The PREGVAXGRIP Study: a Cohort Study to Assess Foetal and Neonatal Consequences of In Utero Exposure to Vaccination Against A(H1N1)v2009 Influenza

Abstract

Background

In October 2009, in the context of an A(H1N1)v2009 influenza pandemic, a vaccination campaign was launched in France, in which one of the priority groups was pregnant women, on account of the high risk of developing complications following infection by this virus.

Objective

The aim of this multicentric, prospective, observational study was to assess safety and pregnancy outcomes in a cohort of pregnant women when receiving the A(H1N1)v2009 influenza pandemic vaccine.

Methods

This was a prospective study that followed up pregnant women recruited mainly in vaccination centres and maternity departments. Following the expected delivery date, follow-up data were collected concerning the delivery, the infant, and, if appropriate, the reasons why the pregnancy did not reach its term.

Results

Between 1 November 2009 and 31 March 2010, 2,415 pregnant women were included at the time of vaccination; 97.6 % of women received a vaccine without adjuvant and 2.4 % received an adjuvanted vaccine. Ninety-two (3.9 %) women were vaccinated during the first trimester of pregnancy, 1,090 (46.5 %) during the second trimester, and 1,162 (49.6 %) during the third trimester. One hundred and thirty-three adverse events (5.5 % of women) were reported, of which 12 were unexpected or serious. There were 2,246 (93.0 %) known pregnancy outcomes with 12 spontaneous abortions (0.5 %), 6 stillbirths (0.3 %), and 4 therapeutic abortions (0.2 %). There were 65 neonates with congenital anomalies, among which 31 were major. But only one congenital malformation (1.4 %) was reported for the 92 women vaccinated in their first trimester. Of the women, 93.3 % were delivered full term and 6.7 % preterm. For 96 (4.2 %) neonates, a disorder was reported in the neonatal period and 130 (5.6 %) were transferred to the neonatology department.

Conclusions

This study suggests that exposure to the A(H1N1)v2009 pandemic influenza vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes. However, because of the relatively small number of women exposed during the first trimester, other studies are needed to exclude an increased risk of malformation.

Introduction

The first cases of A(H1N1)v2009 influenza appeared in April 2009 in Mexico. This strain, originating from pigs, infected large numbers of people in Mexico and then in the USA, leading to several deaths. Unlike the usual patterns observed in seasonal influenza epidemics, during which 90 % of the deaths are among the elderly, most of the serious forms and most of the deaths relating to the A(H1N1)v2009 influenza epidemic were among individuals under 60 years of age. In addition, around a third of the deaths occurred among subjects without associated co-morbidity [1].

On 11 June 2009, WHO officially declared a state of pandemic for A(H1N1)v2009 influenza. In France, the first cases were isolated in May 2009, with an epidemic wave in September 2009 [2]. At the time of the peak of the epidemic (the end of November 2009), around 750 consultations per 1,000,000 inhabitants per week for suspected A(H1N1)v2009 influenza were reported. In addition, the number of people infected was estimated to be between 7.7 and 14.7 million (i.e. 12 to 23 % of the French population) with 31 deaths attributed to A(H1N1)v2009 influenza [2].

As expected on the basis of earlier pandemics, pregnant women were identified as more liable to develop complications following infection by this influenza virus, in particular respiratory distress and death [3, 4]. This greater susceptibility of the mother and foetus towards influenza infection in pregnancy can be explained by a fall in the immune response in pregnant women, in particular in the third trimester of pregnancy [5]. Influenza-linked morbi-mortality in pregnant women has indeed been found to be higher in both seasonal epidemics and previous pandemics [3, 57].

In a recent review covering all publications relating to pregnant women and A(H1N1)v2009 influenza, the authors evaluated the proportion of pregnant women infected by the virus who were hospitalised to be at 52.3 %, among whom 23.3 % were admitted to intensive care [8]. Pregnancy also seems to be a risk factor for A(H1N1)v2009 influenza-related deaths, since, in the same review, the death rate among pregnant women following infection by the A(H1N1)v2009 influenza virus was estimated to be 8 %, and pregnant women accounted for 5.7 % of A(H1N1)v2009 influenza-related deaths. In France, some authors [9] confirmed a high incidence of complications among infected pregnant women, in particular in the third trimester of pregnancy, but the morbi-mortality rate was below that initially described, in the USA and Australia in particular [1012].

