review vaccines in pregnancy: a review of their … · rev. hosp. clÍn. fac. med. s. paulo...

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REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(5):263-274, 2003

From the Children’s Institute, Hospital dasClínicas, Faculty of Medicine, University ofSão Paulo - São Paulo/SP, Brazil.

Received for publication onApril 08, 2003.

REVIEW

VACCINES IN PREGNANCY: A REVIEW OF THEIRIMPORTANCE IN BRAZIL

Lucia Ferro Bricks

BRICKS LF - Vaccines in pregnancy: a review of their importance in Brazil. Rev. Hosp. Clín. Fac. Med. S. Paulo 58 (5):263-274, 2003.

Neonates and young children remain susceptible to many serious infectious diseases preventable through vaccination.In general, current vaccines strategies to prevent infectious diseases are unable to induce protective levels of antibodies inthe first 6 months of life. Women vaccinated during pregnancy are capable of producing immunoglobulin antibodies thatare transported actively to the fetus, and maternal immunization can benefit both the mother and the child. With fewexceptions, maternal immunization is not a routine, because of the concerns related to the safety of this intervention. Ethicaland cultural issues make the studies on maternal immunization difficult; however, in the last decade, the development ofnew vaccines, which are very immunogenic and safe has reactivated the discussions on maternal immunization.

In this paper we present a review of the literature about maternal immunization based on MEDLINE data (1990 to2002).

The most important conclusions are: 1) there is no evidence of risk to the fetus by immunizing pregnant women withtoxoids, polysaccharide, polysaccharide conjugated and inactive viral vaccines; 2) most viral attenuated vaccines areprobably safe too, but data is still insufficient to demonstrate their safety; therefore these vaccines should be avoided inpregnant women; 3) in Brazil, there is a need for a maternal immunization program against tetanus.

Many new candidate vaccines for maternal immunization are available, but studies should be conducted to evaluatetheir safety and efficacy, as well as regional priorities based on epidemiological data.

DESCRIPTORS: Vaccines. Pregnancy. Maternal immunization. Infectious diseases. Neonatal.

Immunization is considered one ofthe most important measures to controlinfectious diseases and the recommen-dations for routine immunization arebased on the analysis of risks, benefitsand cost of immunobiologicals1,2 . De-spite the huge impact of immunizationprograms on the reduction of morbid-ity and mortality associated with vac-cine preventable diseases, newbornsand breast-feeding babies remain vul-nerable to several diseases caused byviruses and bacteria1-24.

The immune system of breast-feed-ing babies is not mature enough to re-spond to some types of immunobio-

logicals and, even when vaccines areadministered in the first few months oflife, a latency period is required to ob-tain antibody titers in sufficientamounts to confer protection on thechild. Another concern is the possibil-ity that the antibodies acquired pas-sively from the mother could affect theresponse to vaccines containing liveattenuated viruses3-10.

Pregnancy offers an excellent op-portunity to increment mothers’ andbabies’ immunity. Pregnant women arecapable of producing suitable amountsof antibodies and the transfer of suchantibodies to the fetus through the pla-centa occurs during the last 4 to 6weeks of pregnancy9. Most IgG classantibodies are capable of crossing theplacenta barrier. The concentration ofsubclass IgG1 antibodies can be higherin the cord blood than in maternalblood, thus suggesting that there is anactive transfer of antibodies in the pla-centa9. The antibodies acquired pas-sively by the child can confer protec-

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REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(5):263-274, 2003Vaccines in pregnancy: a review of their importance in BrazilBricks LF

tion on the newborn against a varietyof serious diseases3-10.

Until the 1960’s, knowledge aboutthe possible deleterious effects of theproducts administered to pregnantwomen on fetuses was very limited,and many vaccines were administeredto pregnant women. In the UnitedStates, from 1957 to 1966 vaccinesagainst influenza and poliomyelitiswere routinely administered in mater-nal immunization programs. Resultsfrom a major seven-year study nation-wide (Collaborative Perinatal Project)involving more than 50,000 pregnantwomen and their children, where oc-currences such as malformations, learn-ing disorders, hearing deficiency andrisk of neoplasias were investigated,demonstrated that the vaccines againstpoliomyelitis (oral and inactivated),influenza, diphtheria, tetanus andsmallpox did not have adverse conse-quences for mother or fetus7,9.

After verifying the deleterious ef-fects of thalidomide on babies frompregnant women who had taken thatdrug, a deep concern was aroused overthe safety of pharmaceutical drug use(including vaccines and immuno-globulins) during pregnancy. Despiteno evidence of risk of malformationbeing associated with vaccines, thereis great fear that immunobiologicalscan cause some type of harmful effecton the fetus. Therefore, whenever pos-sible, vaccines recommended for preg-nant women should be administered inthe latter stages of pregnancy, whenthe fetus has already formed. This stepseeks to prevent that any malforma-tions and abortions that may occur, ir-respective of vaccination, be ascribedto the vaccines3-10.

