If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
The 2009-2010 A/H1N1 pandemic provided a unique setting to study the safety of MF59-adjuvanted vaccination in pregnancy.
Study Design
This was an observational cohort study of the safety of an MF59-adjuvanted A/H1N1 vaccine (Focetria) conducted among 4508 pregnant women (2295 vaccinated vs 2213 unvaccinated), with 3 month follow-up of neonates.
Results
No maternal deaths or abortions occurred among the vaccinated women. No differences between the vaccinated and unvaccinated cohorts were observed for gestational diabetes, preeclampsia, stillbirth, low birthweight, neonatal deaths, or congenital malformations. The risk of premature birth was significantly decreased among the vaccinated women (adjusted proportional hazard, 0.69; 95% confidence interval, 0.51–0.92). No differences were observed in rates of congenital malformations after vaccination in the first (2.1%), second (2.7%), or third (2.1%) trimesters.
Conclusion
There was no evidence of a safety risk for MF59-adjuvanted A/H1N1 vaccination in pregnant women; protection was observed against premature birth.
In the United States, pregnant women had a 4-fold greater risk of hospitalization because of A/H1N1 infection than the general population at the start of the pandemic,
and in the first months of the pandemic, 13% of all A/H1N1-related deaths reported in the United States occurred among pregnant women. Anticipated effects of A/H1N1 infection on the health of newborns
were confirmed in the United Kingdom, where the risks of perinatal mortality as well as premature birth were 4-fold higher in mothers infected with A/H1N1 during their pregnancy.
Centers for Disease Control and Prevention (CDC) Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011.
A recent randomized controlled interventional trial in Bangladesh showed a significant reduction in the influenza burden in both vaccinated pregnant women and their offspring.
Focetria (Novartis Vaccines and Diagnostics, Cambridge, MA), an egg-derived A/H1N1 influenza vaccine adjuvanted with MF59, was one of the first A/H1N1 vaccines to be licensed in Europe.
MF59 is a squalene-based oil-in-water emulsion used in Europe since 1997 in the seasonal influenza vaccine, Fluad (Novartis Vaccines and Diagnostics). More than 50 million doses have been distributed to date, with no safety signals other than some increased local injection site reactions and general reactions associated with vaccination (myalgia, headache, fatigue, and malaise) up to 7 days after the vaccination.
A comprehensive preclinical assessment (including embryofetal toxicity and teratogenicity studies) and clinical trials in more than 20,000 subjects did not show any safety signal with the MF59 adjuvant.
An analysis of the outcomes among 103 inadvertently vaccinated pregnant women in these trials did not find any adverse effect on the pregnancy outcomes.
To further assess the safety of the MF59 adjuvant in pregnancy, we conducted an observational study to evaluate outcomes in pregnant women who received the MF59-adjuvanted A/H1N1 influenza vaccine during the recent pandemic.
Materials and Methods
This was an observational comparative cohort study conducted in 3 countries in which the MF59-adjuvanted A/H1N1 vaccine was the only vaccine administered to pregnant women: The Netherlands, Italy, and Argentina.
Recruitment and follow-up
There was no distinction in the way vaccinated women and controls were recruited. In The Netherlands, women were recruited at 27 midwife practices (76.0%) and 7 hospitals (23.4%) across the country. A small group (0.6%) was recruited by general practitioners. In Italy and Argentina, women were recruited at 2 hospitals (Rome and Cordoba). Recruitment ran from January to August 2010 in The Netherlands, May to June 2010 in Italy, and July to August 2010 in Argentina. To maximize the number of subjects, enrolment included both currently pregnant women (enrolled during antenatal care visits) and women whose pregnancy had already ended but covered the timing of the pandemic vaccine's availability. The latter group was identified from the delivery list in the midwife or hospital unit and then recruited sequentially. All women who provided informed consent were enrolled except those who had received a different pandemic influenza vaccine or if the investigator believed that data collection or follow-up would be difficult.
Investigators collected information on demographics (date of birth, ethnicity, education, occupation, and income), previous obstetric history and past or current risk factors (tobacco, alcohol and recreational drug use, concurrent medications), results of any prenatal testing and the pregnancy outcomes, including all birth characteristics, at the prenatal consultations or at birth for the women enrolled while still pregnant. For women enrolled after delivery, this information was extracted from the medical records. Information from the pediatric 3 month visit was requested to identify any congenital malformations not detected at birth.
All data were collected on site via electronic data capture. Serious adverse events (SAEs) were also collected separately throughout the study and reconciled with the study outcomes, thereby providing an additional level of data verification for most outcomes of interest. Source documentation was verified for all study outcomes.
