Tyra Grove Krause

Risk of Adverse Fetal Outcomes Following Administration of a Pandemic Influenza A(H1N1) Vaccine During Pregnancy

CONTEXT Assessment of the fetal safety of vaccination against influenza A(H1N1)pdm09 in pregnancy has been limited. OBJECTIVE To investigate whether exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was associated with increased risk of adverse fetal outcomes. DESIGN, SETTING, AND PARTICIPANTS Registry-based cohort study based on all liveborn singleton infants in Denmark, delivered between November 2, 2009, and September 30, 2010. In propensity score-matched analyses, we estimated prevalence odds ratios (PORs) of adverse fetal outcomes, comparing infants exposed and unexposed to an AS03-adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy. MAIN OUTCOME MEASURES Major birth defects, preterm birth, and small size for gestational age. RESULTS From a cohort of 53,432 infants (6989 [13.1%] exposed to the influenza A[H1N1]pdm09 vaccine during pregnancy [345 in the first trimester and 6644 in the second or third trimester]), 660 (330 exposed) were included in propensity score-matched analyses of adverse fetal outcomes associated with first-trimester exposure. For analysis of small size for gestational age after second- or third-trimester exposure, 13,284 (6642 exposed) were included; for analyses of preterm birth, 12,909 (6543 exposed) were included. A major birth defect was diagnosed in 18 of 330 infants (5.5%) exposed to the vaccine in the first trimester, compared with 15 of 330 unexposed infants (4.5%) (POR, 1.21; 95% CI, 0.60-2.45). Preterm birth occurred in 31 of 330 infants (9.4%) exposed in the first trimester, compared with 24 of 330 unexposed infants (7.3%) (POR, 1.32; 95% CI, 0.76-2.31), and in 302 of 6543 infants (4.6%) with second- or third-trimester exposure, compared with 295 of 6366 unexposed infants (4.6%) (POR, 1.00; 95% CI, 0.84-1.17). Small size for gestational age was observed in 25 of 330 infants (7.6%) with first-trimester exposure compared with 31 of 330 unexposed infants (9.4%) (POR, 0.79; 95% CI, 0.46-1.37), and in 641 of 6642 infants (9.7%) with second- or third-trimester exposure, compared with 657 of 6642 unexposed infants (9.9%) (POR, 0.97; 95% CI, 0.87-1.09). CONCLUSIONS In this Danish cohort, exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was not associated with a significantly increased risk of major birth defects, preterm birth, or fetal growth restriction.

Vaccination against pandemic A/H1N1 2009 influenza in pregnancy and risk of fetal death: cohort study in Denmark

Objective To investigate whether an adjuvanted pandemic A/H1N1 2009 influenza vaccine in pregnancy was associated with an increased risk of fetal death. Design Nationwide register based cohort study. Setting Denmark. Participants All clinically recognised singleton pregnancies that ended between November 2009 and September 2010. Individual level data on exposure to an inactivated AS03 pandemic A/H1N1 2009 influenza vaccine (Pandemrix) and potential confounders were linked to the study cohort using a unique person identifier. Main outcome measures The primary outcome measure was risk of fetal death (spontaneous abortion and stillbirth combined) in H1N1 vaccinated compared with unvaccinated pregnancies, adjusting for propensity scores. Secondary outcome measures were spontaneous abortion (between seven and 22 weeks’ gestation) and stillbirth (after 22 completed weeks’ gestation). Results The cohort comprised 54 585 pregnancies; 7062 (12.9%) women were vaccinated against pandemic A/H1N1 2009 influenza during pregnancy. Overall, 1818 fetal deaths occurred (1678 spontaneous abortions and 140 stillbirths). Exposure to the H1N1 vaccine was not associated with an increased risk of fetal death (adjusted hazard ratio 0.79, 95% confidence interval 0.53 to 1.16), or the secondary outcomes of spontaneous abortion (1.11, 0.71 to 1.73) and stillbirth (0.44, 0.20 to 0.94). Estimates for fetal death were similar in pregnant women with (0.82, 0.44 to 1.53) and without comorbidities (0.77, 0.47 to 1.25). Conclusion This large cohort study found no evidence of an increased risk of fetal death associated with exposure to an adjuvanted pandemic A/H1N1 2009 influenza vaccine during pregnancy.

Frequency of atopy in the Arctic in 1987 and 1998.