The difficulties in conducting stu-dies in pregnant women limit theevaluation of the results due to thesmall number of cases. However, manywomen of childbearing potential werevaccinated before knowing they werepregnant, and the follow-up of these

women and their children has pro-duced important information on vac-cine safety both for mother and baby.In addition, in the past decade the de-velopment of increasingly safer andmore immunogenic vaccines againstseveral infectious agents that cause se-rious diseases in breast-feeding babieshas reawakened discussions about therisks and benefits of vaccinating preg-nant women, particularly where thereis a high risk that the pregnant womanand/or fetus develop infection with se-rious consequences3-10.

In this study we present reviseddata from the literature about the in-dications and contraindications of theuse of vaccine and immunoglobulinsby pregnant women, through the sur-veying of publications on the subjectissued over the past 10 years.

Considerations of the advantagesand disadvantages of maternalimmunization

Newborns belong to a group whichis highly vulnerable to several viral andbacterial infections1,11-18. Since, for themost part, vaccines are recommendedfor breast-feeding infants on three-doseschemes, at 2, 4 and 6 months, beforethe sixth month of life children are un-protected, or only partially protectedagainst vaccine preventable diseases1,3-10.The vaccination of pregnant womencould overcome this difficulty, confer-ring passive protection on the baby andaffording a valuable opportunity toprovide mother and child with immu-nity. The best example of the efficacyof this measure is the disappearance ofneonatal tetanus in developed countries,where routine vaccination of pregnantwomen against tetanus has been a com-mon practice for several decades3-10.

In industrialized countries, group BStreptococcus and gram-negative en-terobacteria are the main bacterialagents for serious neonatal infec-tions14,20,21.

Except for the neonatal period,during the first 6 months of life theStreptococcus pneumoniae is the mainbacterial agent for pneumonias andbacteremias in most countries1,14. Al-though the S. pneumoniae rarelycauses sepsis in the neonatal period,171 cases of neonatal sepsis by thatbacterium were identified in the USA;in cases of early development sepsis(< 48 hours) the prognostic and deathrate were higher than in cases of latedevelopment sepsis20.

Whereas infections byHaemophilus influenzae type b havevirtually disappeared in developedcountries, in developing countries thatbacterium is still responsible for alarge number of pneumonia, meningi-tis, bacteremia and sepsis cases in chil-dren under 5, particularly in nonbreast-feeding infants1,14.

The prevalence of infectionscaused by Neisseria meningitidisvaries largely, being higher in popu-lations living in poor conditions; nev-ertheless, even in developed countriesthese infections present high rates ofmorbidity and mortality in breast-feed-ing babies14,22,23.

Among viral infections are to beincluded those caused by the respira-tory syncytial virus and rotavirus, re-spectively the most important agentsfor respiratory disease and gastroen-teritis in breast-feeding babies. The vi-ruses of influenza, parainfluenza, her-pes simplex, cytomegalovirus and en-terovirus are also an important causeof morbidity among breast-feeding ba-bies15-19.

The objective of maternal immu-nization is to afford newborns andbreast-feeding babies sufficient quan-tities of specific antibodies against thepathogens that cause serious infec-tions during this highly vulnerable pe-riod2-10.

During pregnancy, women are capa-ble of producing sufficient quantitiesof antibodies. Although class IgM, IgA,

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REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(5):263-274, 2003 Vaccines in pregnancy: a review of their importance in BrazilBricks LF

IgD and IgE antibodies do not cross theplacenta, class IgG antibodies can beactively transferred to the fetus throughthe placenta. The half-life of maternalantibodies is 3 to 4 weeks and the per-sistence of these antibodies depends onthe initial titers. Typically, after 6months of age, maternal antibodieshave already disappeared or are presentin low titers; however, during the sec-ond semester of life, children who havebeen suitably immunized alreadypresent their own antibodies againstvaccine antigens. Women vaccinatedduring pregnancy can also transfer spe-cific antibodies against several patho-genic agents through the colostrum andmaternal milk and, in this case, there isalso a transfer of IgA class antibodiesin addition to that of IgG9.

The main difficulties in imple-menting vaccination programs forpregnant women as a public health in-tervention relate to the theoretical con-siderations over the potential risks ofvaccines for pregnant women and fe-tus, the relatively limited knowledgein that field and the technical, ethicalas well as legal difficulties in conduct-ing studies on the risks and benefits ofvaccination for pregnant women2-10.

The potential risks of maternal im-munization are, generally speaking,the same as those for the population,and are directly related to the specificproduct. However, during this periodthere is a concern that the occurrenceof adverse events could have implica-tions on the course of the pregnancyor induce premature labor. The expe-rience with the vaccines habituallyrecommended for maternal immuniza-tion offers no backup for this concern;still, it is recommended that vaccina-tion during the first trimester of preg-nancy be avoided1-10.

The main disadvantages of mater-nal immunization include absence ofthe benefits of this measure when thereis premature birth, the potential riskthat the mother’s antibodies would af-

fect the immunological response of thenewborn, whether by inducing immu-nological tolerance or by inactivatingcertain vaccines containing live at-tenuated viruses. In the first situation,one should consider that the produc-tion of maternal antibodies after vac-cination is not immediate and that thetransfer of maternal antibodies to thefetus only occurs in the last 4 to 6weeks of pregnancy8,9.

