Introduction

Varicella infection in pregnancy, especially during the first 20 weeks, may cause serious complications in pregnancy including spontaneous abortion, premature delivery, and stillbirth [1–3]. Various studies estimate the risk of primary maternal VZV infection to be 0.5–3 cases per 1,000 pregnancies [1, 4]. The most frequent maternal complication is VZV-associated pneumonia which occurs in 10%–20% of pregnant women infected with varicella, 40% of these patients may require mechanical ventilation [3, 5]. In offspring, varicella infection manifests as neonatal varicella (infection within the first 10 days of life) [6] or congenital varicella syndrome (CVS) [1, 7, 8]. CVS is a severe condition affecting about 2%, it affects multiple organs causing limb hypoplasia, skin lesions, neurological abnormalities, and eye damage, and has an estimated mortality of 30% [3, 7, 9]. The risk of severe neonatal varicella is from 20% to 50% if mother acquired infection five days antepartum to two days postpartum [10], and the estimated risk of CVS is at 0.8 per 100,000 live births [11]. CVS usually does not occur after herpes zoster (HZ) during pregnancy [3].

VZV-associated immunity in pregnancy can be detected through antenatal screening whereas the infection can be prevented by vaccinating susceptible women before conception. Antenatal varicella screening combined with post-partum vaccination may be a cost-effective strategy to prevent occurrence of VZV in the next pregnancy and reduce the risk of complications [12]. Information about VZV-associated immunity can be obtained by serological testing or through a self-reported history of varicella or herpes zoster disease. Currently, pregnant women in Norway are offered universal screening for hepatitis B, human immunodeficiency virus, and syphilis; varicella screening is recommended only if a woman with no verified varicella infection history has been exposed during pregnancy[13].

In Norway, non-immune pregnant women exposed to varicella during pregnancy are offered varicella zoster-immunoglobulin (VZIG) within 96 hours of exposure, mainly to protect the woman from a severe course of infection and complications [13]. In addition, infants born to seronegative women who developed varicella close to delivery, especially four days before and two days after the delivery, and preterm infants exposed to varicella, are also recommended to receive VZIG due to a high risk of severe disease [13]. VZIG in Norway can be obtained from three manufacturers: Varicellon P (CSL Behring, King of Prussia, Pennsylvania, USA), Varizig (Emergent Biosolutions, Rockville, Maryland, USA) and Varitec CP (Biotest Pharma GmbH, Dreieich, HE, Germany).

Susceptibility to VZV varies by geographic regions and women born in tropical and subtropical regions have lower rates of childhood exposure and immunity to varicella [14–17]. Such women may remain susceptible during reproductive age and thus may have a higher probability of being infected with varicella during pregnancy. This may lead to increased risk of disease and complications in this particular group.

Previously, no population-based study has been conducted in Norway to assess the prevalence of VZV-associated infections in pregnancy. A single study assessed the VZV-associated immunity among pregnant women of Pakistani origin in Norway, reporting that 7% were seronegative [16]. However, the study size (n = 206) and its design does not allow generalization of the findings to the entire Norwegian population. Of approximately 58,500 Norwegian babies born per year, about 26% had mothers with a foreign background, of which mostly were from Asia and Africa (2011–2018 data)[18]. Additionally, a recent national study reported that 25 pregnant women with varicella-associated diagnoses and ten patients with CVS were hospitalized during 2008–2014 and 46 varicella related deaths were reported (26 reported as underlying condition) during 1996–2012 [19]. Moreover, a recent seroepidemiological study of Norwegian population demonstrated that only 88.6% of Norwegian women of reproductive age (15–49 years), regardless of their pregnancy status, were immune against varicella, whereas 5.3% were seronegative [20]. In comparison, a higher seroprevalence of 96.2% to 98.5% among Finnish pregnant women was found [21, 22].

In Norway, no universal varicella or herpes zoster vaccination programme is currently implemented. Several live varicella vaccines with a good safety profile are available on the Norwegian market. These vaccines have an estimated effectiveness of 70%–90% for one dose and 98% for two doses [23]. Varicella vaccination can be initiated from 9 months of age, and is recommended in Norway for non-immune adolescents and adults, including women of reproductive age, and persons in defined risk groups [24]. Varicella vaccination is contraindicated during pregnancy, but vaccine can be administered after delivery to prevent infection during the subsequent pregnancies.

The objectives of our study were to 1) determine VZV seroprevalence and seroconversion rates in a national cohort of pregnant women, 2) to evaluate association between a self-reported history of VZV infection and VZV immunity status, and 3) to explore associations between serological status and mothers age, gestational age, year of child’s birth and women’s country of birth. This is in order to assess a need for antenatal varicella screening and inform policy decision on varicella immunization of women of reproductive age.

Methods

Study sample

The study sample included 1,350 mother-infant pairs, assuming 2% pregnant women being seronegative for VZV based on the literature [28]. The sample size was expected to provide results with confidence intervals’ total widths of about 1.5% [29]. The 1,350 women were randomly selected to form a control group in a separate case-control study nested within the MoBa cohort [30, 31]. This control group was included in the above mentioned study where their plasma samples were tested for cytomegalovirus, and parvovirus B19. Of these, 1,184 women had sufficient sample volume to allow examination of IgG antibodies for VZV, and thus were included in our study (Fig 1).

