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Adjuvanted vaccines in pregnancy: no evidence for effect of the adjuvanted H1N1/09 vaccination on occurrence of preeclampsia or intra-uterine growth restriction

European Journal of Obstetrics & Gynecology and Reproductive Biology, pages 14 - 19



During the H1N1/09 pandemic, pregnant women in the Netherlands were vaccinated with an adjuvanted vaccine. During pregnancy, the maternal immune system changes to enable placental development and growth and acceptance of the semi-allogeneic fetus. As an adjuvant is a pro-inflammatory substance, it may interfere with these immunological changes, resulting in poor placentation or placental growth, which may result in preeclampsia (PE) and fetal intra-uterine growth restriction (IUGR). This study investigated a possible association between adjuvanted H1N1/09 vaccination and the development of PE and/or IUGR.

Study Design

Case-control study. Cases were Dutch women with PE and/or IUGR occurring during H1N1/09 vaccination program. Controls had uncomplicated pregnancies during the same period. Maternal characteristics, pregnancy and neonatal outcomes were collected from medical files. Participants were contacted by telephone to enquire about vaccination. Data were analyzed usingt-tests, Chi-square tests or Fisher's exact tests. Multivariate analysis was conducted to control for confounders.


We included 254 cases and 247 controls. Of the cases, 90 (35.4%) were vaccinated, compared to 87 (35.2%) of the controls (OR:1.009, 95% CI:0.70–1.46,p:0.961). The majority (73.5%) had been vaccinated in second and third trimester. In multivariate analysis, there were no confounders influencing these results. Exploratory subgroup analysis did not show an association between vaccination status in subgroups of women with either PE or IUGR.


Our study showed no association between adjuvanted H1N1/09 vaccination and PE and/or IUGR.

Keywords: H1N1/09, Adjuvant, Vaccination, Preeclampsia, Intra-uterine growth restriction..


At the beginning of 2009 the first cases of a new Influenza A virus were identified and described [1] . This H1N1/09 influenza, informally called swine flu, continued to spread and quickly became a pandemic. Several countries decided to provide vaccines for high-risk groups. Some of these vaccines contained adjuvants which stimulate the immune response, thereby reducing the amount of vaccine needed per person [2] . Pregnant women, especially those in the second and third trimester, were among the high-risk groups for developing complications of infection with H1N1/09 [3] . Therefore, the Dutch government advised vaccination of pregnant women after the first trimester [4] . The Focetria (Novartis) vaccine was used, which contains an oil-in-water adjuvant (MF59) [5] . At that time, clinical evidence for the safety of adjuvanted vaccines in pregnancy was limited. Available publications concentrated on the effect of the adjuvant on extreme outcomes of pregnancy, such as teratogenesis and showed no effects[6], [7], and [8]. Based on these results and results of earlier research on inactivated, unadjuvanted influenza vaccines in pregnancy [9] , the adjuvanted influenza vaccine was assumed to be safe.

An adjuvant is used to boost the immune response mainly by activating the innate immune response [2] . The innate immune response plays an important role during healthy pregnancy. Peripherally, there is generalized activation of the innate immune response. This is characterized by phenotypically activated monocytes and granulocytes [10] , as well as by different cytokine production of these cells[11] and [12]. Locally, at the uterine implantation site, innate immune cells such as uterine NK cells and macrophages play a role in establishing the placenta and supporting placental growth and function [13] . Changes in the local or peripheral immune response are associated with poor placentation or pregnancy complications, such as preeclampsia (PE) or intra-uterine growth restriction of the fetus (IUGR) [13] . Administering an adjuvanted vaccine during pregnancy may influence the maternal innate immune system and thus affect placentation or the course of the pregnancy [14] .

The main objective of this study was to evaluate a possible association between the H1N1/09 vaccinations and the occurrence of PE and/or IUGR by investigating whether women with PE and/or IUGR were more or less likely to be vaccinated, compared to healthy controls.

Materials and methods

This case-control study was conducted in the University Medical Center and the Martini Hospital in Groningen, The Netherlands. The Institutional Review Boards of both hospitals approved the protocol.


Cases were pregnant women during the vaccination program who delivered in either of the two hospitals. In the Netherlands, vaccination occurred between November 9th, 2009 and February 26th, 2010. Women who delivered after November 8th, 2009 and were due before November 19th, 2010 (38 weeks after the last possible date of vaccination) were included.