Situation of vaccine preventablediseases in Brazil

Over the past 20 years there hasbeen a sharp reduction in the numberof cases of some vaccine preventablediseases in Brazil, mainly due to in-creased vaccine coverage and to theintroduction of mass vaccination cam-paigns. While some diseases weregradually disappearing, others wererecognized as being important for pub-lic health (Table 1).

The best example of the impactthat vaccination had on disease reduc-tion is poliomyelitis, which was elimi-nated from this country after the intro-duction of mass vaccination cam-paigns in the 1980’s. The last case ofparalytic polio in Brazil was registered

in 1989. An inverse example is tuber-culosis, which persists as a major pub-lic health issue despite the excellentvaccine coverage. The tuberculosisvaccine is quite effective in the pre-vention of serious forms of the disease,e.g. tuberculous meningitis; however,to control this disease other measuresare necessary besides vaccination.

Despite the substantial reductionin cases of diphtheria, tetanus andwhooping cough in the year 2001, 19cases of diphtheria (3 deaths), 1,464cases of whooping cough (13 deaths),366 cases of accidental tetanus (86deaths) and 34 cases of neonatal teta-nus (27 deaths) were registered. Thedeath rates for these diseases are con-siderably high, reaching 79% in casesof neonatal tetanus23.

In 1997 there was a measles epi-demic in Brazil, with 53,664 cases and61 deaths.

After a national vaccination cam-paign against measles and reinforcedactions for epidemic surveillance, cir-culation of the measles virus in Brazilwas finally interrupted, with only 1case being diagnosed in 2001 and an-other in 2002, both imported from Ja-pan. With regard to rubella, up untilthe mid-nineties information on its in-

Table 1 - Number of notified cases of some vaccine preventable diseases in Brazil,in 1982 and 2000, according to the Ministry of Health.

Compulsory notification diseases 1982 2000

Hepatitis B ? 6,396Tuberculosis 87,822 93,360Diphtheria 3,297 58Accidental Tetanus 2,226 525Neonatal Tetanus 584 41Whooping Cough 54,766 2,464Haemophilus influenzae type b meningitis ? 577Measles 39,370 36Rubella ? 14,767Congenital Rubella Syndrome ? 79Yellow Fever 24 85Meningococcal Disease 1,226 4,592Human Rabies 127 26Hepatitis A ? 20,310

Source: Ministry of Health/FUNASA/CENEPI

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cidence in this country was virtuallynil; in 1997, when notification becamecompulsory, 32,825 cases of rubellaand only 17 cases of congenital ru-bella syndrome (CRS) were confirmed.Considering the difficulty in confirm-ing CRS diagnosis, one can argue thatthis information surely underestimatesits importance. In 1999 and 2000 anepidemic of rubella broke out, with ahigh percentage of the cases being di-agnosed in women in fertile age andso a national vaccination campaignwas launched against rubella for thisgroup. The number of CRS cases in1999, 2000 and 2001 was 39, 79 and39 respectively. Probably, these num-bers underestimate the real importanceof rubella in Brazil because of themany difficulties involved in makinga diagnosis of CRS. There is no na-tional record for the number of mumpsand chickenpox cases and we shouldnote that case notification for manydiseases do not reflect their actual in-cidence, due to the large number ofoligosymptomatic or asymptomaticcases and to the difficulties in estab-lishing etiological diagnosis22,23.

Information on meningitis causedby Haemophilus influenzae was scarceuntil the early 1990’s; the largestnumber of Hib meningitis cases in Bra-zil (1,684) was registered in 1995. Thevaccine against Hib was introducedinto the national immunization calen-dar in the latter part of 1999, inicially

only for children less then 24 month;during that year the number of Hibmeningitis cases was 1,368, droppingto 577 in 2001 and to 234 in 2001.

In the year 2000, respiratory dis-eases were the second cause of hospi-talization in Brazil (16.2%). Althoughthe main causes of hospitalization forrespiratory disease are ascribed topneumonia, caused by S. pneumoniae,H. influenzae, influenza virus and Res-piratory Syncytial Virus, we do nothave information available on the in-cidence of these infections.

Vaccines routinely recommendedfor pregnant women

Vaccines recommended for preg-nant women should be littlereactogenic, safe for mother and fetusand capable of inducing a good re-sponse of class IgG1 antibodies. Ide-ally, vaccine components should bespecific, highly purified and a singledose should be sufficient to obtainhigh antibody titers. In order to obtaina suitable transfer of antibodies to thefetus, the minimum interval betweenvaccine administration and childbirthshould be two weeks1-10.

Although several vaccines havebeen investigated for use in pregnantwomen, currently few vaccines areroutinely recommended, as shown intable 21.

