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Impact of Vaccines Given During Pregnancy on the Offspring of Women Consulting a Travel Clinic: A Longitudinal Study Valérie D’Acremont, MD, MiH,* Sylvie Tremblay,* and Blaise Genton, MD, PhD*† *Travel Clinic, Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland; †Department of Public Health and Epidemiology, Swiss Tropical Institute, Basel, Switzerland DOI: 10.1111/j.1708-8305.2007.00175.x
Background. Little is known on the impact of travel vaccinations during pregnancy on child outcomes, in particular on the long-term psychomotor development. The objectives of the study were (1) to estimate the rate of premature births, congenital abnormalities, and mental and physical development problems of children born from mothers who had been vaccinated during pregnancy and (2) to compare these rates with those of children whose mothers had not been vaccinated during pregnancy. Methods. Longitudinal study including (1) retrospectively pregnant women having attended our travel clinic before (vaccinated) and (2) prospectively mothers attending our clinic (nonvaccinated). We performed phone interviews with mothers vaccinated during pregnancy, up to 10 years before, and face-to-face interviews with nonvaccinated age-matched mothers, ie, women attending the travel clinic who had one child of about the same age as the one of the case to compare child development between both groups. Results. Fifty-three women vaccinated during pregnancy were interviewed as well as 53 nonvaccinated ones. Twentyeight (53%) women received their vaccination during the first trimester. The most frequent vaccine administered was hepatitis A (55% of the cases), followed by di-Te (34%), IM poliomyelitis (23%), yellow fever (12%), A-C meningitis (8%), IM typhoid (4%), and oral poliomyelitis (4%). Children were followed for a range of 1 to 10 years. Rates of premature births were 5.7% in both groups; congenital abnormalities were 1.9% in the vaccinated cohort versus 5.7% in the nonvaccinated one; children took their first steps at a median age of 12 months in both cohorts; among schoolchildren, 5% of the vaccinated cohort versus 7.7% of the nonvaccinated attended a lower level or a specialized school. Conclusion. In this small sample size, there was no indication that usual travel vaccinations, including the yellow fever one, had deleterious effect on child outcome and development.
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isk of vaccination during pregnancy on the developing fetus is primarily theoretical. Indeed, there is no clear-cut evidence of adverse events, either before delivery or during the first years of life of the child.1,2 Benefits of vaccinating pregnant women usually outweigh potential risks when the likelihood of disease exposure is high and/or when infection would pose a risk to the mother or fetus. Pregnant women are generally advised to avoid live virus vaccines (measles, mumps, rubella, varicella, and yellow fever).
Corresponding Author: Blaise Genton, MD, PhD, Ifakara Health Research and Development Center, PO Box 78373, Dar Es Salaam, Tanzania. E-mail: blaise.
[email protected]
In practice, four levels can be distinguished: (1) the vaccines that are always contraindicated, such as measles, mumps, rubella, varicella, and BCG vaccines; (2) the ones that are usually contraindicated, such as yellow fever vaccine; (3) the ones where there are no good data available, such as typhoid vaccine, Japanese encephalitis, and meningitis vaccines; and (4) the ones that are considered safe, such as diphtheria, tetanus, poliomyelitis (inactivated), and hepatitis A & B vaccines. The usual recommendation is that a vaccine can be administered to a pregnant woman only if the travel to an endemic area is unavoidable and if a substantial risk of exposure exists. During pretravel consultation, we are often faced with women who have planned a trip for leisure, business, or for visiting family in their home country
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78 and who are not willing to postpone their journey until after delivery. It happens that women decide, when possible, to change their destination for a country where no live-attenuated vaccines (against yellow fever especially) are needed or no malaria is transmitted. More often, they stick to their planned travel, and the risk/benefit of each vaccine has to then be assessed. In some instances, vaccines that are not usually recommended are given, the most frequent being the yellow fever vaccine. It also happens that a meningitis vaccine is administered because of an ongoing epidemic. All attempts should be made to have these vaccines administered during the second or third trimester rather than during the critical phase of the first trimester. In our experience, after extensive information on the risk/benefit ratio of the different vaccines, the pregnant travelers usually choose to get the inactivated vaccines recommended and, when indicated and no equivalent inactivated vaccine is available, the live-attenuated one(s) too. To our knowledge, there is no assessment available on the impact of vaccination during pregnancy on long-term child development. Few studies have investigated the effect of vaccination during pregnancy on the development of the fetus and the birth outcome. In none of them, a clear-cut adverse event could be identified. Besides very small case series, there was one study with 202 pregnant women injected with rabies vaccine,3 two studies