Immunization in Pregnancy

The concept of adult immunization in general and immunization during pregnancy has been receiving increased attention by medical and popular press writers. Pediatric immunization practices are well established and accepted, but continuing immunization practice in adults is irregular and has been largely ignored in pregnant women. Adult immunization practices may be changing, however, because of heightened public awareness of reducing medical costs by preventing disease, the availability of safe vaccines for use in pregnancy, and the gradual education of physicians concerning the safety of vaccination of adults, including pregnant women. The general public is aware of the significant reduction that has occurred in the incidence of measles, mumps, rubella, polio, diphtheria, and tetanus. Failure to maintain an immune status to diseases such as tetanus, diphtheria, hepatitis A, hepatitis B, pertussis, herpes zoster, varicella, influenza, and pneumococcal disease can result in serious consequences. Because effective vaccines exist for each of these diseases, they need to be considered seriously for adult immunization.

Immunization with non-live virus vaccines during pregnancy is considered safe. The risk from vaccination during pregnancy has not been defined, and no convincing evidence exists that non-live virus vaccines cause risks to the fetus or to the mother in excess of the risks of any adult to immunization. The benefit of vaccination among pregnant women is (1) to protect the mother from disease and (2) to protect the neonate from disease with passive maternal antibodies.

Immunobiologic agents include antigenic substances, such as vaccines and toxoids, and antibody-containing preparations, such as globulins and antitoxins from human or nonhuman donors. These products can be used for active or passive therapy. Active immunity occurs when an appropriate antigenic substance induces the formation of antibodies. Passive immunity is achieved through an injection of preformed antibody without a propensity to reproduce itself.

There are six types of immunobiologic agents commonly used in the United States¹:

1. Vaccines  Vaccines are suspensions of live (usually attenuated) or inactivated microorganisms (e.g., bacteria, viruses) or fractions of the microorganisms to induce an antibody response resulting in immunity, which prevents the infectious disease. Live virus vaccines usually are not indicated in pregnancy unless an epidemic is present.
   
2. Toxoids  Toxoids are modified bacterial toxins that are made nontoxic. This modified toxin is injected with an adjuvant to induce the formation of an antibody that functions as an antitoxin. Table 1 lists licensed vaccines and toxoids.
   
3. Immunoglobulins (IGs)  IG is a product derived from pooled human plasma. IG is obtained by cold ethanol fractionation of large, pooling plasma and has a 15–18% protein content. IG is intended for intramuscular injection. It is used to maintain immunity in some immunodeficient persons and to achieve passive immunity against diseases such as measles, hepatitis A, hepatitis B, and varicella. IG does not transmit hepatitis B virus, human immunodeficiency virus (HIV), or other infectious agents. Table 2 lists the IGs and antitoxins available in the United States. Pregnant women can receive IG at any time in pregnancy without risk to the fetus, such as Rh immune globulin.
   
4. Intravenous immunoglobulin (IVIG) (human)  IVIG is obtained from human plasma but prepared so that it can be administered intravenously. It is used as replacement therapy in primary immunodeficiency states and as therapy for Kawasaki disease, hypogammaglobulinemia, chronic lymphocytic leukemia, and in some cases of HIV infection. The most common use of IVIG in pregnancy is in the treatment of antiphospholipid syndrome. It had been thought that IVIG did not transmit disease, but several preparations have been recalled because hepatitis C virus was detected in some lots.² Changes in the processing of human plasma have corrected the problem.
   
5. Specific IGs  Specific IGs are special preparations obtained from human plasma from donors preselected for a high antibody titer against a specific antigen (see Table 2).
   
6. Antitoxins  Antitoxins are antibodies against bacterial toxins that have been obtained from animals immunized with these toxins. Antitoxins are used for treatment and convey passive immunity (see Table 2).
   