Vaccines against diphtheria andtetanus1,2

The best example of the effective-ness of vaccinating pregnant women isthe reduced number of cases of neo-natal tetanus in the past decade. In1989, the World Health Organizationset out to eliminate neonatal tetanusbetween 1995 and 2000. With an in-crease in vaccine coverage a substan-tial reduction in cases of neonatal teta-nus was actually observed. However,over 400,000 cases of neonatal tetanusare estimated to occur worldwide,most occuring in developing coun-tries, where vaccine coverage is poorand neonatal tetanus accounts for 23to 73% of deaths during the neonatalperiod27.

Tetanus and diphtheria toxoids areundoubtedly safe, immunogenic andcapable of stimulating the productionof significant amounts of antibodies inpregnant women, inducing protectionfor both mother and baby1-10,25-27.

In Brazil, 296 cases of neonataltetanus were notified in 1990 and thenumber of cases dropped to 41 and 34in 2000 and 2001, respectively23. Mostcases of neonatal tetanus result fromfailure to vaccinate, as 2 doses ofantitetanus vaccine administered nolater than 6 weeks before childbirthprotect both mother and fetus, even ifthe pregnant woman has not receiveda previous dose of the vaccine 1,22,23,27.

Table 2 - Vaccination of pregnant women.

Routinely Recommended Vaccines to be indicated only in Vaccines under investigation Contra-indicated vaccinesVaccines special situations

Adult combined (dT) Against poliomyelitis (oral or inactivated) Pneumo conjugate Measles

Tetanus and diphtheria toxoids Pneumococcal polysaccharide (Pn23-valent) Meningo conjugate MumpsInfluenza Menigococcal polysaccharide Acellular pertussis Rubella

Yellow fever Group B streptococcus ChickenpoxHepatitis A Respiratory syncytial virus BCGHepatitis B Parainfluenza-3Rabies Herpes simplexJapanese encephalitis Attenuated vaccine against

influenza

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Pregnant women who are not vac-cinated, or are only partially vacci-nated against tetanus (< three doses)should receive at least 2 doses of theantitetanus vaccine (T) or the adultcombined vaccine (dT) at a minimumone-month interval in between, prefer-ably after the first trimester of preg-nancy and at least fifteen days prior tochildbirth. Pregnant women who havebeen vaccinated with 3 or more dosesof antitetanus vaccine and have re-ceived a booster dose within the past5 years do not need to be vaccinated.For those who have not received abooster dose, or received the last dosemore than 5 years ago, administrationof 1 dose of antitetanus vaccine (T) oradult combined (dT) is recommendedat least 2 weeks prior to childbirth1,22,23.

Vaccine against influenza

Pregnant women and children lessthan 1 year of age face a high risk ofcomplications associated with the in-fluenza virus. In pregnant women inthe third trimester of pregnancy therisk of complications is higher than inyoung adults who present risk condi-tions 28-35.

Vaccines against influenza containdead viruses or subunits, thus beingnon-infectious. Vaccines containingsubunits only are highly purified andlittle reactogenic, still they are not rec-ommended for children under 6months due to their low immuno-genicity. For the first vaccination chil-dren between 6 and 36 months oldshould receive 2 doses of the vaccine1.Thus, in the first year of life, evenwhen vaccinated, children are highlyvulnerable to infections by the influ-enza virus33.

Since the late 1970’s, it has beendemonstrated that babies with hightiters of antibodies against the influ-enza virus in the cord blood have pre-sented low rates of infection during

epidemic outbreaks; therefore, vacci-nation of pregnant women could ben-efit both mother and child 29,30. A studyconducted in Houston between 1975and 1977 has shown a positive corre-lation between titers of neutralizingantibodies in the cord blood and pro-tection against the strain of influenzaA/Victoria virus, since none of the chil-dren who presented antibody titersabove 1:8 in the cord blood againstthis strain was infected by the influ-enza virus in the first 8 weeks of life29.

Administration of inactivatedvaccines against influenza to pregnantwomen is safe and, in comparison tothe population, pregnant women pro-duce similar antibody titers; passiveprotection conferred on the children ofvaccinated pregnant women persistsfor at least 2 months (half-life from 35to 50 days)29-31.

In the United States, the vaccineagainst influenza is recommended forpregnant women expected to be in thesecond or third trimester of pregnancywhen circulation of the influenza vi-rus is at its peak, and for those whopresent a risk condition, irrespective ofthe stage of pregnancy 33. This recom-mendation is based on information re-lating to vaccine safety during all stagesof pregnancy and on the absence of ad-verse events for the child28-35.

The advantages of vaccinatingpregnant women against influenza in-clude mother’s protection at a timewhen the risk of complications is at itshighest, reduction in the potential ofa mother who, upon contracting theinfection, transfers it to her child in thefirst months of life, and the transfer ofantibodies to the fetus, conferring pas-sive protection in the first weeks of life.Although it is difficult to estimate theduration of passive protection, thehalf-life of antibodies acquired pas-sively is estimated to be of 21 days, yetit is possible that this protection couldbe extended for much longer25-29.