Few studies have measured the frequency of atopy with objective measures, and most of these studies have been done in industrialised countries. We analysed serum samples from 859 15-80-year-old Greenlanders who had participated in population-based screening campaigns in 1987 and in 1998. We defined atopy as a positive result in an assay that tests for specific IgE against the eight most common inhalant allergens in one pool (grass, birch, mugwort, dog, cat, horse, Cladosporum herbarum, house dust mite). The frequency of atopy doubled between 1987 (39 [10%] of 392) and 1998 (87 [19%] of 467; risk ratio 1.88 [95% CI 1.31-2.68]). This increase was largest in 15-19-year olds, but also occurred in older people, suggesting that the risk factors responsible for the increase in atopy do not operate only in childhood.

Live Vaccine Against Measles, Mumps, and Rubella and the Risk of Hospital Admissions for Nontargeted Infections

IMPORTANCE In low-income countries, live measles vaccine reduces mortality from causes other than measles infection. Such nonspecific effects of vaccines might also be important for the health of children in high-income settings. OBJECTIVE To examine whether the live vaccine against measles, mumps, and rubella (MMR) is associated with lower rates of hospital admissions for infections among children in Denmark. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study of Danish children born 1997-2006 and followed up from ages 11 months to 2 years (last follow-up, August 31, 2008). Nationwide Danish registers provided data on vaccinations and hospital admissions. The recommended vaccination schedule was inactivated vaccine against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) administered at ages 3, 5, and 12 months and MMR at age 15 months. MAIN OUTCOMES AND MEASURES Incidence rate ratios (IRRs) of hospital admissions for any infection, comparing receipt of MMR vs DTaP-IPV-Hib as the most recent vaccine. Risks, risk difference, and number needed to vaccinate were calculated for receiving MMR on time. RESULTS The study included 495,987 children contributing with 56,889 hospital admissions for any type of infection during 509,427 person-years (rate, 11.2 per 100 person-years). For the 456,043 children who followed the recommended schedule and received MMR after the third dose of DTaP-IPV-Hib, MMR (rate, 8.9 per 100 person-years) vs the third dose of DTaP-IPV-Hib (rate, 12.4 per 100 person-years) as the most recent vaccine was associated with an adjusted IRR of 0.86 (95% CI, 0.84-0.88) for any admission for infection. There were 19,219 children immunized out of sequence. The adjusted IRR was 0.87 (95% CI, 0.80-0.95) for those receiving MMR (rate, 9.9 per 100 person-years) after the second dose of DTaP-IPV-Hib (rate, 15.1 per 100 person-years). However, in the 1981 children who subsequently received the third dose of DTaP-IPV-Hib (rate, 12.8 per 100 person-years) after MMR, the IRR for hospital admissions for infection was significantly greater (adjusted IRR, 1.62 [95% CI, 1.28-2.05]). The risk of admission for an infection between ages 16 months and 24 months was 4.6% (95% CI, 4.5%-4.7%) for receiving MMR on time and 5.1% (95% CI, 5.0%-5.2%) for not receiving MMR on time. The risk difference was 0.5 percentage point (95% CI, 0.4-0.6), and the number needed to vaccinate with MMR before age 16 months to prevent 1 admission for any infection was 201 (95% CI, 159-272). CONCLUSIONS AND RELEVANCE In a cohort of Danish children, receipt of live MMR vs inactivated DTaP-IPV-Hib as the most recent vaccine was associated with a lower rate of hospital admissions for any infections. These findings require replication in other high-income populations.

Second-trimester maternal serum alpha-fetoprotein and risk of adverse pregnancy outcome

Objective To determine the risk of adverse pregnancy outcome by maternal serum alpha-fetoprotein (MSAFP) level. Methods We followed 77,149 pregnant women and their infants from MSAFP screening in the 15th to 20th week of gestation until 1 year after birth. Information on pregnancy outcome was obtained from national registries. The relative risks (RRs) and 95% confidence intervals (CIs) for adverse pregnancy outcome were estimated according to the level of MSAFP, with adjustment for confounders. Results A total of 638 pregnancies resulted in spontaneous abortion, 289 in stillbirth, and 437 in infant death. Compared with women with MSAFP levels at 0.75–1.24 multiples of the median (MoM), those with MSAFP levels greater than or equal to 2.5 MoM had an increased risk of spontaneous abortion (RR 12.5; 95% CI 9.7, 16.1), preterm birth (RR 4.8; 95% CI 4.1, 5.5), small for gestational age (RR 2.8; 95% CI 2.4, 3.2), low birth weight (RR 5.8; 95% CI 5.0, 6.6), and infant death (RR 1.9; 95% CI 1.2, 2.8). Women with MSAFP levels below 0.25 MoM had an increased risk of spontaneous abortion (RR 15.1; 95% CI 9.3, 24.8), preterm birth (RR 2.2; 95% CI 1.3, 3.8), and stillbirth (RR 4.0; 95% CI 1.0, 16.0); those with levels less than 0.5 MoM had an increased risk of infant death (RR 1.9; 95% CI 1.2, 3.0). The increased risk of infant death remained after the subtraction of recognized conditions associated with extreme MSAFP values. Conclusion Pregnant women with extreme MSAFP values in the second trimester have an increased risk of fetal and infant deaths.