Eligible cases were women with PE, IUGR or both. PE was defined as blood pressure ≥140 mmHg systolic and/or ≥90 mmHg diastolic combined with proteinuria (>0.3 g/24 h or ≥ 2 + on dipstick) [15] or HELLP syndrome (LDH ≥ 600 IU/l, AST or ALT ≥ 70 IU/l, platelets ≤100 × 109 cells/l). IUGR was defined as a birthweight below the 10th percentile, as estimated fetal weight during pregnancy was not available for all participants [16] . Cases were excluded in the event of preexisting hypertension (before 20 weeks of pregnancy), fetal congenital malformations or a medical history of kidney disease, diabetes, antiphospholipid syndrome or systemic lupus erythematosus (SLE).

Controls had an uncomplicated pregnancy and were selected on having delivered less than a week before or after a case in the same hospital. This way, a similar spread of delivery in the case and control group was achieved, thereby minimizing bias caused by seasonal variance in prevailing diseases and possible variation in vaccination uptake caused by public discussion. Exclusion criteria for controls were hypertension (including PE/HELLP syndrome), IUGR, fetal congenital malformations, perinatal death and a history of kidney disease, diabetes, antiphospholipid syndrome or SLE.

Data collection

Data regarding general and obstetric history, maternal characteristics, pregnancy, delivery and neonatal outcomes were collected from medical files. To allow for controlling of possible confounders, factors associated with PE and IUGR were collected[17], [18], [19], and [20]. These included maternal factors such as BMI, age, ethnicity and use of tobacco during pregnancy. In addition, medical history was assessed, including the occurrence of IUGR or PE in a previous pregnancy and a family history of PE, IUGR or cardiovascular disease.

Both cases and controls were contacted by telephone to obtain informed consent and to enquire about vaccinations during pregnancy. Women were asked whether they had been vaccinated against H1N1/09. If yes, they were asked to report on the number of vaccinations received and the trimester in which they had been vaccinated. Women were also asked whether they had received any other vaccinations during their pregnancy.

Data analysis

At the start of study, the percentage of pregnant women that had been vaccinated against H1N1/09 was unknown. Assuming the rate to be between 10% and 50%, we needed 100–170 women in each arm to demonstrate a 15% difference in vaccination percentage between cases and controls (α = 0.05,β = 0.20).

Data-analysis was performed with SPSS version 20. A two-sided probability ofp < 0.05 was considered statistically significant.

Baseline characteristics were studied in cases and controls. We used Chi-square or Fisher's exact test to test differences between cases and controls for categorical variables and Studentst-tests for continuous variables. Data are presented asN(%) or as mean (±SD) as appropriate. Vaccination status is presented asN(%) of cases or controls that were vaccinated and the percentage was compared between cases and controls using Chi-square or Fisher's exact test.

Subgroup analysis

We performed exploratory analysis for the subgroups IUGR and PE. For IUGR, further analysis was done on subgroups with birthweight below 5th percentile and below 3rd percentile. For PE, participants were further divided into early-onset and late-onset PE. Early-onset PE was defined as delivery before 34 weeks of gestation, while delivering during or after 34 weeks of pregnancy was considered late-onset PE. As before, vaccination status was compared between cases and controls within the different subgroups using Chi-square or Fisher's exact test.

Multivariate analysis

Univariate logistic regression analysis was performed to study the relationship between H1N1/09 vaccinations and the occurrence of PE and/or IUGR. To determine possible confounders in this relationship, the association of these variables with both the H1N1/09 vaccination and PE and/or IUGR was studied in univariate analyses. Variables related with PE and/or IUGR (p < 0.05) were considered potential confounders and were entered in a multivariate logistic regression model with H1N1/09 vaccination to assess the impact on the Odds ratio. Variables resulting in a change of odds ratio of more than 10% were considered to be confounders and were retained in the analysis.


Study population

Of all the women who delivered after November 8th, 2009 and were due before November 19th, 2010 in either of the two hospitals, 417 had PE and/or IUGR. After applying the exclusion criteria, a total of 374 women were included. Of these women, 111 could not be reached by telephone (after at least 10 attempts and efforts to obtain different telephone numbers through physicians), seven did not want to participate and two did not remember their vaccination status. As a result, analysis was performed on a total of 254 cases, of which 70 had PE, 176 had IUGR and 8 had both PE and IUGR. Subgroup analysis of PE and IUGR was performed on a total of 78 women with PE and 184 women with IUGR. A total of 247 controls were selected and reached by telephone.