Vaccines recommended forpregnant women in specialsituations only

Vaccines against poliomyelitisOral or injectable vaccines against

poliomyelitis are highly immunogenicand effective for poliomyelitis preven-tion. In the fifties, they were largelyused by American pregnant womendue to the high risk of infection by thewild virus. There was no confirmationof serious adverse events in pregnantwomen or their babies36,37. More re-cently, due to poliomyelitis outbreaksin Finland, more than 3,000 pregnantwomen were given the oral vaccineagainst polio, again demonstrating thesafety of such vaccine 12. In 1988 anepidemic of poliomyelitis caused bypoliovirus type 1 broke out in Israel;in October 1988 all individuals lessthan 40 years old (including pregnantwomen) received the oral vaccineagainst poliomyelitis. No adverse ef-fects were reported in vaccinated preg-nant women or in their offspring, andan analysis of 88 newborns weighingmore than 2,500 g revealed a transferof antibodies against poliovirus type1 and 2; the titers against the poliovi-rus type 3 were low 37.

So far there is no evidence that thevaccines (oral or injectable) againstpoliomyelitis cause unwanted effectsfor the pregnant woman or the fe-tus1,9,12.

In Brazil, since 1980, mass vacci-nation campaigns against polio-myelites have led to elimination of thedisease in the country. No case of po-lio has been reported in the past dec-ade. Since the risk of poliomyelitis iscurrently very low, maternal immuni-zation is not recommended 22,23.

Only in special circumstancesshould pregnant women receive oralvaccine against poliomyelitis. For ex-ample, non-immune pregnant womenwho are expected to go to areas where

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the wild virus still causes endemic dis-ease (some African regions and theSoutheast of Asia) should be vacci-nated against polio1,22,23.

Vaccines against hepatitis BBreast-feeding babies infected by

the hepatitis B virus are at a high riskof becoming chronic carriers of theHBs antigen (HBsAg). The vaccineagainst hepatitis B is highly purified,safe and effective, inducing a high rateof protection among children andadults (> 90%). Although it is not rou-tinely recommended for maternal im-munization, neither pregnant women,inadvertently vaccinated, nor their ba-bies presented adverse effects after ad-ministration of the vaccine and/or spe-cific immunoglobulin (HBIG) 1,38-40.

A study of 37 pregnant womenvaccinated against hepatitis B duringpregnancy showed that all newbornsfrom mothers who had developed an-tibody titers against the HBs antigenabove 1:35 mUI/ml exhibited titers,considered as being protective, in thecord blood (above 1:10 mUI/ml) 39. Inanother study, 49% (39 out of 80)pregnant women vaccinated againsthepatitis B presented seroconversion;this percentage is low; however, mostof them had received 1 or 2 doses ofthe vaccine. Obese pregnant women,smokers or over 25s presented lowerantibody titers than younger, non-obese and non-smoking women40.

The doses and scheme recom-mended for the prophylaxis of preg-nant women after exposure to the hepa-titis B virus are the same as those rec-ommended for the population1,38-40.

In Brazil, up until 1998 the vaccineagainst hepatitis B was only availablefor high-risk groups and few women infertile age were vaccinated22,23. There-fore, we consider it essential to conductspecific serology for hepatitis B dur-ing the prenatal period, since, if themother is an HBsAg carrier, the new-born will have to receive immuno-

prophylaxis within the first 12 hoursof life (vaccine + specific immu-noglobulin). If the pregnant woman isHBsAg negative, she will have to bevaccinated during pregnancy only ifshe belongs to a risk group for hepati-tis B1.

Since the risk of contracting thedisease is high among adolescents andmany pregnant adolescents will gothrough new pregnancies, it is recom-mended that pregnant adolescents whoare seronegative for hepatitis B bevaccinated after childbirth. The vac-cine against hepatitis B is available forthe entire population less than 20years old22,23.

Vaccine against hepatitis AThe vaccines against hepatitis A

contain dead viruses and are not infec-tious; they are highly purified, effec-tive and induce long-lasting protec-tion. It is believed that they are notharmful to pregnant women or the fe-tus; however, since only recently havethey been licensed and are not muchused routinely, there is little informa-tion regarding their safety for pregnantwomen. The risk of vertical transmis-sion of hepatitis A is low, therefore thevaccine is not recommended for preg-nant women.

In cases where post-exposureprophylaxis is needed, normal humanimmunoglobulin is recommendedwithin 15 days of exposure, and thesame schemes and doses as recom-mended for the population apply. If thepregnant non-immune woman intendsto travel to highly endemic regions forlonger than 5 months, the vaccine maybe administered concurrently with theimmunoglobulin, in separate parts1,9,41.

Vaccines against yellow feverYellow fever is a rare disease in in-

dustrialized countries 42; however, inBrazil the wild form is still endemic inseveral parts of the country 22. As deathrates are very high and no specific

treatment is available for this disease,the vaccine against yellow fever hasbeen included in the national vaccina-tion calendar, from 9 months of age,with booster doses every 10 years. Thisrecommendation is valid for nearly theentire national territory (except for afew states in the South and South-east)22,23.

The vaccines against yellow fevercontain live attenuated viruses and sothey are not routinely recommendedfor pregnant women, except when theyreside in risk areas1,42-44.