In October 2009, in the context of the influenza pandemic, a major national vaccination campaign was launched in France. In the course of the winter of 2009–2010, more than 5 million individuals were vaccinated, amounting to some 8 % of the general population [2]. In most cases, vaccines were administered in centres dedicated to the pandemic vaccination campaign. Pregnant women were the second priority group (after health professionals) on account of the potential severity of the infection in this population.

Vaccination was recommended for all pregnant women from the second trimester of pregnancy, with a non-adjuvanted vaccine. The aim of this measure was to reduce the number of serious forms and the number of deaths, more frequent in the second and third trimesters of pregnancy [1]. A vaccine without adjuvant was recommended in the absence of information about clinical safety of AS03-adjuvanted vaccine during pregnancy.

In earlier studies, it was shown that vaccines against seasonal influenza virus did not present any particular risk for pregnant women [13]. It nevertheless seemed important to study the safety of A(H1N1)v2009 vaccines among pregnant women and any effects on the foetus. In the context of the A(H1N1)v2009 influenza pandemic, we were not able to perform a study with a classic protocol design on account of the time span, so the best alternative was that of a large-scale study.

The aim of this study, named PREGVAXGRIP, using an observational prospective cohort design, was to assess the safety and pregnancy outcomes in a cohort of pregnant women who received the A(H1N1)v2009 influenza pandemic vaccine.

Materials and Methods

Inclusion

The prospective study was observational and followed a cohort of pregnant women who were vaccinated against the A(H1N1)v2009 virus in the course of the French vaccination campaign in the winter of 2009–2010.

Vaccinated pregnant women were recruited by health professionals mainly in the vaccination centres and maternity departments across France between 1 November 2009 and 31 March 2010.

An information sheet and a consent form for participation in the study were issued to the subjects after verbal explanations had been provided. Women who agreed to take part in the study were subsequently contacted by phone by a health professional (doctor or pharmacist) from 1 of the 17 regional pharmacovigilance centres that took part in this study.

At the time of the telephone contact, information was gathered on the current pregnancy, as well as on socio-demographic characteristics, gynaecological and obstetrical history, anti-viral treatment received during pregnancy, information on the vaccination against the A(H1N1)v2009 virus (name of the vaccine, date of vaccination, adverse events subsequent to the vaccination), and the name and address of the facility in which the mother was to give birth.

Pregnancy Follow-up

After the expected date of the birth, pregnancy follow-up data were obtained from the maternity departments or the physician in charge concerning pathologies having occurred during pregnancy, treatments received, information on the delivery, the infant, and the reasons why any pregnancy did not reach its normal term.

Data Processing and Statistical Analyses

The inclusion and follow-up data were collected and captured by a health professional in each regional pharmacovigilance centre in a secure and anonymous manner on a dedicated server using the Modalisa® programme, version 4.0 (Kynos, Paris, France). These data were then checked and validated before analysis by the reference regional pharmacovigilance centre of Poitiers. Coherency tests were performed using SAS software version 9.2 (SAS Institute, Cary, NC, USA), and in case of incoherence, clarification was requested from the regional pharmacovigilance centre involved. Certain data were nevertheless not retrieved, despite recalls.

Women for whom the vaccination date or the name of the vaccine were known were retained in the analysis.

Certain pre-existing medical conditions were recorded, such as asthma, diabetes, hypertension, liability to allergy, epilepsy, substance addiction, and HIV infection.

Adverse events linked to vaccination were classified into non-serious expected adverse events, and serious and/or unexpected adverse events, the reporting of the latter to the national French pharmacovigilance database being required in compliance with the legal obligation to notify (decree 95.278, 13 March 1995). According to the French public health code, a serious adverse event was defined as any effect leading to hospitalisation, prolonging hospitalisation, entailing permanent handicap or disability, and life-threatening or fatal condition. These different adverse events were coded according to System Organ Class in the Medical Dictionary for Regulatory Activities (MedDRA®) classification, version 13.0 (MSSO, Chantilly, VA, USA). MedDRA® terminology is the medical terminology developed under the auspices of the International Conference on Harmonization of technical requirements for Registration of Pharmaceuticals for Human Use (ICH).

Spontaneous abortion (SA) was defined as intrauterine death of a foetus of under 500 g or of gestational age under 22 weeks’ amenorrhoea (WA). Stillbirths (SB) were defined as intrauterine death of a foetus of over 500 g or gestational age of more than 22 WA (WHO definitions). Premature childbirth was defined as occurring before 37 WA (WHO).