with 109 and 34 women who received polysaccharide meningitis vaccine,4,5 and one study on anthrax in US army pregnant soldiers,6 all showing no abnormalities in the children. In these studies, the vast majority of the women were vaccinated during the second or third trimester, and the follow-up of the offspring did not exceed 2 years. Regarding yellow fever vaccine, a Brazilian casecontrol study conducted during an epidemic and including 39 women who had spontaneous abortion and 74 controls reported an adjusted odds ratio (OR) of 2.29, which did not reach statistical significance (OR 2.3, CI 0.65–8.03)7 but should still be considered as a signal for a potential deleterious effect of vaccination during pregnancy if the magnitude would hold true in a larger study. A low maternal seroconversion rate but no abnormality in the offspring (followed during 3–4 y) was observed in 101 Nigerian women (of which only 4% had received the vaccine during the first trimester).8 A recent, large prospective study (recruitment was done in late pregnancy, which impeded a study of the risk of miscarriage) including 480 women inadvertently immunized during a mass vaccination did not show J Travel Med 2008; 15: 77–81
any adverse event on the offspring that were followed up to 12 months of age.9 Interestingly, in this study, the seroconversion was very high (98%). The principle of precaution hinders formal largescale safety studies to be conducted. Pharmaceutical companies are not interested in such investigations since the additional commercial benefit they could make with pregnant women is not worth the risk they would have to take. We are therefore left with pharmacovigilance reports. One of the latter showed, in 74 pregnant women having received a yellow fever vaccine, an incidence of spontaneous abortion and of malformations of 12 and 3.4%, respectively, rates which were similar to the ones found in the corresponding general population (14%–19% and 3%–4%, respectively).10 For the above reasons, and because of the paucity of the data, we decided to perform a longitudinal study using the data accumulated in our travel clinic over a period of 10 years. The objectives were (1) to measure the rate of prematurity, congenital abnormalities, and mental and physical development problems of children born from mothers who had been vaccinated during pregnancy and (2) to compare these rates with those found in a matched group of mothers who did not receive any vaccination during pregnancy. Methods We performed a longitudinal study including (1) retrospectively pregnant women having attended our travel clinic before (vaccinated) and (2) prospectively mothers attending recently our clinic (nonvaccinated). Definition of an Exposed (Vaccinated) Mother A woman who received at least one vaccine during pregnancy months or years before. Recruitment of Exposed Cases We first reviewed all medical records of the travelers having attended our travel clinic in the past 10 years. We collected the records where women had answered, either yes or with a question mark, to the question: “Are you pregnant?” and where at least one vaccine had been given during the consultation. We then contacted them by phone when available to know whether they would agree to respond to a short questionnaire on the possible problems they, or their child, experienced after they received their vaccination when pregnant. For those who confirmed that they were in fact pregnant at the time of vaccination, and agreed, we sent a self-administered questionnaire.
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Impact of Vaccination During Pregnancy on the Offspring Definition of a Nonexposed (Nonvaccinated) Mother A woman who had not received any vaccination during the corresponding pregnancy. Each woman was age matched to an exposed case (±3 y). Recruitment of Nonexposed Cases After this first step, we then proposed to women attending our travel clinic and having at least one child of about the same age as the one of the case to fill in (face-to-face interviews) a questionnaire similar to the one filled by the case. We ensured, by asking the mother in depth, by reviewing their vaccination booklet, and by checking the medical record of our clinic when available, that they had not received any vaccine during pregnancy. When the women had several children, we chose only one of them. This study design did not allow us to compare rates of spontaneous abortion and stillbirth between women exposed to vaccine during pregnancy and those not exposed since the latter were recruited according to the age of their child (by definition alive at the time of interview). We were more interested to explore long-term development rather than pregnancy or birth outcomes. We could only count the number of abortion(s) or stillbirth(s) among the exposed women and compare it with the rate in the general population. Questionnaire Content The questionnaire included questions on demographics, type of vaccine(s) received during pregnancy (for the exposed group), gestational age at birth (prematurity), presence of congenital abnormality, age at first step, and school history (grade for age and specialized institution). Table 1