Baseline characteristics and possible confounders are presented in Table 1 . Cases and controls were similar regarding ethnicity, maternal age and parity, but differed significantly in gestational age at delivery and birthweight. Significantly different between cases and controls were a history of PE and/or IUGR, multiple gestation and smoking. When considering controls only, mean birthweight tended to be higher in vaccinated women than in non-vaccinated women (3672.3 g and 3574.5 g respectively, mean difference: 97.8, 95% CI: −218.46 to 22.93,p: 0.112).

Table 1 Baseline characteristics.

    Cases Controls p -value a
    (N = 254) (N = 247)
Ethnicity N (%)
Caucasian   242 (95.3) 238 (96.4) 0.825 b
Other   12 (4.7) 9 (3.6)  
Maternal age at conception (years) Mean (SD) 29.3 (5.5) 29.8 (5.0) 0.329 c
Gestational age at delivery (days) Mean (SD) 265.2 (25.1) 279.7 (8.8) 0.000 c
Birthweight (g) Mean (SD) 2510.1 (753.0) 3609.0 (461.5) 0.000 c
Parity N (%) 0.600 d
Nulliparity   158 (62.2) 148 (59.9)
Multiparity   96 (37.8) 99 (40.1)
History of preeclampsia (PE) and/or intra-uterine growth restriction (IUGR) N (%) 0.003 d
No history of PE and/or IUGR   223 (87.8) 235 (95.1)
    Nulliparity   158 (62.2) 148 (59.9)
    Multiparity without history   65 (25.6) 87 (35.2)
History of PE and/or IUGR
    Multiparity with history   31 (12.2) 12 (4.9)
Multiple gestation N (%) 15 (5.9) 0 (0.0) 0.000 d
Smoking during pregnancy N (%) 64 (25.2) 37 (15.0) 0.004 d
Body Mass Index N (%)
<19   17 (6.9) 14 (5.8) 0.627 d
19–25   142 (57.5) 152 (63.1) 0.208 d
25–35   78 (31.6) 71 (29.5) 0.611 d
>35   10 (4.0) 4 (1.7) 0.114 d
(Missing: N=13 (2.6%))            

a Significant: p-value < 0.05.

b Fisher's Exact test.

c Independent t-test.

d Chi-Square test.

Details on vaccination status in cases and controls are presented in Table 2 . Of all participants, 177 (35.3%) were vaccinated against H1N1/09 during pregnancy. Of those, 71 (40.1%) had received only one vaccination, while 106 (59.9%) had been vaccinated twice. Of the vaccinated women, 130 (73.5%) had received their first (or only) vaccination during the second and third trimester of pregnancy (84 and 46 women respectively). When considering vaccination in first trimester only, of all 90 vaccinated cases and 87 vaccinated controls, seven (7.8%) cases received their first (or only) vaccination during first trimester, compared to two (2.3%) controls (Fisher's Exact, OR: 3.584, 95% CI: 0.72–17.76,p: 0.169). There were no significant differences between cases and controls when considering being vaccinated once or twice and having received other vaccinations during pregnancy.

Table 2 Vaccinations.

  Cases Controls p -value a
(N = 254) (N = 247)
N (%) N (%)
Vaccination status
Not vaccinated during pregnancy 164 (64.6) 160 (64.8) 0.902 b
Vaccinated once during pregnancy 38 (15.0) 33 (13.4)
Vaccinated twice during pregnancy 52 (20.5) 54 (21.9)
Trimester of vaccination
First vaccination (N = 90) (N = 87)  
First trimester 7 (7.8) 2 (2.3) 0.127 b
Second trimester 41 (45.6) 43 (49.4)
Third trimester 19 (21.1) 27 (31.0)
Unknown 23 (25.6) 15 (17.2)
Second vaccination (N = 52) (N = 54)  
First trimester 1 (1.9) 1 (1.9) 0.766 b
Second trimester 21 (40.4) 27 (50.0)
Third trimester 14 (26.9) 14 (25.9)
Unknown 16 (30.8) 12 (22.2)
Other vaccinations/injections
Seasonal influenza 19 (7.5) 17 (6.9) 0.925 b
Tetanus 1 (0.4) 1 (04)
Anti-rhesus D immunoglobulin 3 (1.2) 3 (1.2)

a Significant: p-value < 0.05.

b Fisher's exact test.

No significant relationship was found between vaccination against H1N1/09 during pregnancy and the development of PE and/or IUGR ( Table 3 ). Of all cases, 90 (35.4%) were vaccinated against H1N1/09, compared to 87 (35.2%) controls (OR: 1.009, 95% CI: 0.70–1.46,p: 0.961).