Congenital malformations were classified as major and minor according to the EUROCAT (European Surveillance of Congenital Anomalies) guide (Approach to Coding and Classification, Chap. 3.1, p. 84, September 2005, EUROCAT Guide 1.3 and reference documents—instructions for the registration and Surveillance of Congenital Anomalies, issued: September 2005).

Neonatal pathologies were classified according to ICD-10 classification (International Classification of Diseases, 10th edition, WHO, http://apps.who.int/classifications/icd10/browse/2010/en).

A descriptive analysis of data at inclusion and data relating to pregnancies and childbirth was performed.

The quantitative data are presented as means and standard deviation, and qualitative data as numbers and percentages.

The incidence of congenital abnormalities was compared with French data in the general population extrapolated from malformation registries [14] and from rates of neonatal disorders for the general population provided by Audipog data for the year 2006 (sentinel network for maternity departments, French perinatal database, http://www.audipog.net) [15]. The Audipog data were also used for comparison with the SB rate observed in the present study.

This study was performed as part of the mandate of the regional pharmacovigilance centres in France (Code de Santé Publique 2010, article R.5121-167).

Results

The data (inclusion and follow-up) were collected between 1 November 2009 and 1 April 2011.

Inclusion Data

In the course of the study period, 2,415 women were included.

The following percentage values do not include pregnant women for whom the information was not available.

A total of 1,817 (78.0 %) were recruited in a vaccination centre, 302 (13.0 %) in a maternity department, and 209 (9.0 %) in an occupational medicine department by a gynaecologist in ambulatory consultation or on the initiative of the subject.

Mean age at inclusion was 31 years, range 15–48.

The characteristics of women at inclusion are shown in Table 1.

Table 1 Maternal characteristics and obstetrical history

For 755 women (36.9 %), it was the first pregnancy, while 1,192 (58.3 %) had had 1–3 previous pregnancies. Among these women with previous pregnancies, 235 (18.2 %) had already had an SA, and 87 (6.7 %) had had at least two SAs.

Four hundred ninety-four women (20.5 %) had a pre-existing medical condition (Table 1).

Vaccine Exposure

Vaccination took place for the women in the cohort between 3 November 2009 and 10 March 2010. Of the women included, 97.6 % were vaccinated with PANENZA® (a vaccine without adjuvant, Sanofi Pasteur, Lyon, France) and 2.4 % with an adjuvanted vaccine (PANDEMRIX®, GlaxoSmithKline Biologicals SA, Rixensart, Belgium, or FOCETRIA®, Novartis Vaccines and Diagnostics SRL, Sienna, Italy). The details of vaccine exposure are given in Table 2.

Table 2 Type of vaccine and period of vaccination in the pregnancy

Ninety-two (3.9 %) women were vaccinated during the first trimester of pregnancy, 1,090 (46.5 %) during the second trimester, and 1,162 (49.6 %) during the third trimester.

Vaccination using the vaccine without adjuvant was mainly performed in the course of the second and third trimesters of pregnancy (97.4 %) while exposure to the vaccine containing adjuvant mainly occurred in the first trimester (56.1 %, p < 0.0001).

In addition, 67 women received anti-viral treatment, oseltamivir (56) or zanamivir (5), and the name of the drug was not available for six women. In 77.6 % of these cases, the treatment was preventive.

One hundred and thirty-three women (5.5 %) reported adverse events following vaccination, and 15 were unexpected or serious (Table 3). The non-serious adverse events were mainly general disturbances and anomalies at the administration site, in particular local reactions (20 cases), flu-like syndrome or fever (34 cases), and nervous system manifestations (23 cases). Twenty-four women signalled the occurrence of more than one adverse event following vaccination.

Table 3 Adverse reactions reported with A(H1N1) vaccines

Concerning unexpected adverse events, most were cutaneous reactions, mainly transitory (four cases), a sensation of deafness (one case), and active foetal movement after the vaccination (two cases).

The adverse events considered serious (five) were respiratory difficulties (one case), tachycardia and foetal anasarca (one case), paresthesia (one case), intense back pain (one case), and development of bronchitis (one case).

Pregnancy Outcome

Among the 2,415 women included in the study, data concerning pregnancy outcome were available for 2,246, giving a follow-up rate of 93.0 %.

Among these 2,246 pregnancies, 46 multiple pregnancies were observed, 45 cases of twins, and 1 case of triplets.

