This chapter should be cited as follows:
Hunzicker AM, Fortner KB, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.419443

The Continuous Textbook of Women’s Medicine Series – Obstetrics Module

Volume 17

Maternal immunization

Volume Editors: Professor Asma Khalil, The Royal College of Obstetricians and Gynaecologists, London, UK; Fetal Medicine Unit, Department of Obstetrics and Gynaecology, St George’s University Hospitals NHS Foundation Trust, London, UK
Professor Flor M Munoz, Baylor College of Medicine, TX, USA
Professor Ajoke Sobanjo-ter Meulen, University of Washington, Seattle, WA, USA

Chapter

Vaccination in Pregnancy in Specific Circumstances

First published: May 2023

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INTRODUCTION

For at least a decade, only two vaccines were recommended during pregnancy. Seasonal influenza vaccine is recommended for everyone who will be pregnant during influenza season regardless of trimester. In order to provide prevention of pertussis in the newborn, women are recommended to receive Tdap vaccine in the late second or third trimester of each pregnancy. Worldwide, the threat of tetanus remains and vaccination during pregnancy is recommended in the absence of immunity. Following the COVID-19 pandemic, COVID vaccination or booster against COVID are recommended regardless of pregnancy status. Finally, certain conditional provisions exist, such as receipt of hepatitis A or B vaccination, protection against meningococcus, and pneumococcus where indicated. This chapter will serve to review indications for each vaccine, safety, and effectiveness.

INFLUENZA

Influenza seasons following the COVID-19 pandemic are not likely to be viewed by the public or healthcare providers the same when compared to seasons prior to the pandemic. During the pandemic, with masking and social distancing, influenza illness rates in both hemispheres were lessened. As masking and circulating COVID illness declines, subsequent influenza seasons will likely increase, as evidenced by Australia having one of their worst influenza seasons during 2022 compared to the prior 5 years.¹

During the H1N1 pandemic, and prior influenza pandemics, pregnant women have worse outcomes when compared to their nonpregnant counterparts. Influenza vaccination is the most effective prevention strategy.² For this reason, the American College of Obstetricians and Gynecologists (ACOG) has recommended that pregnant women receive inactivated seasonal influenza vaccine regardless of trimester of pregnancy.^1,3

Influenza vaccine safety

Examining influenza safety can be considered from multiple perspectives. Because influenza vaccination has been utilized for so long in the US and other developed countries, far greater data exists. One of the first safety profiles is for the mother. Influenza vaccination is key to reduction of illness and additional safety questions pertain to the pregnancy and fetus. At least two systematic reviews and meta-analyzes are published on maternal influenza vaccination and risks. One such systematic review examined for risk of congenital malformations. In over 15 studies comparing events per vaccinated with those who are unvaccinated no association was found between congenital defects and receipt of the influenza vaccine. The same finding holds true regardless of trimester of receipt.⁴ Further, when examining by vaccines with and without adjuvant, no differences were seen and when assessing for major birth defects, no differences were seen. The second meta-analysis examined receipt of influenza vaccine and birth outcomes including miscarriage and stillbirth. A total of seven studies were examined in the systematic review and included in the meta-analysis were appropriate. Not only did receiving a influenza vaccine not have increased risk of adverse pregnancy outcomes, but instead a protective effect was noted with lower likelihood of stillbirth (relative risk [RR], 0.73; 95% CI, 0.55–0.96). Pooled estimates for association of spontaneous pregnancy loss with receipt of influenza vaccine did not demonstrate any correlation with confidence interval crossing one (RR, 0.91; 95% CI, 0.68–1.22)^5. A recent publication, 2021, used a birth registry with linked data to examine receipt of influenza vaccination during pregnancy with overall early childhood health outcomes and over 28,000 children were evaluated. Child health outcomes were followed for an average of 3.6 years and no significant associations were seen between receipt of maternal influenza vaccine and asthma, sensory impairment, neoplasm, or with urgent and inpatient health service utilization. (See events per vaccinated versus unvaccinated: 859/32,000 774 [2.6%] versus 7644/245,314 [3.1%].)⁶

Finally, influenza vaccine can be given simultaneously with COVID boosters based on V-safe reporting data during the 2021 influenza season with only a mild increase in reported systemic reactogenicity (8% vs. 11%).⁷