Table 3 Vaccinations in cases and controls.

  Vaccinated N (%) OR 95% CI p -value a
Cases Controls
Total group
PE and/or IUGR

(N = 254 cases, 247 controls)
90 (35.4) 87 (35.2) 1.009 0.70–1.46 0.961 b
Intra-uterine growth restriction
Total IUGR<p10

(N = 184 cases, 247 controls)
67 (36.4) 87 (35.2) 1.053 0.71–1.57 0.799 b

(N = 101 cases, 247 controls)
34 (33.7) 87 (35.2) 0.933 0.57–1.52 0.782 b

(N = 55 cases, 247 controls)
19 (34.5) 87 (35.2) 0.971 0.53–1.79 0.924 b
Total PE

(N = 78 cases, 247 controls)
24 (30.8) 87 (35.2) 0.817 0.47–1.41 0.470 b
Early PE (delivery <34 weeks)

(N = 24 cases, 247 controls)
5 (20.8) 87 (35.2) 0.484 0.18–1.34 0.155 b
Late PE (delivery ≥34 weeks)

(N = 54 cases, 247 controls)
19 (35.2) 87 (35.2) 0.998 0.54–1.85 0.996 b

a Significant: p-value < 0.05.

b Chi-Square test.

Subgroup analysis

Dividing the cases into two groups of PE and IUGR, no significant associations were found between these separate conditions and vaccination status ( Table 3 ). Within women with IUGR, analysis was done for subgroups of birthweight. When regarding vaccination status, cases in which birthweight was below 3rd and below 5th percentile were comparable to controls. Preeclamptic women were further divided into early-onset and late-onset PE. In both groups, cases and controls were comparable with regard to vaccination status.

Multivariate analysis

Univariate analysis revealed three variables to be significantly associated with PE and/or IUGR: a history of PE and/or IUGR, smoking during pregnancy and multiple gestation ( Table 4 ). In multivariate analysis, none of these variables were a confounder in the relationship between PE and/or IUGR and H1N1/09 vaccination.

Table 4 Possible confounders: Factors associated with preeclampsia (PE) and/or intra-uterine growth restriction (IUGR).

  Associated factors N (%) OR 95% CI p-value a
Cases (N = 254) Controls (N = 247)
History of preeclampsia (PE) and/or intra-uterine growth restriction (IUGR)
No history of PE and/or IUGR 223 (87.8) 235 (95.1)     0.003 b
    Nulliparity 158 (62.2) 148 (59.9)    
    Multiparity without history 65 (25.6) 87 (35.2)    
History of PE and/or IUGR
    Multiparity with history 31 (12.2) 12 (4.9)      
Maternal age >40 years 2 (0.8) 2 (0.8) 0.972 0.14–6.96 1.000 c
Multiple gestation 15 (5.9) 0 (0.0)     0.000 b
Smoking during pregnancy 64 (25.2) 37 (15.0) 1.912 1.22–3.00 0.004 b
Body Mass Index
<19 17 (6.9) 14 (5.8) 1.198 0.58–2.49 0.627 b
>35 10 (4.0) 4 (1.7) 2.500 0.77–8.08 0.114 b

a Significant: p-value < 0.05.

b Chi-Square test.

c Fisher's exact test.


This study explored a possible association between the H1N1/09 vaccinations and occurrence of PE and/or IUGR, as adjuvant has been thought to influence the physiological maternal immune changes, thereby giving rise to poor placentation or placental growth. Our results did not show a significant difference in vaccination status between cases with PE and/or IUGR and healthy controls.

Of all women participating in this study, 35.3% were vaccinated against H1N1/09. The percentage of vaccinated women varied, with reported vaccination percentages in Denmark, Argentina and Norway of 12.9%, 24% and 54%[21], [22], and [23]. Van Lier and colleagues reported 63% of Dutch pregnant women to be vaccinated as assessed by questionnaire, while 39% had a positive intention to be vaccinated in future pregnancies [5] . The discrepancy with our results may be due to different methodology. Van Lier et al. used a questionnaire which was sent to the general population; numbers may have been influenced by the fact that vaccinated women were more inclined to return the questionnaires than non-vaccinated women, giving rise to non-responders bias. As part of our data relies on self-report, we cannot rule out that our data collection could have given rise to inadequate recall by the participants. Unfortunately, as vaccination in the Netherlands was performed in the general practice, it was not feasible to collect data from all primary care physicians involved.