Table 1. Licensed vaccines and toxoids in the United States by type and use in pregnancy

BCG, bacillus Calmette-Guerin; ID, intradermal; IM, intramuscular; SC, subcutaneous.
^*Use in epidemics.
^† Use when indicated.
Adapted from Advisory Committee on Immunization Practices: General recommendations on immunization. MMWR 2011;60(RR-02):1–60.

Table 2. Immunoglobulins and antitoxins available in the United States

CLL, chronic lymphocytic leukemia; ITP, idiopathic thrombocytopenic purpura.
^*All preparations are given intramuscularly unless otherwise indicated.
^†HRIG administered around wound and intramuscularly.
Adapted from Advisory Committee on Immunization Practices: General recommendations on immunization. MMWR 2011;60(RR-02):1–60.

Recommendations for immunization practices balance scientific evidence of the benefits, costs, and risks of achieving optimal levels of protection against infectious diseases. The recommendations of the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention¹ describe this balance and attempt to minimize risk by providing information regarding dose, route, and spacing of immunobiologics. Information pertaining to contraindications to these immunobiologics has been published. The ACIP recommendations pertain only to the United States because vaccines and epidemiologic circumstances differ in other parts of the world. Information on the use of specific vaccines and other immunobiologics is found in their package inserts. Reading and understanding the package insert helps to ensure the appropriate storage and handling of immunobiologics, such as the reconstitution of vaccines and the recommended temperatures for storage. Some vaccines (e.g., tetanus diphtheria toxoid, hepatitis B, inactivated polio, Haemophilus influenzae type B conjugate, pneumococcal, influenza) are sensitive to freezing.

Routes of administration are recommended for each immunobiologic (see Table 1). The health care worker should not deviate from the recommended routes of injection. In general, vaccines containing adjuvants should be injected into muscles. Subcutaneous injections, using a 5/8 to 3/4-inch 23–25-gauge needle, are administered in the deltoid area in adults. The length of the needle for intramuscular injections varies with the weight of the patient. For people ≤60 kg, a 5/8-inch needle is recommended, but for a person 60–90 kg, a 1-inch needle is needed, and for persons ≥90 kg, a 1½–2-inch needle is required so that the vaccine can be placed intramuscularly. The injections should not be intradermal. The preferred site for intramuscular injections is the anterolateral aspect of the upper thigh or the deltoid muscle of the upper arm. The buttock should not be used as a site of intramuscular injections because of possible injury to the sciatic nerve. Injection of hepatitis B and rabies vaccines into the buttock has been associated with decreased immunogenicity. If the buttock is used for larger doses of IG, only the upper outer region should be used.

As a general rule, inactivated vaccine can be administered simultaneously at different sites. Some vaccines, such as hepatitis A, are associated with accentuated local or systemic symptoms. Tetanus, diphtheria, acellular pertussis, hepatitis B, influenza, and pneumococcal vaccines, which are commonly administered during pregnancy, can be administered successfully simultaneously at separate sites 1 inch apart.

Because the concept of adult immunization is being revisited with enthusiasm, the same enthusiasm should pertain to pregnant women. It is tragic for any pregnant woman to develop an infectious disease that is preventable via a vaccination. This philosophy represents a change from ignoring the pregnant woman and assuming she is protected to a policy of active inquiry as to immunization status and a program of active immunization. Because we know that toxoids and inactivated vaccines are safe to administer in pregnancy, the health care worker should adopt an active policy.

In an ideal world, each woman of childbearing age would be immune to measles, mumps, rubella, tetanus, diphtheria, pertussis, poliomyelitis, and, in the near future, varicella and hepatitis B. Starting at the first prenatal visit, attention should be paid to the immunization history of each pregnant woman with regard to the following vaccines or illnesses or both.