Results Characteristics of Women Enrolled After reviewing all archived medical records corresponding to consultations having taken place in our travel clinic between January 1, 1988, and December 31, 2000, we found 131 files that corresponded to our definition of exposed women (with possible or confirmed pregnancy). After excluding 24 women who could not be reached (mainly because their up-to-date address or phone number could not be found), we contacted 107 women by phone, of whom 49 told us that they were actually not pregnant at the time of the travel consultation and 1 told that she had not yet given birth. Of the 57 women who fulfilled all criteria to be enrolled as a vaccinated case, 1 refused to participate and 3 never sent back their questionnaire, which leaves finally 53 vaccinated women for analysis. To compare these 53 exposed cases, 53 nonvaccinated cases matched for the age of the mother at delivery were recruited. Demographic characteristics of the two groups are described in Table 1. Type of Vaccines Received by the Pregnant Travelers (Exposed Group) The initiation of vaccination began for 28/53 (53%) cases during the first trimester of their pregnancy. The 34/53 (64%) received one vaccination, 18/53 (34%) two, and 1/53 (2%) three. The most frequent vaccination was against hepatitis A [29/53 (55%)]. The 8/53 (15%) received a live-attenuated vaccine, 6 against yellow fever and 2 against poliomyelitis; 3 of these 8 received the vaccine during the first trimester (2 against yellow fever or 1 against poliomyelitis)
Demographic characteristics of the pregnant travelers and their offspring
Age of the mother at delivery: mean (range) Parity: number First born Second born Third born Fourth born Duration of follow-up of the children: mean (range) Vaginal delivery: number Chronic disease already existing in the mother before delivery Allergic rhino-conjunctivitis Asthma Psoriasis Lupus Hepatitis B Basedow disease
Exposed (vaccination during pregnancy), N = 53
Nonexposed (no vaccination during pregnancy), N = 53
29.6 (21.1–37.9)
30.7 (20.6–37.7)
35 10 5 3 4.6 (0.1–12.9) 36
29 18 4 2 7.8 (1.0–17.5) 34
9 3 2 0 0 1
3 3 0 1 2 0
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80 (see Table 2). None of the pregnant travelers received an injection of the measles–mumps–rubella vaccine. Outcome of the Offspring of Vaccinated and Nonvaccinated Women When comparing the offspring of the exposed group (women having received at least one injection during their pregnancy), with the offspring of the nonexposed group (no vaccine during pregnancy), the number of premature babies was three in both groups and the number of congenital abnormalities was one (hypospadias) in the vaccinated group versus three (trisomy, strabismus, and unknown) in the nonvaccinated one. Concerning the physical and mental development items, the median age at which children walked for the first time was 12 months in both groups (range: 9–19 mo in the vaccinated and 9–24 mo in the nonvaccinated group). The number of children who could not follow the usual school program (being at a lower school level than expected for their age), or who were in a specialized school, was 1/20 in the vaccinated group (1 and 0 for the delay or specialized school, respectively) versus 3/39 in the nonvaccinated one (1 and 2, respectively). Number of Spontaneous Abortions in the Vaccinated Group Compared With the Incidence in the General Population Within the group of the vaccinated mothers, 1 woman of 53 (1.9%) had a spontaneous abortion at the third month of pregnancy. She had received an oral poliomyelitis vaccine (Poloral; Berna Biotech, Bern, Switzerland) and a hepatitis A vaccine (Havrix 1440; Glaxo SmithKline, Rixensart, Belgium) beforehand. Since she could not remember the exact date of the miscarriage (between days 0 and 50 postvaccination), we could not assess the causal relationship between the abortion and the vaccination. This
Table 2
is lower than the usual incidence rate of spontaneous abortion in the general population. Discussion Our results showed no deleterious effects of vaccination on several child outcomes, ie, premature birth, congenital abnormalities, and long-term physical or mental development. Contrasting with the few studies available, more than half of the pregnant women had received their vaccine(s) during the first trimester, which is considered as the most critical period. Except for the Nigerian study, which included only four women vaccinated during the first trimester,8 there has been no study that intended to assess the long-term consequences of vaccination during pregnancy because of the practical difficulties of this type of investigation, as well as the general lack of interest for this topic. Long-term follow-up is essential for neurotropic live vaccines, such as the yellow fever one, since they could theoretically alter the development of the central nervous system because of the transient viremia.11 As was already mentioned, the design of our study did not allow to compare the rate of miscarriage between the women vaccinated and the ones nonvaccinated. However, when comparing the incidence of abortion in our sample of vaccinated women to the ones in the general population, the rate was actually lower in the vaccinated ones.12 All our results are in line with previous studies, which could not identify clear-cut adverse events linked with vaccination during pregnancy, whatever vaccine was used. When we designed our study, we calculated a sample size of 150 exposed and 150 nonexposed, which seemed possible to achieve, based on the number of pregnant travelers who had been vaccinated in our center during the preceding years. However, because of increasing concerns on potential legal consequences, the principle of precaution tended to
Number and type of vaccines received by the pregnant travelers Number of women vaccinated during