Many pregnant women unaware oftheir condition were inadvertentlyvaccinated against yellow fever,whether in endemic regions or duringvaccination campaigns. Luckily, to-date, no serious adverse effects havebeen confirmed in the pregnant womenand/or fetuses1,43,44.

Although the vaccine is consideredsafe for both pregnant woman and fe-tus, whenever possible it is recom-mended that pregnant women plan-ning a journey to risk areas shouldpostpone their trip. If this is not possi-ble, the vaccine should be adminis-tered at least two weeks before thepregnant woman travels to riskareas1,22,42-44.

Polysaccharide vaccine againstpneumococcus

The 23-valent vaccine is recom-mended only for individuals who facerisk (patients with chronic diseases,with anatomic or functional asplenia,old-aged and immunodepressed peo-ple) and are over 2 years old. Since thisvaccine is highly purified, safe andimmunogenic among adults, it can beadministered to pregnant women inrisk groups. Since a lot of women onlyhave access to health services duringthe prenatal and delivery period, insuch instances it should be checkedwhether the use of pneumococcal poly-saccharide vaccine is indicated1,45-51.

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Some authors evaluated the re-sponse of pregnant women to polysac-charide vaccines against the pneumo-coccus and the results from all studiesindicated that these vaccines are safeand capable of inducing immunologicresponse. In addition to protectingpregnant women, they are likely toprotect the baby passively throughtransplacental crossing of antibodiesand transfer of antibodies through thecolostrum and maternal milk45-51.

Polysaccharide vaccines againstmeningococci

Polysaccharide vaccines against A,C, Y and W135 groups meningococciare recommended only in risk situa-tions. They are highly purified andimmunogenic vaccines, and they of-fered no risk for vaccinated pregnantwomen nor did they affect response tovaccination in babies whose mothershad been vaccinated during preg-nancy. Although the crossing of anti-bodies from mother to fetus is variable,in addition to conferring protection onthe pregnant woman, the vaccines canafford increased immunity on the new-born1.52-54.

New perspectives: vaccines underinvestigation

During the neonatal period, thegroup B streptococcus and enterobac-teria account for most bacterial infec-tions and, in the first few months oflife, babies are very vulnerable to in-vasive infections by encapsulated bac-teria such as Haemophilus influenzaetype b, Streptococcus pneumoniae andN. meningitidis1-10. The quest for safeand effective vaccines for these agentshas been very successful, particularlywith the development of conjugatevaccines against the Hib, pneumococ-cus and meningococcus, already li-censed in several countries55.

Despite the success, young breast-

feeding babies remain at a high risk ofcontracting these infections, sincemultiple doses of conjugate vaccinesare required. Vaccination of pregnantwomen against these agents is consid-ered a valid alternative to offer protec-tion to babies in the first few weeks oflife56. Although little has been studiedabout vaccination of pregnant womenwith new conjugate vaccines againstHib, pneumococcus and menin-gococcus, results from studies pub-lished in the past decade are verypromising2-10.

Conjugate vaccines against Hib

Hib invasive diseases usually affectyoung babies and, since the eighties,the role of polysaccharide vaccinesagainst Hib in pregnant women hasbeen studied, with the purpose of reduc-ing the impact of the disease on breast-feeding infants. Pregnant women re-spond well to polysaccharide vaccinesand studies have shown that they aresafe both for pregnant woman and fe-tus, besides demonstrating that there isa passive transfer of antibodies throughthe placenta and the maternal milk56-62.Conjugate vaccines against Hib are ca-pable of inducing production of classigG1 antibodies in titers higher thanthose obtained from non-conjugatevaccines. In some studies, antibodytiters against the Hib found in the cordblood were higher than maternal titers,suggesting active transfer of such anti-bodies. We should note that the anti-bodies transferred through the placentado not affect immunological responseto the vaccine administered after sixweeks of life58-62.

After conjugate vaccines againstthe Hib were incorporated into na-tional immunization programs and in-vasive diseases by this bacterium werevirtually eliminated, their indicationfor pregnant women became very lim-ited. Still, studies involving thesevaccines are considered excellent

models for the study of other vaccinesin pregnant women9,56-62.

Conjugate vaccines against S.pneumoniae

S. pneumoniae is the main agentfor pneumonia in almost every agegroup; it is among the 3 main agentscausing bacterial meningitis, besidescausing several types of infection, e.g.acute otitis media, sinusitis, bacteremiaand sepsis, among others1,5,14.

Today more than 90 S. pneumoniaeserotypes are recognized, however, be-cause cross immunity among differentserotypes is low, the prevention of dis-eases caused by the pneumococcus re-quires polyvalent vaccines 1.

Children under two years of ageconstitute a high-risk group for seriousinfections caused by the S.pneumoniae; however, the 23-valentpolysaccharide vaccine is only recom-mended for high-risk groups over twoyears old due to its low immuno-genicity in breast-feeding infants1.