Seroprevalence and Risk Factors for Helicobacter pylori Infection in Greenlanders

Background.  In contrast to most populations worldwide, the incidence of gastric cancer increases among Inuit in Greenland. Contributing factors to this increase are unknown, but Helicobacter pylori may be involved. However, little is known regarding the epidemiology of H. pylori in Arctic communities. With the aim of determining age‐specific prevalence, risk factors, and association with clinical conditions of H. pylori infection, we carried out a population‐based study of H. pylori in Sisimiut, the second biggest town of Greenland.

Atopic sensitization among children in an Arctic environment

Background Asthma has been reported to be rare among Inuits, but so far total and specific IgE levels have never been determined in arctic populations.

Reproductive history and allergic rhinitis among 31145 Danish women.

Background and objective A successful pregnancy is associated with a strong skewing of the immune system towards a Th2‐type immune response. Because such a deviation is also the hallmark of allergic disease, it was investigated whether allergic rhinitis in women was associated with an increased likelihood of becoming pregnant and having a successful outcome of pregnancies.

Effectiveness of vaccine against pandemic influenza A/H1N1 among people with underlying chronic diseases: cohort study, Denmark, 2009-10.

Objective To determine the effectiveness of an adjuvanted monovalent vaccine against pandemic influenza A/H1N1 among people with underlying chronic diseases. Design Historical cohort study. Setting Mandatory national reporting systems, 2 November 2009 to 31 January 2010, Denmark. Participants 388 069 people under 65 years of age with a diagnosis in the past five years of at least one underlying disease expected to increase the risk of severe illness after influenza. Main outcome measures Laboratory confirmed H1N1 infection and influenza related hospital admission with laboratory confirmed H1N1 infection. Estimates of vaccine effectiveness were adjusted for age and underlying disease. Results The effectiveness of pandemic vaccine against confirmed H1N1 infection 14 days after one dose of vaccine was 49% (95% confidence interval 10% to 71%). The effectiveness of vaccine against admission to hospital for confirmed H1N1 infection was 44% (−19% to 73%). Conclusions The adjuvanted monovalent vaccine against pandemic influenza A/H1N1 was offered late in the 2009-10 influenza season. Among chronically ill people, this vaccine offered protection against laboratory confirmed H1N1 infection but only offered non-significant protection against influenza related hospital admissions confirmed as H1N1 infection. This finding is of public health relevance because the population of chronically ill people is a major target group for pandemic vaccinations and because of the delayed availability of pandemic vaccines in a forthcoming pandemic.

Burden of illness of the 2009 pandemic of influenza A (H1N1) in Denmark.

We analysed Danish surveillance data to estimate influenza-associated morbidity and mortality in 2009. To obtain population-based estimates of the clinical attack rate, we combined data from two different primary health care surveillance systems, national numbers of the proportion of positive influenza tests, and data from a web-based interview on health care seeking behaviour during the pandemic. From a national registry, we obtained data on hospital admissions (ICD-10 codes) for influenza related conditions. Admission to intensive care was monitored by a dedicated surveillance scheme. Mortality was estimated among laboratory confirmed cases but was also expressed as excess all-cause mortality attributed to influenza-like illness in a multivariable time series analysis. In total, we estimated that 274,000 individuals (5%) in Denmark experienced clinical illness. The highest attack rate was found in children 5-14 years (15%). Compared with the expected number of hospital admissions, there was an 80% increase in number of influenza related hospital admissions in this age group. The numbers of patients admitted to intensive care approached 5% of the national capacity. Estimates of the number of deaths ranged from 30 to 312 (0.5-5.7 per 100,000 population) depending on the methodology. In conclusion, the pandemic was characterised by high morbidity and unprecedented high rates of admissions to hospitals for a range of influenza-related conditions affecting mainly children. Nonetheless, the burden of illness was lower than assumed in planning scenarios, and the present pandemic compares favourable with the 20th century pandemics.