Influenza vaccine effectiveness

With vaccination, it is effective at reducing rates of influenza illness and hospitalizations among pregnant and nonpregnant persons. In a 2015 meta-analysis, over 23 studies examined the effectiveness of influenza vaccination in healthy adults and pregnant women (totaling around 1.6 million mother–infant pairs). It is worthy to note, very few studies exist utilizing randomized control trials (RCTs) evaluating vaccine efficacy expressly among the pregnant population. Cohort studies identified a protective effect against influenza-like illness among pregnant women receiving the seasonal influenza vaccine, particularly during the H1 N1 pandemic (effectiveness 89%, 95% CI, 79%–94%).⁸ A single RCT comparing receipt of seasonal influenza vaccine with pneumonia vaccine examined maternal and neonatal outcomes. Among the mothers, receipt of influenza vaccine resulted in significantly lower likelihood to have respiratory illness with fever when compared to the control group with a clinical effectiveness of around 30%.⁹ Further, the PREVENT study evaluated public health/healthcare records against vaccination records from 2010 to 2016 and found that receipt of influenza vaccine offered moderate protection against lab-confirmed hospitalizations with influenza.¹⁰

Influenza vaccine of the mother offers protection to the newborn accomplished via passive antibody transfer at a time when the newborn cannot receive vaccine (e.g., does not generate protective response following vaccine). Inclusive of the H1N1 pandemic seasonal influenza vaccine and preceding seasons, infants of influenza vaccinated mothers were approximately 50% less likely to have influenza-related hospitalization when compared to newborns of unvaccinated mothers. These data support not only vertical antibody transmission from mother to fetus but effective prevention of newborn illness and hospitalization during critical months when the newborn cannot otherwise be protected.¹¹ Dr Zaman’s RCT among women in Bangladesh (randomized to receive influenza vaccine or pneumococcal vaccine) during pregnancy was associated with over 60% reduction in influenza illness among infants up to 6 months of age. Infants born to mothers receiving influenza vaccine also had less frequent febrile respiratory illnesses. Additional researchers have been able to demonstrate that receipt of influenza vaccine was associated with reduced risk for influenza illness and hospitalization among their infants for any influenza-like illness up to 6 months of age with persistently increased influenza antibody titers in the infant's through 2 to 3 months of age.¹²

Finally, receipt of seasonal influenza vaccine appears to have additional benefits among pregnant women with respect to rates of miscarriage, stillborn, preterm birth, and birthweight. As discussed above, the meta-analysis assessing safety also noted a composite protective effect among women receiving vaccine had lower rates of miscarriage and stillborn.⁵ Several other studies demonstrated lower rates of preterm birth and small for gestational age (SGA) infants.⁹ Dr Steinhoff found that the proportion of SGA infants was lower during influenza season among women who received the influenza vaccine compared to those who did not.¹³ Using PRAMS (Pregnancy Risk Assessment Monitoring System) data, mothers receiving vaccine were less likely to be premature when compared to nonvaccinated peers during the same time points (aOR = 0.60; 96.5% CI, 0.38–0.94). When examining these same data, the protective effect of influenza vaccine receipt and reduction in preterm birth was even more pronounced during times with higher circulating seasonal influenza (aOR = 0.28; 95% CI, 0.11–0.74).¹⁴

Summary

The influenza vaccine appears to have extensive benefits. Despite consistent vaccine recommendations, influenza vaccine uptake has been historically low. Providers should continue to recommend receipt of the vaccine when pregnant during influenza season. Best strategies to combat lower rates of vaccine uptake center around education, recommendation, maximizing convenience, and normalizing vaccines on obstetric and other well woman visits.² Providers should lean on vaccine hesitancy experiences from COVID and prior influenza seasons and work to dispel myths.