Vaccination
A/H1N1 vaccination of pregnant women occurred in November and December 2009 in The Netherlands,
Rijksinstituut voor Volksgezondheid en Milieu Chronological overview of the 2009/2010 H1N1 influenza pandemic and the response of the Centre for Infectious Disease Control RIVM RIVM Report 215011006/2011.
Italian Multicenter Study Group for Drug and Vaccine Safety in Children Effectiveness and safety of the A-H1N1 vaccine in children: a hospital-based case–control study.
Each woman was asked following enrollment whether and when she had received the MF59-adjuvanted A/H1N1 vaccine. This information was confirmed by either asking the vaccination centers to confirm the vaccination from their records or by examining the vaccination cards. If no such confirmation could be obtained, we followed the pregnant woman's recollection.
Outcomes
The 3 groups of outcomes of interest were pregnancy-related diseases (preeclampsia, gestational diabetes, and maternal death), pregnancy outcomes (spontaneous or induced abortions, stillbirth, or live birth), and birth outcomes (birthweight, prematurity, congenital malformations, and neonatal death). Abortions were considered as losses before 22 weeks of gestation. Congenital malformations were considered only if confirmed following examination of an aborted pregnancy or stillborn child or in a live-born baby at birth or at the 3 month pediatric visit. Each congenital malformation was also reported as an SAE, which included a detailed narrative.
These reports were reviewed and adjudicated by an expert panel, blinded to the vaccination status. Malformations were retained if the diagnosis provided is listed in the European Surveillance of Congenital Anomalies (EUROCAT) guidelines as a congenital anomaly or if the information provided sufficed to so classify it as such.
Cases with a malformation with insufficient information to determine whether it met EUROCAT criteria (eg, hemangioma with unknown location) were conservatively retained. Malformations diagnosed prenatally before vaccination and chromosomal malformations were excluded from the analyses. Outcomes were recorded from time of vaccination in the vaccinated cohort and from the time of enrollment in the unvaccinated cohort recruited during pregnancy and from the whole antenatal care record for the unvaccinated cohort recruited after delivery.
Sample size
A 2% background rate of major birth defects, as observed in The Netherlands, was assumed for the sample size calculation.
Based on a 2 group χ2 test with normal approximation at the 5% significance level (2 sided), 2434 evaluable pregnancies would provide 80% power to detect a doubling of the background rate (ie, anticipated rate in unvaccinated cohort). To allow for approximately 15% of pregnancies being nonevaluable for the assessment of major birth defects and assuming a 25% loss to follow-up, 4056 subjects needed to be enrolled.
Statistical analyses
All analyses were performed using SAS version 9.1 (SAS Institute, Inc., Cary, NC). We used logistic regression models to estimate the odds ratios associated with vaccination for all outcomes. The differences in initiation points for the data collection combined with the timing of the vaccination in pregnancy resulted in a differential follow-up time between the vaccinated and unvaccinated cohort. To account for this differential follow-up time and for the fact that the occurrence of most outcomes depends on the gestational age, we also used proportional hazard (PH) models with gestational age as the time factor for all outcomes except congenital malformations. For these PH models, we imputed the date of the last menstrual period (LMP) from the date of delivery for 10% of women who did not report their LMP and for 7% for whom the reported LMP was considered erroneous as it suggested a pregnancy of more than 42 weeks.
We provide results of both the logistic regression models that use the most complete data and the proportional hazard models that adjust for the differential follow-up time. We also ran the PH models without the women with missing or erroneous LMPs in a sensitivity analysis to assess the potential impact of the LMP imputation. A small proportion of women dropped out from the PH models because of missing vaccination dates (6%) or missing onset dates of the outcome (1%). We adjusted the estimates for all outcomes on parity, smoking, and maternal age.
In addition, we let the automated SAS procedure Stepwise select, per individual outcome of interest, any additional significant variables including enrollment type (during or after pregnancy), type of health care practitioner enrolling, ethnicity, current alcohol use, and previous history of the specific outcome of interest. Other variables were not included because they had too many missing data (education, profession, and income) or because they had very few positive entries (recreational drug use and concomitant medication).
The study was approved by local ethical review committees in each individual country.
