Vaccines: focus on adults - Summa Health System

<strong>Vaccines</strong>:<strong>focus</strong> on adultsThomas M File, Jr MD MSc MACP FIDSA FCCPChair, Infectious Disease DivisionSumma Health SystemAkron, Ohio;Professor of Internal Medicine,Chair ID SectionNortheast Ohio Medical UniversityRootstown, Ohio

Impact of <strong>Vaccines</strong>• <strong>Vaccines</strong> are one of the mostimportant tools we have to protect thehealth of our nation's most vulnerablecitizens, our children. (also adults,especially older adults)• In last 100 years life span of Americanshas doubled; largely as a result ofvaccines and sanitationGA Poland 2011

Ten Great Public HealthAchievements-US1900-1999• Vaccination• Motor-vehicle safety• Safer workplaces• Control of infectious diseases• Decline in deaths from coronary heart diseaseand stroke• Safer and healthier foods• Healthier mothers and babies• Family planning• Fluoridation of drinking water• Recognition of tobacco use as health hazard

Threats to <strong>Vaccines</strong>• Falling rates• Success of past vaccines• Lack of awareness of diseasethat is prevented• Effects of anti-vacccinemovement• Fear, mistrust, ignoranceGA Poland 2011

U.S. Measles Outbreak Sees Cases At15-Year High•Most associated with travel to or travels from France•France > 10,000 cases 2011 (several deaths) as a result ofdecrease in immunization•Increased cases in US (Case at SuperBowl 2012!!!)

Pertussis Outbreaks•California (2010)9,143 cases of pertussis (including ten infant deaths) were reportedthroughout California. This is the most cases reported in 63 years. In2011, disease activity is still at relatively increased levels throughout thestate. Visit the California Department of Public Health website for themost recent information.•Ohio (2010-2011)•In Ohio, Columbus Public Health (CPH) and Franklin County Board ofHealth (FCBH) responded to an outbreak of pertussis during 2010 and2011. In 2010, there were 964 cases reported by Columbus and FranklinCounties. This is the most cases reported in 25 years. Through April 9,2011, 144 cases of pertussis were reported. For the most recentinformation, visit the Columbus Public Health web site.

VACCINE PREVENTABLE DEATHSFOR ADULTS IN US• Adults--50,00-70,000(estimated) annually• Most common “preventable” deaths:• Influenza (20-40,000/yr in US)• S. pneumoniae• Hepatitis B (Cirrhosis, Liver Cancer)• Human Papilloma Virus (Cervical Cancer)• Cost of hospitalization due to vaccinepreventablediseases > $30 billion/year

Burden of Vaccine-Adult PreventableDisease in the United StatesDiseaseInfluenzaInvasivepneumococcaldiseaseHepatitis BHumanpapillomavirusPertussisZosterAnnual Burden of Disease, United States200,000 hospitalizations; 36,000 deaths (> 90% in olderadults)44,000 cases, 4500 deaths (higher rates of both in olderadults and persons with comorbidities)51,000 infections (95% adults); 2000-3000 deaths;1.25 million with chronic HBV infection6.2 million new infections (>4000 women die in USannually; ? Male deaths)10,454 cases reported in 2007 (3152 adults)Severe illness in infants; often transmitted by older child oradult1 million cases; risk for shingles and postherpetic neuralgiaincreases with age

ADULT VACCINES• PneumococcalInactive• InfluenzaInactive/Live• SmallpoxLive• Hepatitis A and BInactive• Tetanus, diptheriaInactive(toxoid)• VaricellaLive• MeningococcalInactive• RabiesInactive• Measles, Mumps, Rubella Live• Polio(2 types)Inactive/Live• Human Papilloma Virus Inactive• ZosterLive• Acellular Pertussis (for adults) Inactive• Human papilloma virus Inactive

Adult vaccines Too Low

Why Adults are not vaccinated

Physician-PatientMiscommunication

Who influences adults decisionsto get immunized?Personal Physicians can overcome negative attitudes of patients!!

The Communications BreakdownRecommendation“Youneed toget thisvaccine.”OR“I wantyou toget thisvaccine.”Vaccine-MotivatedPatientNot a Recommendation“Do youwant thisvaccine?”OR“Thinkaboutgetting thevaccine.”Vaccine-AmbivalentPatient

Is it for fear of needles?Not for most

Need to improve Vaccine Uptake• Clear and unambiguous messageto public, patients, providers• High benefit/risk ratio• SAFE• Low rates lead to outbreaks anddeath• Anti-vaccine movement isharmful to public healthGA Poland 2011

Before vaccines, millions died of Measles,Polio, or Smallpox

<strong>Vaccines</strong>: Very highbenefit/risk ratio• All vaccines have possible sideeffects, most mild, rarely severe• The risk of disease far outweighsthe risk of vaccine• MESSAGE:• <strong>Vaccines</strong> Effective• Safe• Need to recommend

Institute of Medicine Report-August 2011• <strong>Vaccines</strong> offer the promise of protectionagainst a variety of infectious diseases.Despite much media attention and strongopinions from many quarters, vaccinesremain one of the greatest tools in thepublic health arsenal. Certainly, somevaccines result in adverse effects thatmust be acknowledged. But the latestevidence shows that few adverse effectsare caused by the vaccines reviewed inthis report.