A new conjugate vaccine contain-ing seven pneumococcus serotypeshas been licensed recently. It is recom-mended for breast-feeding infants oversix weeks old49. Despite being ex-tremely safe, immunogenic and veryeffective against serious forms of thedisease, the 7-valent conjugate vac-cine is expensive and its scope of pro-tection is limited to the serotypes con-tained in the vaccine. Since it is nec-essary to administer 3 doses of thevaccine, at 2, 4 and 6 months, up un-til the sixth month of life, children lessthan six months are only partially pro-tected. A large percentage of the casesof invasive disease caused by pneumo-coccus occur in breast-feeding infantsless than 6 months old, so it is essen-tial to look for new alternatives of pre-vention for diseases caused by thisbacterium. Polysaccharide vaccinesagainst the pneumococcus adminis-tered to pregnant women in the third

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trimester of pregnancy are safe formother and fetus and, theoretically,they could confer some degree of pro-tection on newborns45-47.

In comparison to polysaccharidevaccines, conjugate vaccines are moreimmunogenic and capable of reducingthe number of S. pneumoniae carriers.It is possible that the vaccination ofpregnant women with these newvaccines should afford higher antibodytiters in babies, conferring extendedprotection; however, their scope of pro-tection is limited. As yet we do notknow whether the new pneumococcalconjugate vaccines administered topregnant women and to breast-feedinginfants will have an impact on collec-tive immunity. We should remember thatthe number of S. pneumoniae serotypescapable of causing invasive diseasesand disease of mucous membranes ismuch higher than that of H. influenzae,which is almost exclusively restrictedto the Hib9,10.

Vaccines against group Bstreptococci

The group B streptococcus (GBS) isamong the most important pathogen inthe neonatal period and in children lessthan three months old 1,63-65. It is esti-mated that the incidence of serious dis-eases caused by the GBS is 3 out of1,000 living newborns. In the USAalone, every year 11,000 cases of sep-sis or meningitis by the GBS are re-ported. GBS accounts for 2,500 deathsevery year and although 1,350 childrensurvive, they are left with serious aftereffects 65. Besides attacking young ba-bies, the GBS causes enormous morbid-ity in pregnant women, and is one of themain agents of urinary infections,chorioamnionitis, endometritis and in-fections from surgical wounds in the pu-erperium. Despite recommendations forthe use of prophylactic antibiotics inrisk groups, the disease still has a highincidence and is very serious63-65.

Studies conducted in the 1970´sestablished a relationship between an-tibody deficiency against the GBS’spolysaccharide capsule in pregnantwomen and the susceptibility of bothmother and fetus to infections. In the1980´s, polysaccharide vaccinesagainst the group B streptococcus weretested in pregnant women, with prom-ising results. Although the vaccinescontaining polysaccharides from theGBS capsule were safe, the immuno-logical response against the differenttypes of GBS varied 63-65.

Immuno-protective response - de-fined as reaching antibody titers above1 mcg/ml, 4 weeks after vaccination -was achieved in approximately 40%of those vaccinated against type Ia,88% against type II and 60% againsttype III, indicating the need for moreimmunogenic vaccines63-65.

Later on, with the technology ofconjugate vaccines, vaccines contain-ing the GBS polysaccharide capsule´s,conjugated with tetanus toxoid againstseveral GBS serotypes (Ia Ib, II, III)were developed. These new vaccinesare highly immunogenic and safe, bothin animals and in adult volunteers, andthey should be useful for pregnantwomen; however, the development ofconjugate vaccines against the GBS ishindered by the number of pathogenicserotypes. It is thus necessary to de-velop multivalent vaccines againstseveral serotypes (Ia Ib, II, III and V).

Conjugate vaccines againstserotypes III and V are currently under-going clinical tests, and their safetyand immunogenicity have alreadybeen demonstrated in adults, includingwomen of childbearing potential. Con-jugate vaccines for use in animal mod-els are currently undergoing tests inorder to evaluate fetus protection66.

Acellular vaccines againstwhooping cough

In developed countries, where

vaccines against the whooping coughhave been largely used for over 40years, the disease persists as an impor-tant cause of morbidity, especiallyamong young babies. In the UnitedStates, Canada and several countries inEurope there has been an increase inthe number of whooping cough cases,with a deviation of the age group withthe highest incidence of the disease.Today 25% to 35% of the cases are di-agnosed in adolescents and adults.These individuals are the main reser-voirs of the B. pertussis and severalcases were documented where themother, grandparents or health careprofessionals were to account for thetransmission of the disease to babies.Most complications, hospitalizationsand deaths from whooping cough oc-cur in the first six months of life, atime when the child is still unprotectedagainst the disease, despite vaccina-tion1,67,68. In Brazil, all 27 whoopingcough deaths registered in the year2000 occurred in children less thanone year old23.

Since the forties, the role of anti-bodies against B. pertussis for diseaseprotection has been known and, in thefifties, pregnant women vaccinatedagainst whooping cough were notedto transfer their antibodies to the fe-tus68. Nonetheless, whole cell vaccinesagainst whooping cough are not rec-ommended after 7 years of age due totheir reactogenicity 1. Recent develop-ment of acellular vaccines against thewhooping cough - already licensed forchildren and adults - has prompted dis-cussion over their indication for ado-lescents, adults and perhaps pregnantwomen, in order to boost protectionagainst this serious disease1,67,68.