Results
Enrollment and follow-up
Of the total 4529 enrolled women, most (4281, 94.5%) were recruited in The Netherlands, followed by Argentina (239, 5.3%) and Italy (9, 0.2%). Twenty-one were excluded from the analyses (7 pregnancies completed prior to the vaccination campaign, 5 received a vaccine other than the MF59-adjuvanted A/H1N1 vaccine, 7 with incomplete or withdrawn consent, and 2 with unknown vaccination status). Because 16 women dropped out before pregnancy completion and 48 had twins, we had a total of 4540 evaluable pregnancy outcomes, of which 4522 were live births. We obtained information on the 3 month pediatric follow-up on 4385 infants (97.0%) (Figure).
FIGUREEnrollment and follow-up of pregnant women and their offspring
The mean age at enrollment was 32 years and most women (83.3%) were of white origin. The vaccinated cohort was comparable with the unvaccinated cohort for most characteristics (Table 1), with the exception that more vaccinated women were enrolled after delivery, belong to the “other” ethnicity or were enrolled by the “other” professional category and less vaccinated women had a previous history of an elective abortion.
There were no maternal deaths. Nearly all pregnancies (99.6 %) resulted in a live birth, a rate mostly explained by the relatively high gestational age at enrollment in the cohort enrolled during pregnancy. For the same reason, there were few spontaneous abortions and elective terminations (0.2% and 0.1%, respectively). The rates of prematurity and low birthweight were relatively low compared with rates in The Netherlands where most women were recruited, suggesting a relatively healthy cohort.
Potential congenital malformations were reported in a total of 365 babies: 188 (8.1%) among the vaccinated and 177 (7.9%) among the unvaccinated. Of these, the adjudication committee retained 106 as true congenital malformations, 9 of which were excluded from the analysis (2 were diagnosed prenatally before vaccination and 7 were chromosomal malformations). Thus, the total number of confirmed congenital malformations included in the analysis was 97.
The logistic regression and proportional hazard analyses did not indicate a significantly increased risk in the vaccinated compared with the unvaccinated cohort for any of the outcomes of interest. Vaccination was not associated with any significant increase in risk of gestational diabetes, preeclampsia, stillbirth, low birthweight, preterm birth, neonatal deaths, or congenital malformations (Table 2). In fact, there was a significant reduction in the vaccinated cohort in premature births in the unadjusted logistic regression and both the adjusted and unadjusted PH models.
Total pregnancies enrolled of which 4492 were followed up until termination (2291 and 2201 among the vaccinated and unvaccinated cohorts, respectively);
Total pregnancies enrolled of which 4492 were followed up until termination (2291 and 2201 among the vaccinated and unvaccinated cohorts, respectively);
Total pregnancies enrolled of which 4492 were followed up until termination (2291 and 2201 among the vaccinated and unvaccinated cohorts, respectively);
The estimates for all outcomes were adjusted for parity, smoking, and maternal age. The automated SAS procedure Stepwise (SAS Institute, Inc., Cary, NC) selected type of health care professional enrolling and previous history of the same outcome to adjust the estimates for the outcomes preeclampsia, gestational diabetes, low birthweight, and preterm birth;
The estimates for all outcomes were adjusted for parity, smoking, and maternal age. The automated SAS procedure Stepwise (SAS Institute, Inc., Cary, NC) selected type of health care professional enrolling and previous history of the same outcome to adjust the estimates for the outcomes preeclampsia, gestational diabetes, low birthweight, and preterm birth;
Percentages are based on the number of live births and elective terminations, therapeutic terminations, fetal deaths, or stillbirths associates with congenital malformations in each cohort.
56 (2.4)
41 (1.9)
97 (2.1)
1.32 (0.88–1.98)
1.33 (0.88–2.00)
n/a
n/a
CI, confidence interval; n/a, not available.
Heikkinen. Safety of MF59-adjuvanted influenza vaccination during pregnancy. Am J Obstet Gynecol 2012.
a Total pregnancies enrolled of which 4492 were followed up until termination (2291 and 2201 among the vaccinated and unvaccinated cohorts, respectively);
b The estimates for all outcomes were adjusted for parity, smoking, and maternal age. The automated SAS procedure Stepwise (SAS Institute, Inc., Cary, NC) selected type of health care professional enrolling and previous history of the same outcome to adjust the estimates for the outcomes preeclampsia, gestational diabetes, low birthweight, and preterm birth;
c Percentages are based on the total number of pregnancy outcomes;
d Percentages are based on the number of live births and elective terminations, therapeutic terminations, fetal deaths, or stillbirths associates with congenital malformations in each cohort.