Adult Vaccination: 3 patients1. 40-year-old woman from Mexico who has a history ofasthma, otherwise healthy. She has come to your officefor a health screen for a school cafeteria job2. 65-year-old male has come to your office for a physicalexamination. He has no medical records, and reports thathe has smoked for many years. Initial evaluation revealsmild emphysema and diabetes.3. 30-year-old pregnant woman with 2 young children. It isthe start of the school year, and Corrine reports neverhaving received a seasonal influenza vaccine.• Which <strong>Vaccines</strong>: Influenza, Tdap, zoster, MMRpneumococcal, Meningococcal

ACIP Adult Immunization Schedulehttp://www.cdc.gov/vaccines/recs/schedules/downloads/adult/adult-schedule.pdf

Influenza vaccine: BenefitBased on risk-benefit considerations, thereception of and the administration ofinfluenza vaccines are arguably themost beneficial health promotinginterventions available to us and ourpatients. Influenza vaccines preventillness and death and are safeALL PERSONS > 6 MONTHS OF AGESHOULD RECEIVE YEARLYINFLUENZA VACCINEEspecially pregnancy

INFLUENZA VACCINE-Importance• Influenza may lead to many complications in adults• secondary pneumonia• exacerbation of underlying disease(i.e., chronic lung or heartdisease)• Influenza virus changes antigens over time; patients maytherefore, not be immune because of prior exposure• Efficacy• Prevents illness in approx 70-90% of persons < 65 years• 30-70% effective in preventing hospitalization in elderly• Can be given at SAME time as pneumococcal vaccine

US Influenza <strong>Vaccines</strong>• TIV: ‘Killed’, injectable “All comers” 6 months and older• TIV Intradermal• Approved May 2011 for 18-64 years [smaller needle]• LAIV: Live-attenuated, cold-adapted nasal (CANNOT replicate at bodytemperature)-nasal spray• very minimal viral shedding; OK to give to nurses unless taking care ofseverely immunocompromised patients (e.g. Stem cell transplant)• Indicated only for healthy people 2-50 years• High-Dose TIV for 65+ population * [first available 2010-11]• Same production process as TIV; higher Ag dose• Seroconversion, seroprotection rates ≥ TIV for A, B strains• Superiority criteria for A, Non-inferiority for B strain• Local reactions more frequent but classified as mild• ‘Real world’ efficacy data not published to dateTIV, trivalent inactivated vaccine*Falsey AR et.al. J Infect Dis. 2009;200:172-180.

INFLUENZA VACCINEHigh Dose• Fluzone High-Dose• Contains 60 mcg each of the 3 Influenzaantigens (compared to 15 each for regular TIV)• Rational: results in higher AB levels in elderly patients;unknown if this will result in better protection but indirectevidence is suggestive• Slightly higher rate of MILD reactions• Indications: Patients > 65 years.• Costs

INFLUENZA VACCINEReduction in Hospitalizations for Cardiac disease andStrokes (Nichols et a. NEJM 348, April 3, 2003)• Observational studies of large cohorts (140,000;146,000), ’98-’99 AND ’99-’00, 3 HMOs, age 65• Vaccination against influenza associated withreduction in hospitalization for :• Cardiac disease (19% both seasons)• Cerebrovascular disease (16%; 23%)• Pneumonia and Influenza (32%; 29%)• All cause Death (48%; 50%)• Possible mechanisms: infect cause alterations inclotting factors, platelet aggregation, amount ofinflammatory- response cytokines which enhancethrombosis

Influenza ‘Nuts and Bolts’ 1• Vaccination season: Soon as available to ~April 1• <strong>Vaccines</strong> approved by FDA for 6 manufacturers; June 2011- shipping• Late season vaccination important and underutilized• Most disease in mid-south in January-March• LAIV , TIV, HD-TIV: 1 dose for adults• Kids

Adverse effects• Local reactions: soreness at vaccination site• Mild, rarely interfered with ability to conduct usualactivities• In placebo-controlled trials no associationwith higher rates for systemic symptoms• Fever, malaise, myalgia, headache• CANNOT get influenza from trivalentinactivated vaccine (TIV)• Rare AEsMorbidity and Mortality Weekly Report. 2009; 58: 1-52