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Fig 1. Selection of the study samples and study results by sample: First sample taken in pregnancy week 17–19 (K1), and second sample taken at birth (K2), Norway, 2001–2009.

https://doi.org/10.1371/journal.pone.0221084.g001

Results

Discussion

Our study is the first to examine the immunity to VZV in a large national pregnancy cohort in Norway. Nearly all women (98.6%) in our study were immune to varicella prior to becoming pregnant but a small proportion (1.2%) was still susceptible during pregnancy, whereas four women (28% of susceptible) seroconverted during pregnancy similar to findings from other studies across Europe [32]. As the information about self-reported history of varicella and herpes zoster was limited, it was impossible to assess the reliability of prior exposure or disease in determining the woman’s immune status.

The strength of this study is coupling of data from serological testing with health information collected in a large national cohort study including over 1,000 Norwegian women. Most of the similar studies among pregnant women in Europe included between 500 and 1,000 participants [14, 21, 22, 33], except the Irish study with 7,980 pregnant women of which 11.3% were susceptible to varicella [34]. The proportion of susceptible women in this study varied depending on the nationality between 6.9% in Irish-born women and 21.7% in women born in sub-Saharan Africa [34].

For serological testing, we used a commercial test kit with a high sensitivity of 99.3%, and specificity of 100% to detect antibodies to VZV. Using this assay made our results more comparable to similar seroprevalence studies utilising the same kit.

We were not able to evaluate the association between the women’s immune status and a self-reported history of varicella or herpes zoster before pregnancy, since only one woman reported varicella before pregnancy. This is partly because the study questionnaire was not designed to capture specifically exposure to VZV.

Ninety two percent of women in our study were born in Norway and the remaining proportion was born in other western countries. Given that 14% of Norwegian population are of foreign descent, of which 47% are from Asian and African countries [35], it is likely that women born outside westernized settings with a different varicella epidemiology were not represented in our data[36]. Thus, we may have overestimated the proportion of seropositive subjects, because higher levels of susceptibility to VZV (7%–10%) in pregnancy are reported from tropical and subtropical countries [14, 15, 17, 34, 37]. In addition, a seroprevalence below 90% was demonstrated among women of reproductive age in other studies in several European countries, including Norway where a seroprevalence of 88.6% in this population was found [20, 38]. As information about the birth country was limited in our study, a further research examining immunity to varicella among women originating from countries outside Western Europe is warranted. Such information would help better define risk groups eligible for antenatal screening of varicella susceptibility.

We compared age at birth among study participants with general population in the same period. Overall, both groups were comparable, but a higher proportion (75%) of study participants was aged 25–34 years compared to women in general (66%). Proportions of our study reflect the age distribution of mothers in MoBa where younger women were underrepresented [36]. Therefore, it is possible that a higher seropositivity among women in our study is related to a higher proportion giving birth at older age compared to the general female population [20].

Although no CVS cases were reported in this study sample, we found ten CVS cases reported during a seven-year period (2008–2014) in a national registry-based study of varicella burden [19]. In view of these observations, we believe that there are more non-immune women of reproductive age in Norway and that the risk of neonatal and congenital varicella cannot be ruled out.

According to current Norwegian recommendations, varicella screening should be considered only for pregnant women with no history of varicella infection or varicella vaccination prior to their pregnancy [13]. Similar recommendations exist in other countries such as the UK and Australia [39, 40]. However, ideally women with unknown VZV immune status should be counselled before pregnancy planning. Most women with spontaneous pregnancies seek antenatal care either when they suspect being pregnant or after the pregnancy is confirmed, which makes such counselling difficult to implement in healthcare practice. However, women who undergo assisted reproduction are easier to access by healthcare professionals and therefore, it may be more feasible to offer counselling to this group, which comprises three to four per cent of the annual birth cohort in Norway [41]. Another group to be considered for counselling and selective screening include healthcare workers and women employed in childcare, which may be exposed to varicella at work. This may be a rather small group in the population, but healthcare providers should be aware of VZV history among such women when assessing the risk of infection and need for vaccination or passive immunization with VZV immunoglobulin [17, 42].

Varicella zoster immunoglobulin is indicated for non-immune pregnant woman and should be administered within 96 hours of exposure to varicella virus. However, not all women may know their exposure status and some women may develop only subclinical disease, which still can cause CVS [43]. Thus, serological testing may be a useful tool to identify women in need for passive immunization and other prophylactic measures. Prophylactic measures would contribute to minimise the risk of CVS in Norway where up to three cases annually have been reported during 2008–2014 [19].

The evidence from our study supports the current Norwegian recommendations on selective screening for varicella in pregnancy [13]. Serological testing is recommended if a woman was exposed to varicella during pregnancy and if the disease history is unclear. In addition, varicella counselling should be included as a part of antenatal care for all women of reproductive age and a need for serological testing and potential vaccination should be reviewed for women employed in settings with a high probability of exposure to varicella zoster virus.

Acknowledgments

The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study.