PERTUSSIS

Vaccination against Bordetella pertussis during pregnancy and the ability to leverage passive antibody transfer to the newborn has been recommended for almost a decade, worldwide.¹⁵ Women are recommended to receive a dose of Tdap during each pregnancy during the third trimester, or earlier in the US, Australia, and United Kingdom.^16,17,18 Recommendation for prenatal Tdap vaccination followed a relatively rapid rise in pertussis outbreaks worldwide, occurring around 2010 in the US, 2012–2015 in 5 of 19 high- and middle-income countries as documented by the WHO.¹⁹ The resurgence of pertussis varies by country and location. Initial attribution was to naturally occurring cyclic patterns, but further study revealed a true epidemic, likely related to waning immunity, decreased vaccine coverage, better diagnoses and subtle changes in the pertussis organism.²⁰ Implementation of vaccine during the latter half of pregnancy was initiated due to the disproportionate rate of illness, in particular severe illness, noted among infants less than 6 months of age, as well as the inability to induce protection using newborn vaccination.^21,22

Prevention of whooping cough, the clinical illness caused by Bordetella pertussis, has been accomplished via vaccines since as early as the 1940s. Initially, the vaccine used for prevention was DTP used whole-cell, inactivated pertussis along with diphtheria and tetanus toxoids. While the whole-cell vaccine prevented illness in 70 to 90% of children, it was extremely reactogenic, and is no longer available in the United States.²³ Other countries worldwide still use the DTP vaccine. In the early 1990s, vaccines using acellular pertussis were created given lower rates of local and systemic reactogenicity. The acellular pertussis vaccine (DTaP or Tdap) given depends on the patient’s age and intended dose of antigen. The initial vaccine series for prevention of pertussis for prevention of illness in children aged 6 weeks through 6 years is accomplished with DTaP. DTaP contains initial priming doses of diphtheria and tetanus toxoids (thus the “D” and “T”), as well as priming doses of antigens against the pertussis bacteria (“P”). In contrast, Tdap vaccines contain smaller doses of diphtheria toxoid and acellular pertussis (thus the “d” and “p”) but the same dose of tetanus toxoid. Tdap vaccines are given as booster doses to individuals aged 10 years through 64 years, or as the initial vaccine for children >7 years and unvaccinated adults. Specific pertussis antigens in the vaccine vary by vaccine product, of which two are currently licensed for use in the United States (Boostrix and Adacel).^24,25

Pertussis (Tdap) vaccine safety

Two large systematic reviews have been published regarding safety of Tdap vaccine in pregnancy. The first, a 2017 systematic review examining safety outcomes among prenatal Tdap vaccine populations in the United States, Europe, South America, Asia Pacific, and the Middle East and a second 2020 systematic review of 22 studies comprising data from 1.4 million pregnant women and 855,546 mother–infant pairs. These two reviews found that exposure to the Tdap vaccine does not appear to increase the risk for adverse birth outcomes, such as preterm birth, SGA, stillbirth, low birthweight, and congenital anomalies.^26,27 With respect to serious adverse events occurring in pregnant women following Tdap vaccine, the same systematic review reveals no increased risks for hypertensive disorders and preterm labor.^19,28 A single retrospective cohort study revealed increased risk for chorioamnionitis among vaccinated women in the study cohort (adjusted RR, 1.19, CI 1.13–1.26) but the finding was not replicated into additional observational studies.^29,30,31 Upon receipt of Tdap vaccine, though less commonly reported adverse events are local reaction, followed by systemic reactions, like headache, myalgia, malaise, and fever with rates reported around 3%.^32,33

TDAP VACCINE EFFECTIVENESS

A retrospective cohort study examining those born in northern California from 2010–2015 demonstrated maternal Tdap vaccination was highly protective against infant pertussis illness with reported vaccine effectiveness at 91.4% (C 95% CI, 19.5–99.1) seen for the first 2 months of life and 69.0% (C 95% CI, 43.6–82.9) for the first year of life after birth.³⁴

The NACI evaluated the burden of pertussis illness in Canada and vaccine effectiveness and upon review of 59 articles found that receipt of maternal Tdap vaccination resulted in an over 90% effectiveness in reducing pertussis illness in infants less than 2 months of age, with no neonatal deaths found in mothers receiving the vaccine prior to 36 weeks of gestation.