There was also a significant reduction in the vaccinated cohort in gestational diabetes with logistic regression; however, no significant reduction was seen in the PH models for this outcome. Odds ratios and proportional hazards could not be obtained for spontaneous and elective abortions because no case was reported in the vaccinated cohort versus 9 cases (0.4%) and 3 cases (0.1%), respectively, in the unvaccinated cohort. Congenital malformations in the vaccinated cohort were not more frequent among women who received the first vaccination in the first trimester (2 of 94, 2.1%) than among women who received the first vaccination in the second (35 of 1319, 2.7%) or third trimesters (19 of 889, 2.1%). The distribution of various malformations was also comparable between the 2 cohorts with the exception of numerical imbalances for ventricular septum defects (11 cases among the vaccinated and 2 among the unvaccinated) and for cleft lip and/or palate (0 among the vaccinated and 5 among the unvaccinated).
The sensitivity analysis removing the subjects with imputed LMP did not show any different results.
Comment
The 2009 A/H1N1 pandemic and the concerns over the large-scale use of newly licensed vaccines prompted manufacturers, regulators, and academic groups to conduct a large number of interventional and observational safety studies, several of which included pregnant women.
Our study of more than 4500 pregnant women is the largest comparative safety study of an MF59-adjuvanted vaccine in pregnancy and one of the largest studies with prospective follow-up of pregnant women for any vaccine.
We did not find any adverse effect of the MF59-adjuvanted A/H1N1 vaccine on the ongoing pregnancy or on the health of the mother or the newborns. The rates of gestational diabetes, preeclampsia, abortions, stillbirth, low birthweight, prematurity, neonatal deaths, and congenital malformations among the more than 2000 vaccinated women and their offspring showed no increase compared with those in unvaccinated controls.
conducted a review of the safety of influenza vaccination in pregnancy and concluded that no study to date has shown adverse consequence following influenza vaccination in pregnancy. One of the few clinical trials of flu vaccination conducted in pregnant women showed no increase in adverse events compared with recipients of a pneumococcal vaccine.
A review of the spontaneous reports made to the Vaccine Adverse Event Reporting System on pregnant women vaccinated with the H1N1 vaccine in the United States, equally did not detect any safety concerns.
Adverse events following administration to pregnant women of influenza A (H1N1) 2009 monovalent vaccine reported to the Vaccine Adverse Event Reporting System.
Pregnancy and safety outcomes in women vaccinated with an AS03-adjuvanted split virion H1N1 (2009) pandemic influenza vaccine during pregnancy: a prospective cohort study.
prospectively assessed the safety of another adjuvanted A/H1N1 vaccine used in the United Kingdom in a limited cohort of 267 women and did not observe any adverse effect on the pregnancy outcomes or the offspring of the vaccinated women when compared with the rates from the literature.
The overall rate and pattern of major congenital malformations observed in this study was comparable with what has been previously reported in The Netherlands.
The rate of malformations was also not higher in the women who received their first vaccination in the first trimester. The numerical imbalances for ventricular septum defects (against the vaccinated cohort) and for cleft lip and/or palate (in favor of the vaccinated cohort) are most likely related to a chance finding. Compared with EUROCAT data, the rates of both events were unusually low in the cohort with the fewest cases. There was also no pattern of malformations (eyes, ears) in the vaccinated women that are associated with teratogenic exposures in the second trimester, when most women were exposed to the vaccine.
We observed a significantly lower risk of preterm birth among vaccinated women in the proportional hazard model, which accounts for differences in follow-up times between cohorts. Prematurity has been linked to A/H1N1 infection in the United Kingdom and The Netherlands,
and it is thus plausible that vaccination could offer a protective effect. A similar observation was made in the state of Georgia, where babies born between 2004 and 2006 to mothers vaccinated against seasonal influenza during pregnancy were less likely to be premature than infants of unvaccinated mothers born in the same period (adjusted odds ratio, 0.60; 95% confidence interval, 0.38–0.94).
Analyses that take into account the timing of pregnancy in relation to exposure to the pandemic and to study initiation would be needed to further explore this beneficial effect of vaccination in our study.
On the other hand, the significantly decreased odds for gestational diabetes is most likely related to the differential follow-up times, as illustrated by the absence of any effect in the proportional hazard model. The same is likely to be true for the numerical difference observed in the number of abortions.
Our study has several strengths, related to its size, rigor, and design. The study had high power to detect adverse outcomes in late pregnancy and among the offspring of the vaccinated women, as illustrated by the narrow 95% confidence intervals around some of the risk estimates. In addition, the high follow-up rate at 3 months of age ensured that few outcomes such as congenital malformations not obvious at birth would have been missed. We went beyond classical epidemiological practice to apply some good clinical practices such as source document verification and serious adverse events collection and follow-up. Adjudication of congenital malformations by a blinded committee increased the validity of this outcome. Finally, information on both cases and controls was collected through direct contact with all players involved in the pregnancy and perinatal care, including the health care practitioners providing vaccinations and treatment, the mothers, and the pediatricians.