As indicated in Table 4, 2,222 pregnancies reached their term with 2,269 births. Twenty-four pregnancies failed, mainly because of SA (n = 12, 0.5 %), SB (n = 6, 0.3 %), and therapeutic termination of pregnancy (n = 4, 0.2 %). Details concerning these pregnancies (SA and SB) are given in Table 5.

Table 4 Pregnancy outcomes
Table 5 Pregnancies that failed to reach their term

For pregnancies reaching their term, childbirth occurred on average at 39 WA (Table 4), mainly by normal delivery for 80.4 %, and Caesarean section was performed for 19.6 %. Premature delivery, i.e. before 37 WA, occurred in 6.7 % of cases. One hundred and fifty-four newborns (6.8 %) had a birthweight under 2,500 g (Table 4).

Sixty-five newborns presented a malformation at birth, and 31 of these malformations were major, mainly cardiovascular (12 cases), renal (5 cases), or external genital organ anomalies (4 cases) [Table 6]. But only one (1.4 %) malformation, which was major, was observed in a child born to a woman who had been vaccinated in the first trimester of pregnancy with PANDEMRIX® (adjuvanted vaccine). The malformation was peri-membranous interventricular communication with pulmonary artery hypertension. Respectively, 30 (3.0 %) and 34 (3.0 %) malformations were observed among children born to women vaccinated in the course of the second and third trimesters of pregnancy.

Table 6 Congenital malformations and neonatal pathologies

Ninety-six neonatal pathologies (4.2 %) were reported (Table 6). Among these, 27 were respiratory and cardiovascular conditions specific to the neonatal period, mainly concerning episodes of respiratory depression, and 21 were infections specific to the perinatal period. With regard to the vaccination exposure period, the neonatal pathologies were significantly more frequent when the vaccination took place in the course of the first trimester of pregnancy (10.0 % vs. 3.8 % and 4.4 %, respectively, for trimesters 2 and 3, p = 0.043). Respectively, 7/96, 38/96 and 50/96 neonatal morbid conditions were observed among women vaccinated in the first, second, and third trimester of pregnancy.

Finally, three deaths were notified, two of which concerned very premature triplets (25 WA) who died following high-grade cerebral haemorrhage. The mother had been vaccinated during the second trimester of pregnancy with a vaccine without adjuvant, and childbirth occurred 2 months after vaccination. The third death was reported for a very premature newborn (25 WA) presenting hyaline membrane disease with pulmonary haemorrhage, severe hypotrophy, and ulcerating-necrotising enterocolitis. In this case, the mother had been vaccinated in the second trimester of pregnancy with a vaccine without adjuvant, and childbirth occurred 1 week after vaccination, in a context of severely retarded intrauterine growth and hypertension.

Discussion

In this cohort, we followed 2,415 pregnant women prospectively after vaccination against the A(H1N1)v2009 influenza virus, by way of collaboration across the French network of pharmacovigilance centres. The very small number of pregnancies for which the outcome was unknown (7.0 %) does not impact the analysis of the results of this study, in particular with respect to pregnancy outcomes. Moreover, there is a very high probability that the pregnancies that were lost to follow-up were uneventful. Indeed, if there had been a negative outcome, there would be a strong incentive for reporting or contacting their physicians.

Overall, recommendations concerning vaccination quoted above were complied with, since most women (2,252) were vaccinated in the course of the last two trimesters of pregnancy (96.1 %) with a vaccine that did not contain adjuvant—PANENZA® for 97.6 %. The uses of a vaccine containing adjuvant (PANDEMRIX® or FOCETRIA®) occurred mainly in the first trimester, and this failure to comply with the recommendations could be explained by the fact that the women concerned did not know they were pregnant at the time of the vaccination and so fell under the measures adopted for the general population, i.e. vaccine with adjuvant. Indeed, in most cases, subjects were aware they were pregnant at the time of vaccination. But a few were included in the cohort after having discovered their pregnancy after vaccination.

In this study, we looked for any adverse event potentially linked to vaccination in the pregnant women in our cohort having received the vaccine. The overall percentage of these adverse events was 5.5 %. The non-serious adverse events reported in the cohort are similar to those described for the general population by Caillet et al. [16]. In this study, the authors analysed all adverse events reported by practitioners and patients in regional pharmacovigilance centres in France and registered in the French national pharmacovigilance database. Among the non-serious adverse events reported, “general disturbances and anomalies at the administration site” (65.9 % for PANDEMRIX® and 47.0 % for PANENZA® vs. 54.5 % for cases in our study), and “manifestations of the nervous system” (17.6 % for PANDEMRIX® vs, 16.9 % for cases in our study) were the most often described [16]. The adverse events found in our study were also comparable with those described in a study assessing vaccine safety in a population of healthcare personnel [17]. Generally, the profile of undesirable side effects is not specific to this particular vaccine, since it is also noted for other vaccines, in particular that for seasonal influenza [18, 19].