Other vaccines

Several vaccines against otheragents that cause serious infections inyoung children are being developed.Vaccines containing live attenuated

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viruses against influenza, rotavirus,respiratory syncytial virus, herpes sim-plex and parainfluenza are now under-going advanced testing stages inadults and children. If they prove safefor these age groups, they may then betested in pregnant women to protectnewborns indirectly2-10,69,70.

Vaccines contraindicated duringpregnancy

Vaccines against tuberculosis, mea-sles, mumps, rubella and chickenpoxare contraindicated for pregnantwomen, it being advisable that womenin fertile age should avoid pregnancyduring the month following vaccina-tion71-79.

It is possible that these vaccines aresafe during pregnancy; the results fromstudies conducted in the United Statesand Canada involving more than 400pregnant women inadvertently vacci-nated against rubella are reassuring be-cause of the absence of cases of con-genital rubella syndrome; however,these numbers are not sufficient to en-sure that the vaccine will not causeany harm to the fetus74.

From March 17, 1995 to March 16,

2000, 362 pregnant women were ex-posed to the vaccine against chicken-pox in the United States; 92 were se-ronegative and 58 received the vaccinein the first trimester of pregnancy.None of the 56 newborns presentedany type of malformation. Due to thesmall number of cases studied, it wasnot possible to ensure that the vaccineis exempt of risks for pregnant womanand fetus79.

Where non-immune pregnantwomen are exposed to measles orchickenpox, passive immuno-prophy-laxis is recommended1,80.

CONCLUSIONS

In addition to increasing motherprotection, the vaccination of pregnantwomen is an excellent opportunity toconfer protection on babies by trans-ferring antibodies passively, whetherthrough the placenta or throughbreast-feeding. All current evidencesare indicative that the vaccines whichdo not contain live agents and theimmunoglobulins being currentlyrecommended for adults are safe andimmunogenic for pregnant women and

that, even vaccines containing live at-tenuated viruses, e.g. yellow fever, oralpolio and rubella, do not pose risks forthe fetus. However, before one can rec-ommend large-scale use, new studiesinvolving a sufficient number ofmother-baby pairs are necessary so asto assure the absence of risks for preg-nant women and babies. We shouldmention that, during pregnancy, thevaccination scheme against diphtheriaand tetanus should be updated; it isalso essential to identify pregnantwomen in risk groups - who should bevaccinated against influenza and pneu-mococcus - as well as to check whetherthe pregnant woman was suitably im-munized against rubella and hepatitisB. Children whose mothers are HBsAgcarriers should receive vaccine andspecific immunoglobulin, preferablywithin the first 24 hours of life, andthose in the puerperium period who arenon-immune to hepatitis B or rubellashould be vaccinated against thesediseases at that time.

It is expected that in the near fu-ture the vaccine calendar for pregnantwomen will be widely expanded, withnew vaccines being incorporated.

RESUMO

BRICKS LF - Vacinação em gestantes:considerações sobre sua importân-cia no Brasil. Rev. Hosp. Clín. Fac.Med. S. Paulo 58 (5):263-274,2003.

Recém-nascidos e lactentes jovenspermanecem vulneráveis a diversasdoenças causadas por vírus e bactéri-as. Em geral, as estratégias de imuni-zação são inefetivas para que a crian-ça produza anticorpos em quantidadessuficientes nos primeiros seis meses devida. Gestantes podem produzir anti-corpos IgG que são transportados ati-

vamente através da placenta e podembeneficiar tanto a mãe quanto a crian-ça. Entretanto, com poucas exceções,as vacinas não são recomendadas roti-neiramente para as gestantes, devidoàs preocupações relacionadas à segu-rança desse procedimento. A realizaçãode estudos para avaliar os riscos e be-nefícios da vacinação em gestantesimplica em dificuldades éticas e cul-turais, tendo baixa aceitação.

Na última década, o desenvolvi-mento de vacinas, muito seguras eimunogênicas, reativou o debate sobreos riscos e benefícios da vacinação de

gestantes, particularmente, quandoexiste alto risco de a gestante e/ou ofeto apresentarem infecção com gravesconseqüências.

Neste trabalho, apresentamos umarevisão da literatura sobre a imuniza-ção em gestantes, utilizando dados doMEDLINE (1990-2002).

Conclusões: 1) não existem evi-dências de risco para o feto quando agestante é imunizada com toxóides,vacinas polissacarídicas, conjugadasou contendo vírus mortos; 2) provavel-mente, a maioria das vacinas conten-do vírus atenuados também é segura,

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mas os dados sobre sua segurança ain-da são insuficientes; 3) no Brasil, é ne-cessário melhorar a cobertura vacinalde gestantes contra o tétano.

Novas vacinas são candidatas para

uso em gestantes, porém, é necessáriorealizar pesquisas para avaliar sua se-gurança, eficácia e possíveis indica-ções, considerando-se dados epide-miológicos regionais.

DESCRITORES: Vacinas. Gravi-dez. Imunização materna. Doençasinfecciosas. Neonatal.

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