Our study also has some limitations. Because A/H1N1 vaccination was recommended for women in their second or third trimester, we enrolled relatively few women (n = 94) vaccinated in their first trimester. This limited our ability to assess the impact of vaccination on outcomes occurring early in pregnancy such as spontaneous abortions. It is reassuring to note that the rates of congenital malformations among these women were not elevated, although the number of first-trimester exposures remains too low to permit any firm conclusions regarding safe first-trimester use.
We cannot exclude that women who opted for vaccination were more or less likely to have adverse pregnancy outcomes or an inclusion bias of vaccinated women who were more or less likely to have an adverse pregnancy outcome. Vaccination rates in the cohort enrolled following delivery (61%) were consistent with published rates in The Netherlands, where most women were recruited, suggesting that recruitment after delivery was not related to vaccination status.
Before delivery some investigators may, however, have preferentially included vaccinated women with suspicion of an adverse outcome, thus creating a falsely increased risk in the vaccinated cohort. Of the 6 women who had a prenatal diagnosis of a congenital malformation and who were enrolled before delivery, 5 (83%) were vaccinated. This relatively high proportion, more than double the vaccination rate of 37% in the cohort enrolled before delivery, suggests such preferential enrolment may have occurred.
In addition, as pointed out in a report by the Dutch Health Council, it is likely that in The Netherlands relatively more pregnant women with underlying medical conditions were vaccinated because the original A/H1N1 vaccine recommendation was to immunize only pregnant women with underlying medical conditions.
This recommendation was changed very late, just before the actual immunization campaign started. We did not collect information on these conditions and therefore could not adjust for such a potential bias, which would have resulted in falsely elevated risks in the vaccinated cohort. It is reassuring that despite these potential sources of bias against the vaccinated cohort, no safety signal was detected.
For a small proportion of the vaccinated women (11.9%), we could not obtain verification of their vaccination status from the general practitioner. However, given the exceptional pandemic situation and the public debate around the vaccination campaign, we expect the recall to be accurate for most of these women.
Influenza vaccination rates remain low among pregnant women, despite the increase observed following the 2009 pandemic in the United States.
Our study found no safety risk among more than 2000 pregnant women receiving the MF59-adjuvanted A/H1N1 vaccine. These and similar results from other studies should provide reassurance when offering influenza vaccination, including MF59-adjuvanted formulations to all pregnant women.
Acknowledgments
We acknowledge all who made the study possible in the difficult setting of the H1N1 pandemic, including all midwives and the Leyden Delta Organization in The Netherlands, and Drs Angel Minuez and German Bernardi from the Hospital Nuestra Señora de la Misericordia in Cordoba.
References
Centers for Disease Control and Prevention (CDC)
Novel influenza A (H1N1) virus infections in three pregnant women—United States, April-May 2009.
Adverse events following administration to pregnant women of influenza A (H1N1) 2009 monovalent vaccine reported to the Vaccine Adverse Event Reporting System.
Pregnancy and safety outcomes in women vaccinated with an AS03-adjuvanted split virion H1N1 (2009) pandemic influenza vaccine during pregnancy: a prospective cohort study.
This study was supported by Novartis Vaccines and Diagnostics.
E.v.B. and H.F. report no conflict of interest. J.Y. is employed by the United Biosource Corporation and was commissioned by Novartis Vaccines and Diagnostics to conduct the study. T.H. and T.V. have received consultancy fees from Novartis Vaccines and Diagnostics. J.G.W. and G.D.C. are employees of Novartis Vaccines and Diagnostics.
Cite this article as: Heikkinen T, Young J, van Beek E, et al. Safety of MF59-adjuvanted A/H1N1 influenza vaccine in pregnancy: a comparative cohort study. Am J Obstet Gynecol 2012;207:177.e1-8.
The high mortality rates observed among pregnant women during the 1957 through 1958 influenza pandemic prompted the US Surgeon General to issue a report in 1960 that recommended routine seasonal influenza vaccination for pregnant women.1 During the past half century, recommendations in the United States have evolved, with influenza vaccination recommended for all pregnant women regardless of trimester beginning in 2004. Despite these recommendations, influenza vaccination rates among pregnant women were generally low (<15%) until the 2009 H1N1 influenza A pandemic when vaccination rates increased to about 50%.
00744-2&id=gr1.jpg){kind=link}