In the present study, we did not find a difference between cases and controls regarding the percentage of vaccinated women; 35.4% of cases had been vaccinated, compared to 35.2% of controls. Conducting multivariate analysis to control for confounders yielded identical results, as no confounders were identified. We can conclude that vaccination with this adjuvanted vaccine in second and third trimester does not influence the development of PE and/or IUGR. However, as women in the Netherlands were advised to get vaccinated in their second and third trimester, this study is insufficiently powered to draw any conclusions on the effects of vaccination in first trimester. This is the period in which development of the placenta largely takes place and in which differences between cases and controls are most likely to occur. In this study, among the very few participants who had been vaccinated in the first trimester there were more cases than controls.

We further analyzed cases with IUGR and PE separately. The results of these subgroup analyses were in line with the overall results, showing no effect of vaccination on developing IUGR or PE. Also, after dividing IUGR into subgroups according to percentile (below 5th and below 3rd percentile), no differences were found between cases and controls. To further explore a possible effect of vaccination, we also analyzed birthweight in controls, comparing vaccinated and non-vaccinated women. Among our 247 controls, birthweight was found to be slightly, but not significantly, higher in those women vaccinated against H1N1 compared to women who had not been vaccinated (mean 3672.3 g and 3574.5 g respectively,p: 0.112).

We further divided PE into early-onset and late-onset PE according to delivery, using a cut-off at 34 weeks of pregnancy. In literature, a distinction is made between these types of PE based on underlying pathophysiology. While early-onset PE is considered a fetal disorder arising from poor placentation, late PE is believed to be a maternal disorder not associated with placental dysfunction [24] . Our results showed no significant association between vaccination status and early-onset or late-onset PE. Unfortunately, our study was not sufficiently powered to detect small differences in subgroups. There are no other studies on the effect of adjuvanted vaccines in pregnancy differentiating between early-onset and late-onset preeclampsia.

Following the H1N1/09 pandemic, there have been relatively few publications focusing on the safety of adjuvanted H1N1/09 vaccines in pregnancy. Pasternak and colleagues found no association between the use of AS03 adjuvanted vaccines (Pandemrix) and major birth defects, preterm birth, fetal growth restriction or fetal death (spontaneous abortion and stillbirths combined)[22] and [25]. Similarly, recent studies in the United Kingdom and Sweden showed no increased risk of adverse pregnancy outcomes in women receiving an AS03 adjuvanted vaccine[26] and [27]. Källén and colleagues found that the risk of low birthweight was lower in women who had been vaccinated with Pandemrix, compared to women who had not been vaccinated [26] . These studies, although focusing on a different type of adjuvant, are in line with our results in the subgroup IUGR. The effect of MF59 adjuvanted vaccines on ectopic pregnancy, spontaneous abortion and stillborn delivery was investigated by Tsai and colleagues, showing no increased risk of any of these complications [28] . Trotta et al. found a slightly higher risk of eclampsia and gestational diabetes in vaccinated women, but no difference in perinatal deaths or small for gestational age [29] . Only two previous studies focused on the effect of the MF59 adjuvanted vaccine Focetria on low birth weight and preeclampsia and showed no safety risk[23] and [30]. Our results confirm these data. To conclude, the results of the current study showed no association between the H1N1/09 vaccinations and the occurrence of PE and/or IUGR in pregnant women, indicating that adjuvanted vaccines can be used safely in second and third trimester. Further research investigating an effect of adjuvanted vaccination in first trimester is warranted. Furthermore, we did not find significant associations in subgroup analysis of IUGR, IUGR below 5th and 3rd percentile, PE, early-onset PE and late-onset PE. Future research should aim to investigate these subgroups more extensively.

Funding statement

No specific funding was obtained for this research.


This study shows no evidence for an association between the H1N1/09 vaccinations and the occurrence of preeclampsia or intra-uterine growth restriction

Conflicts of interest

Authors report no conflicts of interest


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a University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, Groningen, The Netherlands

b Martini Hospital Groningen, Department of Obstetrics and Gynecology, Groningen, The Netherlands

c University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands

d University of Groningen, University Medical Center Groningen, Department of Pathology and Medical biology, Section Medical biology, Groningen, The Netherlands

e Onze Lieve Vrouwe Gasthuis, Department of Obstetrics and Gynecology, PO Box 95500, 1090 HM Amsterdam, The Netherlands

lowast Corresponding author: Tel.: +31205999111, 1114 (tracer number).

This study was conducted in Groningen, The Netherlands.