Measles and mumps

Persons born before 1957 are to be considered to have been naturally infected and therefore immune to measles and mumps. For persons born after 1957, the indications of immunity are (1) documentation of live virus vaccine administration after the first birthday, (2) positive antibody test to measles and mumps, and (3) physician-diagnosed disease.³

Rubella

A documented history of vaccination after the first birthday or serologic evidence of detectable antibody is considered evidence of immunity to rubella; a history of rubella disease is not.⁴ Women who are susceptible to rubella should be immunized with measles, mumps, rubella (MMR) vaccine in the postpartum period before discharge from the hospital.

Tetanus, diphtheria, pertussis

The baseline immunization schedule for tetanus, diphtheria and acellular pertussis vaccines is a three-dose regimen administered at 0, 1, and 6–12 months.⁵ Two of the doses should be DT and one dose Tdap. Most persons who live in the United States received the baseline vaccination as children. Acellular pertussis vaccine for adults was approved by the FDA in 2005 and is given with tetanus and diphtheria vaccines as one vaccine (Tdap). Since the vast majority of people are susceptible to pertussis, ACIP has recommended that all adults receive one dose of Tdap regardless of when they received their last DT vaccine.

The ACIP recently (June 22, 2011) recommended that all pregnant women receive Tdap during pregnancy after the 20th week of gestation. This route of immunization will allow pregnant women to develop pertussis antibodies which will cross the placenta to the infant and protect the infant for the first to 3–5 months of life until the infant can be actively immunized.⁶ 

The prior recommendation of “cocooning”⁷ that is administration of Tdap to postpartum women and all persons in the family constellation has been ineffective and a logistical and funding nightmare. Additionally, the “cocooning” plan has not been effective despite five years of trials.

Varicella

Varicella vaccine (Varivax) was approved by the FDA in early 1995. This is a live virus vaccine that may be combined with the MMR vaccine. The immune status of the pregnant woman must be determined by obtaining a serologic test (IG G) for varicella or by obtaining a positive history of varicella from the patient. Vaccination during pregnancy is not indicated, but postpartum immunization should be done.^{8, 9} Patients who have received varicella vaccine prior to pregnancy should receive a serological test (IgG) for varicella antibodies.

Hepatitis B

Worldwide, hepatitis B virus is a major cause of acute and chronic hepatitis, cirrhosis, and primary hepatocellular carcinoma. The frequency of infection and patterns of transmission vary widely in different parts of the world; in the United States, Western Europe, and Australia, only 0.2–0.9% are chronically infected. Hepatitis B is highly endemic to China, Southeast Asia, Pacific Rim countries, the Middle East, Africa, and the Amazon Basin. Prevention strategies for hepatitis B control are directed toward hepatitis B vaccination of infants to prevent perinatal and childhood transmission of infection.¹⁰ A comprehensive prevention strategy includes (1) prenatal testing of pregnant women for hepatitis B surface antigen (HBsAg) to identify newborns who require immunoprophylaxis with hepatitis B Ig and hepatitis B vaccine and to identify household contacts who should be vaccinated, (2) routine birth dose vaccination of children born to HbsAg-negative mothers, (3) vaccination of adolescents, and (4) vaccination of adults at increased risk of infection and vaccination of adults ever screened for an STD.¹¹

There are no apparent risk of adverse effects for developing fetuses when hepatitis B vaccine is administered to pregnant women.¹¹ The vaccine contains noninfectious HBsAg particles and causes no risk to the fetus. Hepatitis B infection affecting a pregnant woman can result in severe disease for the mother and chronic infection for the newborn. Neither pregnancy nor lactation is a contraindication to vaccination of women.