Vaccine Yellow fever Oral (live) poliomyelitis Inactivated poliomyelitis Diphtheria–tetanus Hepatitis A Meningitis A-C Inactivated typhoid At least one vaccine, n (%)
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First trimester
Second trimester
Third trimester
2 1 7 12 16 3 1 28/53 (53%)
4 1 4 4 12 0 1 21/53 (40%)
0 0 1 2 1 1 0 4/53 (8%)
Any time during pregnancy, n (%) 6/53 (11) 2/53 (4) 12/53 (23) 18/53 (34) 29/53 (55) 4/53 (8) 2/53 (4)
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Impact of Vaccination During Pregnancy on the Offspring prevail more and more. Therefore, the number of pregnant, or potentially pregnant, women who have been vaccinated in our center significantly decreased over time. Our sample size of 106 is clearly too small to draw firm conclusions. However, it provides additional documentation on the safety of travel vaccinations during pregnancy and confirms that we still have no reason to believe that travel vaccines have deleterious effect on child outcome and development. Since no pharmaceutical company wants to embark on a large-scale prospective study, we can only rely on cumulative evidence. Eventually, all available data will be sufficient to perform a systematic review and meta-analysis. The real question now is to decide whether we should make every possible effort to get more information on safety of vaccines during pregnancy, or if the data obtained until now are sufficient to propose vaccination to pregnant women more widely, even for vaccines such as measles–mumps–rubella, which have never been associated with deleterious effects on the mother or the child.13 Wider use does not apply obviously for new live vaccines such as varicella, where only little information on inadvertent vaccination during pregnancy is available. If more data are needed, what is now the best study design to be able to draw firm conclusions? Ideally, a large case-control study to assess long-term development problems in offspring should be conducted in a population with a reasonable proportion of pregnant women vaccinated with live vaccines, which is now difficult to find in Western countries. It should include children of different ages and with the type of development impairment that is expected to be associated with particular vaccines. The problem of recall bias for vaccines received during a pregnancy that occurred years before would be an obvious pitfall in such an investigation. Therefore, a large cohort study initiated at the time of a vaccination campaign against a particular disease (which exists only for yellow fever, meningitis, or Japanese encephalitis but not for the other vaccines), with a follow-up of several years, is probably the only solution. Follow-up of children could be performed through large demography surveillance systems that are in place in several countries that are the target of such campaigns.14 We could dream of an interest group among travel medicine specialists that would embark on a large multicentric study to look at these issues but this is unlikely to happen since there is not much hope for significant financial support for such a cohort study over several years. Up until more is known, we have to rely on existing data, and our study provides addi-
tional reassurance on the issue of long-term effect of vaccine on child psychomotor development. Declaration of Interests The authors state that they have no conflicts of interest. References 1. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998; 338:1128–1137. 2. Kroger AT, Atkinson WL, Marcuse EK, Pickering LK. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006; 55:1–48. 3. Chutivongse S, Wilde H, Benjavongkulchai M, et al. Postexposure rabies vaccination during pregnancy: effect on 202 women and their infants. Clin Infect Dis 1995; 20:818–820. 4. O’Dempsey TJ, McArdle T, Ceesay SJ, et al. Immunization with a pneumococcal capsular polysaccharide vaccine during pregnancy. Vaccine 1996; 14:963–970. 5. Letson GW, Little JR, Ottman J, Miller GL. Meningococcal vaccine in pregnancy: an assessment of infant risk. Pediatr Infect Dis J 1998; 17:261–263. 6. Wiesen AR, Littell CT. Relationship between prepregnancy anthrax vaccination and pregnancy and birth outcomes among US Army women. JAMA 2002; 287:1556–1560. 7. Nishioka SA, Nunes-Araujo FR, Pires WP, et al. Yellow fever vaccination during pregnancy and spontaneous abortion: a case-control study. Trop Med Int Health 1998; 3:29–33. 8. Nasidi A, Monath TP, Vandenberg J, et al. Yellow fever vaccination and pregnancy: a four-year prospective study. Trans R Soc Trop Med Hyg 1993; 87:337–339. 9. Suzano CE, Amaral E, Sato HK, Papaiordanou PM. The effects of yellow fever immunization (17DD) inadvertently used in early pregnancy during a mass campaign in Brazil. Vaccine 2006; 24:1421–1426. 10. Robert E, Vial T, Schaefer C, et al. Exposure to yellow fever vaccine in early pregnancy. Vaccine 1999; 17:283–285. 11. Tsai TF, Paul R, Lynberg MC, Letson GW. Congenital yellow fever virus infection after immunization in pregnancy. J Infect Dis 1993; 168:1520–1523. 12. Zinaman MJ, Clegg ED, Brown CC, et al. Estimates of human fertility and pregnancy loss. Fertil Steril 1996; 65:503–509. 13. Bar-Oz B, Levichek Z, Moretti ME, et al. Pregnancy outcome following rubella vaccination: a prospective controlled study. Am J Med Genet A 2004; 130:52–54. 14. Available at: http://www.indepth-network.org/. (Accessed 2007 Nov 27)
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