Among the 2,246 women whose pregnancy was followed up, 2,222 pregnancies (98.9 %) reached their term with 2,269 births.

Concerning SA, the proportion observed in our study (0.5 %) is well below the overall rate reported in the general population, which varies according to study from 10 to 15 % [2024]. This very marked difference could be explained by the fact that the pregnant women were recruited at the time of vaccination, that is to say, as noted earlier, in the second and third trimesters of pregnancy. SA is much more frequent in the early weeks of pregnancy, and decreases between the 8th and 12th week of gestation [20, 22, 24]. Thus, in the present study, given the small number of women vaccinated in the first trimester, it seems difficult to conclude to any effect of the vaccine on the risk of SA. Concerning SB, the proportion found by the present study (0.3 %) is below the rate observed in the general population, estimated at 0.7 % according to Audipog data. Again, it is difficult to draw conclusions, since 1,162 (49.6 %) of women were vaccinated in the third trimester, which could partly explain why the proportion is so small. This study therefore shows that vaccination against A(H1N1)v2009 influenza probably does not increase the risk of spontaneous miscarriage (SA and SB combined).

This result appears to confirm data from the French national pharmacovigilance database analysed in a recent publication [25]. In this study, the authors noted 30 serious adverse events observed in pregnant women and notified to regional pharmacovigilance centres. Among these, there were 13 cases of SB and 12 cases of SA, which is well below the proportions expected in the general population, thus leading to the conclusion that there was no reason for concern for this vaccination among pregnant women, despite limitations inherent in this type of surveillance (under-reporting).

Regarding pregnancies that reached their term, deliveries were mainly normal, since the proportion of Caesarean section was estimated to be 19.6 %, a proportion that is superimposable on that for the general population, estimated at 18.8 % (Audipog 2006). Delivery occurred at 39 WA on average, and prematurity was observed in 6.7 % of cases, which is close to the figure of 7.1 % reported by Audipog. Finally, no difference was found in birthweight (3,281 g vs. 3,282 g in the general population, Audipog) and stature (49.5 cm vs. 49.6 cm in the general population, Audipog) compared with the general population.

Congenital abnormalities were reported for 2.9 % of the neonates, and this proportion does not differ from that expected in the general population. However, if solely the women vaccinated in the first trimester of pregnancy are considered, only one malformation was observed, amounting to a rate of 1.4 %, which is below that expected in the general population. Indeed, according to a French weekly epidemiological bulletin published in 2008 in France, congenital malformations concern around 3 % of live births. This incidence is estimated from 4 French registries performing epidemiological surveillance of pregnancy outcomes in 14 French administrative areas, accounting for around 16 % of French births. To the 65 congenital anomalies observed in this study should be added 4 cases of therapeutic abortion, 2 of which followed disclosure of chromosome abnormalities (trisomy 18 and 21), 1 on account of a renal disorder (anamnios), and 1 for retarded growth. In the last instance, the termination was selective, on a twin with a serious malformation (details not available). The pregnant women had all been vaccinated in the second trimester of pregnancy using a vaccine without adjuvant with the exception of the last case, which occurred in the third trimester also using a vaccine without adjuvant.

The absence of any difference between malformation rates in the general population and in the present study population suggest that there is no causal link between the appearance of the abnormalities and vaccine exposure. Further to this, the risk of morphological effects is highest in the course of the first trimester, the period of organogenesis. It is therefore difficult to attribute the anomalies observed in the study to the administration of the vaccine, given that the exposure mainly occurred in the course of the second and third trimesters. Conversely, it is also difficult to conclude the absence of any teratogenic effect of the vaccine on account of the small number of subjects vaccinated in the first trimester. Moreover, the follow-up data were collected mainly 1 week after the delivery data, so that certain minor malformations that are not always immediately detected at birth may have been missed. Moreover, in most files there was no information on whether or not the patient was taking folates, but we consider that our study population was representative of the general population in France. Indeed, an overprescription of folates in our population is unlikely considering the fact that, in France, the prescription of folates during pregnancy is not usual. Another parameter that was not taken into account in our study is that use of potential teratogenic medication was not an exclusion criterion.