Summary

In the US, Tdap should be given between 27 and 36 weeks of gestation regardless of date of prior Tdap vaccine received. Interestingly, even on the national scene,

pertussis vaccine appears to be accepted at higher rates during pregnancy when compared to influenza. This finding has been documented at least in the United States, the UK, and Spain, further emphasizing the importance of vaccine education and communication in public health campaigns, but also the enthusiasm generated by the mother's role to offer indirect protection to their newborn.³⁵

COVID-19

The COVID-19 pandemic brought an unprecedented opportunity for vaccine innovation, global deployment, and emphasized the impact on exclusion of pregnant women in vaccine trials. Given the significant world-wide morbidity and mortality from COVID-19 infection, combined with substantial risk of complications and vulnerability among pregnant persons, infection prevention was paramount. Unfortunately, in the early wave of COVID-19 vaccine development and distribution, no clinical trial expressly evaluated receipt among pregnant women.³⁶

The COVID-19 pandemic prompted efficient and unprecedented arrival of vaccine to market providing distribution to worldwide mass immunization programs. Much of the speed and arrival of the initial vaccines can be attributed to emerging vaccine platforms created for use in different pandemic threats. The viral vector technology utilized by AstraZeneca's COVID vaccine built upon prior work developed, and currently approved for, disease prevention of Ebola in nonpregnant adults. Preliminary human studies demonstrated promising safety profiles but had not been expressly tested in pregnant and lactating women. With respect to an mRNA vaccine platform, prior preliminary human studies had shown favorable safety and immunogenicity data when used for illness prevention of influenza, Zika virus, and rabies; however, as above, pregnancy data were reassuring but limited.^36,37,38

At the time of this publication, according to the World Health Organization, there are 172 vaccines in clinical development, nearly 200 and preclinical development worldwide. Of these vaccines, nearly 30% utilize a protein subunit platform, just over 20% utilize an mRNA platform, followed by roughly 10% with a viral vector or inactivated virus.³⁹ In the United States, 19 vaccines are available for administration, two utilizing mRNA (produced by Pfizer Biotech⁴⁰ and Moderna)⁴¹, and adjuvanted recombinant protein vaccine (produced by Novavax)⁴² and a viral vector vaccine (produced by Jansen/Johnson & Johnson).⁴³

COVID vaccine safety

Of the above-mentioned vaccine platforms, none can cause COVID-19 illness given the absence of the virus or antigen itself.⁴⁴ Instead, these vaccines use either genetic instructions for producing antigens or a modified antigen to stimulate antibody production from the immune response. Although serious side effects have been reported, they remain exceedingly rare among pregnant and nonpregnant individuals. Reported risks of vaccinations include the following: thrombosis with thrombocytopenia syndrome, myocarditis and pericarditis, and Guillain–Barré syndrome. In evaluation of frequency of these events, for every 1 million doses of vaccine given, 13 cases of TTS are identified in females aged 18–49 while 127 ICU admissions have been prevented and 657 hospitalizations have been prevented.⁴⁵

Cases of myocarditis or pericarditis both occurring at a frequency of around 1–2 per 100,000 have been reported in the United States following receipt of messenger RNA COVID-19 vaccination.⁴⁶ Onset is usually within a few days following vaccination and is more frequent after the second dose than the first. Incidence of Guillain–Barré syndrome appears to be higher among individuals receiving the Johnson & Johnson/Jansen vaccine. Continued reassuring results with respect to risk of miscarriage and developmental reproductive toxicity are limited. Specifically, no region registries report increased risk for miscarriage among vaccinated versus unvaccinated individuals. Data from the European medicines agency reported the mRNA vaccines in animal trials do not appear to have any indirect or direct adverse effect on pregnancy, embryo or fetal development, parturition, or postnatal development.⁴⁷

With respect to obstetric outcomes and safety of COVID-19 vaccines in pregnancy, the Pfizer-BioNtech mRNA vaccine (BNT162b2) and Moderna mRNA vaccines have had no obvious safety concerns identified from 23,779 participants in the Vsafe pregnancy registry as of May 2, 2022.⁴⁸ Further, no evidence of adverse outcomes were identified in nearly 400 women who received the Pfizer vaccine. With respect to local and systemic reaction to the vaccine, at least nine studies have examined side effects experienced by pregnant women when compared to nonpregnant, and they do not appear to experience any difference in their reaction to the mRNA COVID-19 vaccines.⁴⁹ Care should be taken to explain side effects during counseling and reassurance given that any low-grade fever or malaise can be treated with antipyretics and is a normal reaction of the immune system in response to vaccination. In the Pfizer trial, fever greater than 38°C occurs in roughly 4% after the first dose and roughly 18% after the second dose. For Moderna, lower rates of fever after the first dose have been noted at less than 1% while roughly 16% have low-grade fever after the second dose. In the Johnson & Johnson/Jansen trials, likely 9% of individuals had a fever greater than 38.0°C following vaccination. Roughly five studies have examined pregnancy loss/adverse neonatal outcomes following COVID-vaccine in pregnancy. No significant differences have been found among either vaccinated women compared to baseline frequencies or vaccinated women compared to unvaccinated cohorts.^50,51