Adverse effects: rare or notassociated• Immediate hypersensitivity: 1 per 500,000• GBS:• IN general population annual incidence 10-20/million• Except for possibly associated with 1976 vaccine, nocompelling evidence of association with influenza vaccine(including 2009 H1N1)• Ocularespiratory Syndrome• In one placebo-controlled trial, 2%• Red eyes, cough, wheezing, chest tightness within 2-24hours; resolve within 24 hours; If no evidence ofhypersensitivity can receive subsequent TIV• AUTISM: Absolutely NO ASSOCIATION!!!!!Morbidity and Mortality Weekly Report. 2009; 58: 1-52

Influenza and Pregnancy• Pregnant woman at high risk forsevere complications and death• Cellular immune response diminished• Maternal influenza associated withincreased (Zaman et al. NEJM 2008)• Maternal hospitalization• Fetal malformation• Other illnesses• Prevention is best approach• Newborns are at high risk forsevere complications• Several reports of 2 nd MRSA infection• No approved vaccine for infants < 6 monthsof age• All care givers need to be free from possibletransmission to this vulnerable population

Benefits/Obligations of Influenza vaccinefor Healthcare providers• As HCW we all have an obligation to protect ourpatients• Transmission may occur without illness• May be asymptomatic carriers• Infectious prior to onset of symptoms• Studies show reduced transmission after vaccination• Protection form acute illness• For H1N1 greatest morbidity and mortality is in ‘healthy’individuals aged 20-50.• Protection of family members (especially if veryyoung or with medical conditions)• Mandatory immunization of all HCW being proposed

Centers for Disease Control and Prevention. 2010. Active Bacterial Core Surveillance Report, EmergingInfections Program Network, Streptococcus pneumoniae, 2009. http://www.cdc.gov/abcs/reportsfindings/survreports/spneu09.pdf.Accessed February 3, 2011.Pneumococcal Diseases causes more deaths peryear in US than Breast Cancer or Prostate CancerXu. Et al. Deaths: Prelimanary data for 2007. Natl Vital Stat Rep. 2009; 58: 1-51

Pneumococcal <strong>Vaccines</strong>-adults• 90 known serotypes of S. pneumoniae• Pneumococcal polysaccharide vaccine (PPSV23)• Inactive vaccine; contains 23 serotypes which account for majority (75-80%)of clinical disease.• Approved for use in adults of any age; ? Efficacy for pneumonia• CDC recommends PPSV23 for adults age 65 years and older ;and youngeradults with risk factors• Pneumococcal conjugate vaccine (PCV13) approved for use inadults age 50 and older• Inactive vaccine, conjugated with diptheria CRM 197 protein); 13 serotypeswhich account for approx 45-50% of invasive disease• Approval from FDA announced December 30, 2011 for adults 50 years andolder• Previously approved and recommended for use in children• CDC’s Advisory Committee on Immunization Practices (ACIP) recommendsuse for patients who are immunocompromised

PNEUMOCOCCAL VACCINEPolysaccharide (PPV23) Conjugate (PCV13)# serotypes 23 13Protein carrier No YesInduction B memory cellsand amnestic response No YesReduction of carriageof vaccine types No YesApproved for adults Yes YESApproved for pediatrics No Yes

PNEUMOCOCCAL VACCINEPolysaccharide VaccineVACCINE CHARACTERISTICS• Efficacy: Reduces invasive(bacteremia)disease by 50-81% in adults• Most studies show it DOES NOT reduce incidence ofpneumonia in adults but DOES reduce InvasivePneumococcal Disease (bacteremia, meningitis, mortality)due to pneumonia• NOT effective for children < 2 years of age• Does not reduce ‘colonization’• Contains the antigens from the 6 serotypes most oftenassociated with penicillin resistance• Eventual declining immunity after first dose(may requireredosing)File TM, et al. Infect Dis Clin Pract. 2012;20:3-9.

Indications for 23-valent PneumococcalPolysaccharide Vaccine• All adults 65 years of age and older• Age 19 - 64 years who has a long term health problemsuch as:• heart dis, lung dis, sickle cell dis, diabetes, alcoholism, cirrhosis,leaks of cerebrospinal fluid or cochlear implant• Age 19- 64 years who has condition that lowersresistance to infection (immunocompromised), such as:• Hodgkin’s disease, lymphoma or leukemia, kidney failure,myeloma, nephrotic syndrome, HIV/AIDS, hyposplenism, organtransplant, steroids, certain cancer drugs• Any adult 19 through 64 years of age who:• is a smoker• has asthmaCDC: Advisory Comm on Immunization Practices

Clin Infect Dis. 2008; 46: 1015-23

From Medscape Infectious Diseases > Expert CommentaryPneumococcal Immunization Strategies for AdultsThomas M. File, Jr., MDPosted: 12/17/2010• Should PCV or PPV be considered for those approaching theage of indication (65 years) who do not have comorbidconditions?• I am personally interested because I, too, will soon reach theage of indication. Would it be better for me to receive PCV13 orPPV23 as my initial pneumococcal vaccine? We can only relyon the immunogenicity studies and a few studies performed inspecial populations (such as HIV-infected individuals). It ispossible that an initial dose of PCV13 followed by PPV23 (toenhance the number of serotypes covered) may provide betterimmunity and, more important, better effectiveness in diseasereduction. For this reason, I am leaning toward this strategyrather than the use of PPV23 followed by PCV13.