Hepatitis A

In February 1995, the Food and Drug Administration approved a hepatitis A vaccine. This inactivated vaccine is safe to use in pregnancy; this fact is important when counseling pregnant women. The initial history should include inquiries pertaining to previous hepatitis infection and jaundice. Prevention and control of hepatitis A infection can be accomplished through pre-exposure active immunization, or passive prophylaxis and postexposure passive immunoprophylaxis plus active immunization.¹²

Influenza

Influenza is an important cause of excess morbidity and mortality in the United States, and the influenza vaccine has been shown to be cost-effective in reducing morbidity and mortality.¹³ Influenza-associated excess mortality among pregnant women has not been documented except in the pandemics of 1918–1919, 1957–1958 and 2009–2010. Although fewer fatal cases have been documented, the literature supports the concept that pregnancy itself imposes a higher risk of death from influenza and severe morbidity, especially in the third trimester of pregnancy.^{14, 15, 16, 17} Physiologic alterations of pregnancy place pregnant women in the high-risk category for pulmonary diseases. Influenza vaccine should be administered to any person who wishes to reduce the chance of acquiring influenza infection. All women who will be pregnant during the influenza season (October to March) should receive the vaccine.¹⁸

Pneumococcal vaccine

Pneumococcal vaccine¹⁹ is composed of purified capsular polysaccharide antigens of 23 types of Streptococcus pneumoniae. It is safe to use in pregnancy and is indicated in pregnant patients with chronic illnesses, such as cardiovascular disease, pulmonary disease, diabetes mellitus, alcoholism, cirrhosis, or who are smokers. It also is indicated in immunocompromised adults with splenic dysfunction, anatomic asplenia, Hodgkin’s disease, lymphoma, multiple myeloma, chronic renal failure, nephrotic syndrome, or organ transplantation. Adults with HIV infection should receive the pneumococcal vaccine. Revaccination should be considered when an interval of 6 years has elapsed.

Polio

Women should be immune to poliomyelitis before pregnancy. Because the last case of poliomyelitis in the United States resulting from wild virus occurred in 1979 and the Western Hemisphere was declared polio-free in 1992, there is little enthusiasm for routine immunization in pregnancy. Administration of oral polio vaccine to children has been discontinued and is not available in the US. Enhanced inactivated polio vaccine is recommended when polio vaccine is indicated.²⁰ If polio vaccine becomes necessary because of travel to polio endemic areas, enhanced inactivated polio vaccine should be used during pregnancy.

The physician should assess each pregnant woman’s risk of exposure. If she had been immunized before becoming pregnant, her risk of infection is either low or absent. The pregnant woman should be advised not to travel outside the United States, Canada, or Europe during pregnancy. The risks of hepatitis A, yellow fever, typhoid fever, hepatitis E, and cholera are present in or endemic to much of the rest of the world. Appropriate hygienic precautions reduce the risk of cholera, hepatitis A, and typhoid for travelers to underdeveloped countries.

Misconceptions exist concerning the contraindications to adult immunization. Some of these are included in the following list. (This is not a list of contraindications to vaccination.)

1. Reaction to previous vaccination consisting of one or more of the following: mild-to-moderate local tenderness, redness, or swelling or fever less than 40.5°C
   
2. Mild acute upper respiratory or gastrointestinal illness with fever less than 38°C
   
3. Current antimicrobial therapy or convalescence from a recent illness
   
4. Pregnancy in another member of the same household
   
5. Recent exposure to an infectious disease
   
6. Breastfeeding
   
7. Personal history of allergies, including an allergy to penicillin (see Contraindications to Immunization)
   
8. Family history of allergies, adverse reactions to vaccination, or seizures.

There are contraindications to vaccination, most related to hypersensitivity to one or more of the vaccine’s components. No currently approved vaccine contains penicillin, so penicillin allergy is not a contraindication to immunization. The following is a list of vaccines and their putative allergic components:

1. Yellow fever, influenza vaccine  Vaccination is contraindicated for persons with a history of anaphylactic reactions to eggs or egg protein.
   
2. MMR  Vaccination is contraindicated for persons with a history of anaphylactic reaction to neomycin.
   
3. Typhoid  Severe systemic reactions can occur after administration of this vaccine, but they probably are toxic reactions rather than hypersensitivity reactions. Revaccination should be avoided if possible.
   
4. Live vaccines  In general, immunizations with live vaccines should be avoided in patients who are immunocompromised as a result of disease or medical treatment.
   