Finally, 96 newborns (4.2 %) presented a neonatal disorder, which is a proportion that is well below that found in the general population (25.3 %, Audipog). Several hypotheses could explain this difference, such as lack of homogeneity in the definition of the disorder, difficulty in diagnosing the disorder, and the fact that some regional pharmacovigilance centres might have not taken the usual pathologies observed in neonates into account, such as neonatal jaundice (0.2 % in our study vs 9.2 % in Audipog).

This study aimed to gain knowledge about any possible repercussions of mass vaccination against A(H1N1)v2009 influenza in a particular population, that of pregnant women, since data on the clinical safety of vaccines in this population are often sparse [2633]. It entails certain limitations. Indeed, as mentioned earlier, it appears difficult to draw certain conclusions, for instance on any teratogenic effect, because the vast majority of the women were vaccinated in the second or third trimester of pregnancy, i.e. after the organogenesis phase. Likewise, it is also difficult to assess the impact of vaccination on the occurrence of SA, given the period of vaccine exposure among the women in the cohort. The small number of women exposed in the first trimester included in the present study is accounted for by the fact that the recommendation was for vaccination in the second and third trimesters. Among women vaccinated during the first trimester, 31 received the adjuvanted vaccine (PANDEMRIX) with one SA and one major congenital abnormality, which was not different compared with the general population, but the number of women vaccinated with PANDEMRIX was too small to allow us to draw a conclusion.

The second main limitation of this study is the lack of a control group. Indeed, in the setting of a pandemic the establishment of a control group was not possible because of the time span. We therefore compared our results with data from the general population of pregnant women extrapolated from the Audipog perinatal network or from data recorded in the malformations registry.

It is also difficult to determine from this study whether or not the population of women included, who had decided or were advised to accept vaccination, were comparable from all points of view with the general population of pregnant women, in particular for age, social characteristics, risk factors, or gynaecological and obstetrical history, which are factors that can have an influence on the occurrence of spontaneous miscarriage [19, 22, 23]. Indeed, despite recommendations, according to health watchdog figures, only 22.7 % of pregnant women were vaccinated during the vaccination campaign of the winter of 2009–2010 [2].

The strength of our study is the large number of French women included and a very good follow-up rate of 93 %, reflecting marked interest from pregnant women and physicians for this study and considerable involvement and effort by the French network of regional pharmacovigilance centres, explaining this good follow-up rate.

Conclusions

This study conducted on a large sample of pregnant women via collaboration with the French network of regional pharmacovigilance centres has made it possible to show that vaccination against A(H1N1)v2009 influenza does not appear to increase the risk of miscarriage or the occurrence of congenital malformations compared with rates observed in the general population of pregnant women, despite the fact that the number of women vaccinated in the first trimester of pregnancy was insufficient for final conclusions to be reached. The impact of this data is important because of the demonstrated risk of severe complications for mother and foetus following infection by the A(H1N1) virus and the fact that vaccination at present appears to be the best means of preventing these complications in pregnancy.

References

  1. 1.

    French Advisory Council for Public Health. Guidance on health priority setting for the use of pandemic vaccines against A(H1N1) 2009 influenza virus. 2009 (cited 2009). Available from: http://www.hcsp.fr/docspdf/avisrapports/hcspa20090907_H1N1.pdf.

  2. 2.

    Bone A, Guthmann JP, Nicolau J, Levy-Bruhl D. Population and risk group uptake of H1N1 influenza vaccine in mainland France 2009–2010: results of a national vaccination campaign. Vaccine. 2010;28(51):8157–61.

    PubMed  Article  Google Scholar 

  3. 3.

    Jamieson DJ, Honein MA, Rasmussen SA, Williams JL, Swerdlow DL, Biggerstaff MS, et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet. 2009;374(9688):451–8.

    PubMed  Article  Google Scholar 

  4. 4.

    Siston AM, Rasmussen SA, Honein MA, Fry AM, Seib K, Callaghan WM, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA. 2010;303(15):1517–25.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Neuzil KM, Reed GW, Mitchel EF, Simonsen L, Griffin MR. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol. 1998;148(11):1094–102.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Dodds L, McNeil SA, Fell DB, Allen VM, Coombs A, Scott J, et al. Impact of influenza exposure on rates of hospital admissions and physician visits because of respiratory illness among pregnant women. CMAJ. 2007;176(4):463–8.