COVID vaccine effectiveness

Covid vaccination appears to be effective. In summarizing the effectiveness of the two mRNA vaccines for approval in the US (Pfizer-BioNTech and Moderna), effectiveness in preventing COVID-19 illness was stratified by prior infection.^52,53 Among individuals without prior COVID-19 infection, the Pfizer mRNA vaccine was 94.6% effective in preventing COVID-19 infection (95% CI, 89.9–97.3).⁵⁴ And the Moderna mRNA vaccine was 93.2% effective in preventing COVID-19 infection (95% CI, 91.0–94.8).⁵⁵ Both of these studies did not specifically examine pregnant or lactating participants although both are reported within their data set. Thus far, one study has examined COVID-19 vaccine effectiveness when administered during pregnancy. In evaluating patients (N = 140) who received the vaccine during pregnancy, vaccinated participants were less likely to develop COVID-19 infection prior to delivery (2/140 [1.4%] compared to 210/1861 [11.3%]; p < 0.001).⁵⁶

With respect to passive protection of the newborn via placental antibody transfer, studies exist evaluating cord blood antibody titers among vaccinated women.⁵⁷ Of the seven studies to date, all demonstrated either (a) placental transfer ratio^58,59 or (b) IgG titers in cord blood^60,61,62 among those who received the second vaccine dose before delivery. Other studies explored the time interval between vaccination and delivery, and a general trend was the finding of a positive linear relationship between timing of first and/or second dose and delivery and the IgG titers in cord blood.⁶¹ Further, vaccinated mother–infant pairs had a more robust binding and neutralizing antibody response when compared to infected, non-vaccinated pairs.⁵⁷ Some studies have evaluated antibody titers present in breastmilk, among vaccinated and unvaccinated individuals and no clear consensus in antibody trends were identified thus far.^61,63,64 In summary, the immunogenicity data regarding COVID vaccine receipt indicate significant humoral responses in maternal blood with efficient transfer to cord blood as well as impact of functional immunity responses. Several studies note higher transfer of antibody to the neonate with increasing time from prenatal vaccination to the delivery of the infant.

COVID vaccine summary

In summary, the National Advisory Committee on Immunizations (NACI), Society of Obstetricians and Gynecologists of Canada (SOGC), Centers for Disease Control and Prevention (CDC), American College of Obstetricians and Gynecologists (ACOG), and the Society for Maternal-Fetal Medicine (SMFM) all recommend vaccination against COVID-19 to prevent and mitigate illness in pregnant and lactating individuals.^65,66,67,68 Safety and efficacy data in the nonpregnant population were reassuring as well as receipt of the vaccine among those who were pregnant and had sufficient significant risk for COVID-19 infection. Through early patient tracking systems, data quickly accumulated regarding post-emergency use authorization and demonstrated an acceptable safety profile for use in pregnancy. Subsequent publications continue to provide reassurance regarding safety and efficacy of mRNA COVID-19 vaccination. At this point in time, for ages 12 and above, an initial vaccine series is recommended followed by booster with a 5 valent vaccine at least 2 months following the last vaccine dose. Post-EUA licensure studies examining COVID-19 vaccination during pregnancy have not identified increased incidence and adverse outcomes. Systemic and local reactions appear to be similar in pregnant individuals when compared to nonpregnant with a less than 1% risk of medically attended, which is similar between pregnant and nonpregnant. Although prevalent in social media and nonmedical literature concerns regarding effect on fertility, first-trimester pregnancy loss, fetal development, pregnancy outcomes, and postnatal infant development have not been demonstrated.^69,70

VACCINATION IN PREGNANCY IN SPECIFIC CIRCUMSTANCES AND THOSE CONTRAINDICATED IN PREGNANCY

Sometimes persons who are pregnant have conditions that increase the risk for vaccine preventable diseases. Some of those conditions may either be immune suppression, occupational exposure, travel plans, or even areas of exposure. Patients in these circumstances should be offered immunization against vaccine preventable diseases providing there is a vaccination that is not contraindicated during pregnancy. Live vaccine should be avoided when possible and otherwise relatively few actual contraindications exist. The following vaccines may be warranted under specific clinical circumstances.