Immunobiologics should be actively used during pregnancy in the same manner as if the woman were not pregnant with the exception of live virus vaccines. The current indications for vaccine and IG use in pregnancy are listed in Tables 3 and 4.

Table 3. Immunoglobulin use in pregnancy

Modified from General Recommendations on Immunization: MMWR 2011;60(RR-02):1–60.
HBIG, hepatitis B immunoglobulin; HB_SAg, hepatitis B surface antigen; HBV, hepatitis B virus; IG, immunoglobulin; IM, intramuscularly.

Table 4. Immunization during pregnancy

Modified from General Recommendations on Immunization: MMWR 2006;55(RR-15).
eIPV, enhanced inactivated polio vaccine; HBIG, hepatitis B immunoglobulin; HB_SAg, hepatitis B surface antigen; HDC, human diploid cell; IM, intramuscularly; OPV, oral polio vaccine; SC, subcutaneously.

Pregnant women who are at high risk for hepatitis B infection are candidates for hepatitis B vaccine in pregnancy include, but are not limited to, those with the following risk indications:^{10, 11}

1. Percutaneous drug abuse
   
2. Acute episode of any sexually transmitted disease
   
3. Multiple sexual partners
   
4. Work in any health care field or public safety field
5. Occupation of police, firefighter, or correction officer
6. Household contact with hepatitis B carrier
   
7. Work or treatment in a hemodialysis unit
   
8. Receipt of clotting factor concentrates for bleeding disorders
9. Ever screened for STD
10. Sexually active not in a long-term mutually monogamous relationship
11. Persons developmentally disabled in long-term care facilities
12. Persons with chronic liver disease
13. Persons with HIV infections
14. Persons with HCV infections
15. International travelers to endemic areas
16. Persons treated for a sexually transmitted disease
17. Persons receiving tattoos
18. Persons receiving acupuncture.
    

The following groups are among those who have been shown to be at risk of hepatitis A infection:¹²

1. Travelers to developing countries are at substantial risk for acquiring hepatitis A. The risk to travelers who do not receive either hepatitis A vaccine or IG is 3:1000 to 5:1000 per month of stay.
   
2. Percutaneous drug abusers
   
3. Veterinary workers
   
4. Sewage workers
   
5. Day care center workers
   
6. Workers or residents in institutions for developmentally disabled
   
7. Health care workers.
   

ACIP recommendations should be followed for the administration of IG and for the use of specific IGs and vaccines. Health care workers must be more active in ensuring that pregnant women are provided with appropriate immunobiologics to prevent the occurrence of vaccine-preventable diseases. New vaccines for hepatitis A, pertussis, and varicella have been approved by the Food and Drug Administration, which should allow a further decrease in these serious diseases.

Tetanus immunization is one of the most neglected vaccines and should be considered important because maternal antibodies cross the placenta and prevent neonatal tetanus. Hepatitis B protection is crucial for the pregnant woman and newborn who are at high risk of infection. Morbidity and mortality can be reduced for pregnant women who receive the influenza vaccine during the influenza season (October to March).

Preconceptional immunization is preferred to prenatal immunization, but this is difficult to accomplish. Because there is no risk to the fetus presented by non-live virus vaccines, the pregnant woman must not be ignored in her need for prevention against vaccine-preventable infectious diseases. For administration in all bodily regions, the needle must be long enough to reach the muscle. In adults, the deltoid muscle is the recommended site for routine intramuscular vaccination, using a 20–25-gauge needle 1–1¼ inches in length.

Experimental evidence and clinical experience strengthen the scientific basis for administering certain vaccines simultaneously.^{12, 22, 23, 24} Many of the commonly used vaccines can be administered safely on the same day when the vaccines are administered at different sites. Simultaneous administration may be important in several clinical situations, as in imminent exposure to several infectious diseases, preparation for foreign travel, and uncertainty as to whether the patient will return for subsequent doses.