    PubMed  Google Scholar 

  7. 7.

    Jain S, Kamimoto L, Bramley AM, Schmitz AM, Benoit SR, Louie J, et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April–June 2009. N Engl J Med. 2009;361(20):1935–44.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Mosby LG, Rasmussen SA, Jamieson DJ. 2009 Pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature. Am J Obstet Gynecol. 2011;205:10–8.

    Google Scholar 

  9. 9.

    Dubar G, Azria E, Tesniere A, Dupont H, Le Ray C, Baugnon T, et al. French experience of 2009 A/H1N1v influenza in pregnant women. PLoS One. 2010;5(10).

  10. 10.

    Hewagama S, Walker SP, Stuart RL, Gordon C, Johnson PD, Friedman ND, et al. 2009 H1N1 influenza A and pregnancy outcomes in Victoria, Australia. Clin Infect Dis. 2010;50(5):686–90.

    PubMed  Article  Google Scholar 

  11. 11.

    Creanga AA, Johnson TF, Graitcer SB, Hartman LK, Al-Samarrai T, Schwarz AG, et al. Severity of 2009 pandemic influenza A (H1N1) virus infection in pregnant women. Obstet Gynecol. 2010;115(4):717–26.

    PubMed  Article  Google Scholar 

  12. 12.

    The ANZIC Influenza Investigators and Australian Maternity Outcomes Surveillance System. Critical illness due to 2009 A/H1N1 influenza in pregnant and postpartum women: population based cohort study. BMJ. 2010;340:c1279.

    Google Scholar 

  13. 13.

    Tamma PD, Ault KA, del Rio C, Steinhoff MC, Halsey NA, Omer SB. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol. 2009;201(6):547–52.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Perthus I, Amar E, De Vigan C, Doray B, Francannet C. Registries of congenital malformations in France: situation in 2008. BEH. 2008;28–29:246–8.

    Google Scholar 

  15. 15.

    Vendittelli F, Riviere O, Crenn-Hebert C, Claris O, Tessier V, Pinquier D, et al. Audipog perinatal network. Part 1: principal perinatal health indicators, 2004–2005. Gynecol Obstet Fertil. 2008;36(11):1091–100.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Caillet C, Durrieu G, Jacquet A, Faucher A, Ouaret S, Perrault-Pochat MC, et al. Safety surveillance of influenza A(H1N1)v monovalent vaccines during the 2009–2010 mass vaccination campaign in France. Eur J Clin Pharmacol. 2011;67(6):649–51.

    PubMed  Article  Google Scholar 

  17. 17.

    Hwang SM, Choe KW, Cho SH, Yoon SJ, Park DE, Kang JS, et al. The adverse events of influenza A (H1N1) vaccination and its risk factors in healthcare personnel in 18 military healthcare units in Korea. Jpn J Infect Dis. 2011;64(3):183–9.

    PubMed  Google Scholar 

  18. 18.

    Vellozzi C, Burwen DR, Dobardzic A, Ball R, Walton K, Haber P. Safety of trivalent inactivated influenza vaccines in adults: background for pandemic influenza vaccine safety monitoring. Vaccine. 2009;27(15):2114–20.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Fiore AE, Uyeki TM, Broder K, Finelli L, Euler GL, Singleton JA, et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep. 2010;59(RR-8):1–62.

  20. 20.

    Wilcox AJ. Surveillance of pregnancy loss in human populations. Am J Ind Med. 1983;4(1–2):285–91.

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Zinaman MJ, Clegg ED, Brown CC, O’Connor J, Selevan SG. Estimates of human fertility and pregnancy loss. Fertil Steril. 1996;65(3):503–9.

    PubMed  CAS  Google Scholar 

  22. 22.

    Saraiya M, Berg CJ, Shulman H, Green CA, Atrash HK. Estimates of the annual number of clinically recognized pregnancies in the United States, 1981–1991. Am J Epidemiol. 1999;149(11):1025–9.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Goldhaber MK, Fireman BH. Re: “Estimates of the annual number of clinically recognized pregnancies in the United States, 1981–1991”. Am J Epidemiol. 2000;152(3):287–9.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Nybo AA, Wohlfahrt J, Christens P, Olsen J, Melbye M. Is maternal age an independent risk factor for fetal loss? West J Med. 2000;173(5):331.

    PubMed  Article  Google Scholar 

  25. 25.

