. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) of GDM. RESULTS: Very high thyroglobulin concentration (>95% percentile; >83 µg/L) was not associated with significantly altered odds of GDM compared to those with normal levels (OR 0.41; 95% CI: 0.12, 1.38). High concentrations of TSH were also not associated with increased odds of GDM compared to normal levels of TSH (OR 0.45; 95% CI: 0.06, 3.18). Women in the lowest 5th percentile (<1.58 ng/mL) of iodine did not have increased odds of GDM compared to those with iodide in the highest quartile (OR 0.39; 95% CI: 0.11, 1.35). CONCLUSIONS: Low levels of iodide and thyroid function in early pregnancy are not associated with increased risk of GDM in this mildly iodine-deficient population.

Smoking during pregnancy in Finland - Trends in the MATEX cohort.

Aims: In Finland, smoking rates in the general population are decreasing due to increased awareness of the adverse effects and tightened tobacco legislation. However, previous studies have shown that smoking in pregnant Finnish women remained as high as in the general Finnish female population at around 15% in 2010. Our aim was to describe temporal and spatial trends in smoking behaviour, and determinants of changes in smoking behaviour between first and second pregnancy. Methods: Self-reported smoking from the Finnish Medical Birth Register covered the years 1991-2015 (N=1,435,009). The association of maternal age and socioeconomic status with smoking rate was analysed. Spatial trends were assessed at municipality level. Results: The overall smoking rate during early pregnancy remained fairly stable at around 15% from 1991 to 2015, but increased in teenage and young women below 25 years of age. The mean smoking rate (36%) was higher in these age groups than in older pregnant women (11%). Through the study period the smoking rate remained higher in blue collar workers compared with higher socioeconomic groups. Between the first and second child, on average only 4% of women started to smoke and 41% quitted. Smoking rates developed less favourably in Eastern Finland. Conclusions: The observed increase in smoking rate during pregnancy in teenage and young women is concerning. Pregnancy is a trigger point for smoking cessation in a big fraction of pregnant women. More studies are needed to explain the opposite trends of smoking rates in Northern and Western Finland compared with Eastern Finland.

Impact of gender-neutral or girls-only vaccination against human papillomavirus-Results of a community-randomized clinical trial (I).

Human papillomavirus (HPV) vaccine is efficacious but the real-life effectiveness of gender-neutral and girls-only vaccination strategies is unknown. We report a community-randomized trial on the protective effectiveness [(PE) = vaccine efficacy (VE) + herd effect (HE)] of the two strategies among females in virtually HPV vaccination naïve population. We randomized 33 Finnish communities into Arm A) gender-neutral vaccination with AS04-adjuvanted HPV16/18 vaccine (11 communities), Arm B) HPV vaccination of girls and hepatitis B-virus (HBV) vaccination of boys (11 communities) or Arm C) gender-neutral HBV vaccination (11 communities). All resident 39,420 females and 40,852 males born 1992-95 were invited in 2007-09. Virtually all (99%) 12- to 15-year-old participating males (11,662) and females (20,513) received three doses resulting in uniform 20-30% male and 50% female vaccination coverage by birth cohort. Four years later (2010-14) 11,396 cervicovaginal samples obtained from 18.5 year-old women were tested for HPV DNA, and prevalence of cervical HPV infections by trial arm and birth cohort was the main outcome measure. VEs against HPV16/18 varied between 89.2% and 95.2% across birth cohorts in arms A and B. The VEs against non-vaccine types consistent with cross-protection were highest in those born 1994-95 for HPV45 (VEA 82.8%; VEB 86.1%) and for HPV31 (VEA 77.6%, VEB 84.6%). The HEs in the non HPV-vaccinated were statistically significant in those born 1994-95 for HPV18 (HEA 51.0%; 95% CI 8.3-73.8, HEB 47.2%; 6.5-70.2) and for HPV31/33 in arm A (HEA 53.7%; 22.1-72.5). For HPV16 and 45 no significant herd effects were detected. PE estimates against HPV16/18 were similar by both strategies (PEA 58.1%; 45.1-69.4; PEB 55.7%; 42.9-66.6). PE estimates against HPV31/33 were higher by the gender-neutral vaccination (PEA 60.5%; 43.6-73.4; PEB 44.5%; 24.9-60.6). In conclusion, while gender-neutral strategy enhanced the effectiveness of HPV vaccination for cross-protected HPV types with low to moderate coverage, high coverage in males appears to be key to providing a substantial public health benefit also to unvaccinated females. Trial registration www.clinicaltrials.gov.com NCT000534638.

Gender-neutral vaccination provides improved control of human papillomavirus types 18/31/33/35 through herd immunity: Results of a community randomized trial (III).

With optimal strategy, human papillomavirus (HPV) vaccines have the potential to control HPV. We have assessed vaccine efficacy (VE), herd effect (HE) of HPV vaccination and overall protective effectiveness (PE) against high-risk HPV infections by HPV type and vaccination strategy in a community-randomized trial using the bivalent HPV16/18 vaccine. We randomized 33 communities to gender-neutral HPV vaccination (Arm A), HPV vaccination of girls and hepatitis B-virus (HBV) vaccination of boys (Arm B) and gender-neutral HBV vaccination (Arm C). Entire 1992-1995 male (40,852) and female (39,420) birth cohorts were invited, and 11,662 males and 20,513 females vaccinated with 20-30% and 45% coverage in 2007-2010. During 2010-2014, 11,396 cervicovaginal samples were collected from 13,545 18.5-year-old attendees. HPV typing was performed by a high-throughput PCR. VE was calculated for HPV vaccinated women and HE for non-HPV-vaccinated women, using the HBV vaccinated, for HE all non-HPV vaccinated, Arm C women as controls. PE was calculated as coverage rate-weighted mean of VE + HE. HPV16/18/45 and 31/33/35 VEs varied between 86-94% and 30-66%, respectively. Only the gender-neutral vaccination provided significant HEs against HPV18 (61%) and HPV31 (72%) in the 1995 birth cohort-increased HEs against HPV33 (39%) and HPV35 (42%) were also observed. Due to the increased HEs, PEs for HPV16/18/45 and HPV31/33/35 were comparable in the gender-neutral arm 1995 birth cohort. High vaccine efficacy against HPV16/18/45 and, gender-neutral vaccination-enforced, herd effect against HPV18/31/33/35 by the bivalent vaccine rapidly provides comparable overall protective effectiveness against six oncogenic HPV types: 16/18/31/33/35/45.