Pneumococcal

Individuals at increased risk for invasive pneumococcal disease should be considered to receive pneumococcal vaccination.⁷¹ Ideally the vaccine can be given pre-pregnancy but is not contraindicated for use during pregnancy. Individuals at an increased risk include the following: those with pre-existing conditions such as diabetes, chronic lung or liver diseases, chronic alcoholism, sickle cell, and asplenia (functional or acquired via splenectomy.⁷² Acquired conditions can also include development of malignancy, such as multiple myeloma, Hodgkins, HIV, or solid organ transplants. Pneumococcal disease can be prevented effectively with vaccination.

Haemophilus influenzae B or HiB

Individuals who are not immune or do not have documented immunity against HiB should receive vaccination during pregnancy.⁷³ Specifically, when indicated, administered HiB vaccination during the third trimester has been shown to be both safe and immunogenic. Some of the challenges in accomplishing HIB vaccination are related to the available formulations and combinations of HiB vaccination.⁷⁴

Meningococcal disease

Pregnant persons with increased risk for invasive meningococcal disease should receive vaccination. Persons who are at increased risk for meningococcal disease are based on medical conditions or exposures and can include the following: those with complement deficiencies, asplenia, HIV, occupations exposing repeatedly to meningococcus, travel to endemic areas, residence halls or close group living quarters. See ACIP Recommendations for further specifics.⁷⁵ Several of the available registered vaccine products utilize protein conjugates and do not contain live or attenuated bacteria posing exceedingly limited risk.⁷⁶ Several smaller reports have not found concerning safety signals.

Hepatitis B

Screening for immunity to hepatitis B virus (HBV) is a part of routine prenatal care in the United States. Among those who are not immune and become infected during pregnancy, there is risk of mother-to-child transmission. Vaccination against hepatitis B is most often accomplished as part of childhood immunization programs. However, for individuals who are unvaccinated and pregnant, there are several indications to proceed with administration of the hepatitis B vaccine during pregnancy.⁷⁶ HBV vaccines are recombinant inactivated vaccines and thus do not pose more than theoretical risks whereas HBV infection poses true risk to mother and fetus. For persons initiating the vaccine series prior to conception, their immunization with the 3 series (at 0, 1, and 4 months), the vaccine should continue to be given during pregnancy. For those who are found to be non-immune or undervaccinated, and are not actively infected, and have risk factors (sexually transmitted infections, ongoing injection drug use) for acquiring infection during pregnancy, the vaccine series should be initiated.⁷⁷ Review of HBV vaccine in pregnancy revealed no increased adverse obstetric events and is approximately 90% effective by the third vaccine dose.

Hepatitis A

As with hepatitis B, hepatitis A infection is usually prevented via childhood immunization series. All three formulations of hepatitis A vaccine include inactivated or recombinant formulations and thus generally accepted as safe in pregnancy⁷⁸ For individuals who are not immune and have risk factors such as planned international travel, injection drug use, ongoing occupational exposures, or have other liver diseases, vaccination should be considered. Hepatitis A is a cause of hepatitis, and has been known to cross the placenta in rare case reports.^79,80

Several vaccines can be considered for use in pregnancy when travel to an endemic area cannot be avoided. These vaccines include the following: yellow fever, typhoid fever, Japanese encephalitis, and polio. Yellow fever vaccine is a live, attenuated vaccine and is one of the only live, attenuated vaccines not contraindicated for use in pregnancy.⁸¹ Risks of exposure and infection should be weighed against risk of vaccine. Typhoid fever appears to pose serious risks when acquired in pregnancy, and if exposure cannot be avoided, vaccination should be considered. Both a capsular polysaccharide and live-attenuated vaccines are available, but the capsular polysaccharide is the preferred vaccine in pregnancy.⁸² Japanese encephalitis has been known to pose critical risks to pregnant patients and vaccination appears safe but there are no published data. There are two types of polio vaccines, live-attenuated oral polio vaccine (OPV) and inactivated polio vaccine (IPV). The injectable IPV form is preferred for use in pregnancy.⁸³

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