    Lacroix I, Damase-Michel C, Kreft-Jais C, Castot A, Montastruc JL. 2009 H1N1 influenza vaccines in pregnant women: the French Pharmacovigilance survey. Vaccine. 2011;29(7):1357–8.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Dlugacz Y, Fleischer A, Carney MT, Copperman N, Ahmed I, Ross Z, et al. 2009 H1N1 vaccination by pregnant women during the 2009–10 H1N1 influenza pandemic. Am J Obstet Gynecol. 2012;206(4):339 e1–8.

    Google Scholar 

  27. 27.

    Tavares F, Nazareth I, Monegal JS, Kolte I, Verstraeten T, Bauchau V. Pregnancy and safety outcomes in women vaccinated with an AS03-adjuvanted split virion H1N1 (2009) pandemic influenza vaccine during pregnancy: a prospective cohort study. Vaccine. 2011;29:6358–65.

    Google Scholar 

  28. 28.

    Pasternak B, Svanstrom H, Molgaard-Nielsen D, Krause TG, Emborg HD, Melbye M, et al. Vaccination against pandemic A/H1N1 2009 influenza in pregnancy and risk of fetal death: cohort study in Denmark. BMJ. 2012;344:e2794.

    PubMed  Article  Google Scholar 

  29. 29.

    Pasternak B, Svanstrom H, Molgaard-Nielsen D, Krause TG, Emborg HD, Melbye M, et al. Risk of adverse fetal outcomes following administration of a pandemic influenza A(H1N1) vaccine during pregnancy. JAMA. 2012;308(2):165–74.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Fell DB, Sprague AE, Liu N, Yasseen AS 3rd, Wen SW, Smith G, et al. H1N1 influenza vaccination during pregnancy and fetal and neonatal outcomes. Am J Public Health. 2012;102(6):e33–40.

    PubMed  Article  Google Scholar 

  31. 31.

    Lin TH, Lin SY, Lin CH, Lin RI, Lin HC, Chiu TH, et al. AdimFlu-S((R)) influenza A (H1N1) vaccine during pregnancy: the Taiwanese Pharmacovigilance Survey. Vaccine. 2012;30(16):2671–5.

    PubMed  Article  Google Scholar 

  32. 32.

    Moro PL, Tepper NK, Grohskopf LA, Vellozzi C, Broder K. Safety of seasonal influenza and influenza A (H1N1) 2009 monovalent vaccines in pregnancy. Expert Rev Vaccine. 2012;11(8):911–21.

    Article  CAS  Google Scholar 

  33. 33.

    Oppermann M, Fritzsche J, Weber-Schoendorfer C, Keller-Stanislawski B, Allignol A, Meister R, et al. A(H1N1)v2009: a controlled observational prospective cohort study on vaccine safety in pregnancy. Vaccine. 2012;30(30):4445–52.

    PubMed  Article  Google Scholar 

Download references

Acknowledgements

MedDRA® trademark is owned by the International Federation of Pharmaceutical Manufactuers & Associations (IFPMA) on behalf of the ICH. The authors would like to thank all the regional pharmacovigilance centres that recruited the patients, ANSM (Agence Nationale de Securité du Médicament) for funding the study, and especially Christel Saussier and Fanny Raguideau, Olivier Rivière, Françoise Venditelli, and the Audipog Network (Association des Utilisateurs de Dossiers Informatisés et Pédiatrie, Obstétrique et Gynécologie) [http://www.audipog.net], Delphine Gabiller, Angela Verdier for the translation of the article, and the pregnant women who agreed to take part in the study.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to F. Chavant.

Additional information

A. P. Jonville-Bera, C. Plazanet, V. Gras-Champel, L. Lagarce, M. Zenu, A. Disson-Dautriche, S. Logerot, M. Auffret, A. Coubret-Dumas, M. L. Bruel, M. Boyer, M. A. Bos-Thompson, G. Veyrac, P. Carlier, M. N. Beyens, S. Lates, and C. Damase-Michel contributed equally to this work

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chavant, F., Ingrand, I., Jonville-Bera, A.P. et al. The PREGVAXGRIP Study: a Cohort Study to Assess Foetal and Neonatal Consequences of In Utero Exposure to Vaccination Against A(H1N1)v2009 Influenza. Drug Saf 36, 455–465 (2013). https://doi.org/10.1007/s40264-013-0030-1

Download citation

Keywords

  • Influenza
  • Pregnant Woman
  • Pregnancy Outcome
  • Oseltamivir
  • Spontaneous Abortion