Recommendations for PCV13 and PPSV23for immunocompromised adults** Advisory Comm Immunization Practices, ACIP, CDC

PCV13 Recommended forImmunocompromised Patients

PNEUMOCOCCAL VACCINE13 valent conjugated vaccine study for adultsCAPITA Study (Community Acquired PneumoniaImmunization Trial in Adults)• RCT trial in Netherlands• Design• 13 valent conjugate vaccine (same as pediatricvaccine)• Placebo controlled (1:1); approx 85,000 subjects,> 65 years of age, community dwelling• Endpoints:• Primary-prevention of CAP (serotype specific)• Secondary-all cause CAP, colonization (2000subjects), mortality, bacteremiaHak et al. Netherlands J Med. 2008; 66: 378-381

Polysaccharide VACCINERevaccination• A 35 y/o immunocompetent male is a smoker andreceives pneumococcal vaccine. When should hereceive revaccination?• A 35 y/o male with HIV receives pneumococcalvaccine. When should he receive revaccination?• A 65 y/o male receives pneumococcal vaccine. Whenshould he receive revaccination?OPTIONS:A. In 5 yearsB. Age 65C. No revaccination indicated

polysaccharide VACCINERevaccination• Revaccination per CDC recommendations• Immunocompetent but with underlying medicalcondition (e.g., : If > 5 years since 1 stAdministration; and aged < 65 at time of 1stAdministration; and now > 65 years of ageor• One-time revaccination after 5 years forpersons with significant underlying conditions(i.e., chronic renal failure, HIV, leukemia,lymphoma, myeloma, Hodgkins, long-termsteroids)

Pertussis Vaccine: Adults• DTaP (Pediatric vaccine)• Daptacel, Infanrix, Tripedia• Contains higher concentration of diptheria toxoid and acellularpertussis• Tdap = Tetanus and Diptheria Toxoid, and AcellularPertussis• Adacel (Sanofi Pasteur); Boostrix (GSK)• Single dose for persons 11-18 years of age who have completed thechildhood series• Single dose for adults aged 19 years and older (Including adults 65+[esp. those with infant contact)• Tdap should be administered regardless of interval since the lasttetanus-containing vaccine, especially if the patient will have contactwith children

ACIP Recommendations: Tdap Vaccine• Single dose for children 7 to 10 years of age andwho are not fully vaccinated against pertussis.• Single dose for persons 11-18 years of age whohave completed the childhood series.• Single dose for adults aged 19 years and older.• Including adults 65+ [esp. those with infant contact]• Tdap should be administered regardless ofinterval since the last tetanus-containingvaccine, especially if the patient will havecontact with children

ACIP Tdap RecommendationsSpecific Priority Groups• Pregnant women at more than 20 weeks'gestation• Adults, regardless of age, who are inclose contact with infants younger thanage 12 months (e.g., parents,grandparents, or child-care providers)• Healthcare Providers

Herpes Zoster(Shingles)• Approx 1 million cases of herpes zoster annually inUS; 50% in those >60 years; pain can be severe.• Complications: postherpetic neuralgia; eye, visceral,nerve palsies; secondary bacterial infectionPhotographs courtesy of Thomas M. File, Jr, MD

Zoster Vaccine (Zostavax )• Live vaccine• Approved for the prevention of herpes zoster(shingles) in persons aged 50 years andolder.• In 38,000 patient study, reduced the incidence ofshingles by 51% in persons aged 60 years andolder (less effective in older patients)• Incidence of postherpetic neuralgia less by 39%.

Zoster Vaccine (Zostavax )• Single SC injection within 30 minutes ofreconstitution.• Does not require documentation of priorvaricella to give• Proper time after zoster is controversial.Expert recommendations vary from 6 monthsto 2 yrs.• Contraindications• Allergy to gelatin, neomycin• Immunodeficiency (administer preferably 4 wks prior toimmunosuppressive therapy, can give if in remission fromleukemia or lymphoma for 3 months; low dose steroids, < 20 mg/d for < 14 days, is OK)• Active TB• Pregnancy

Human Papillomavirus (HPV) Vaccine:first cervical cancer vaccine• Impact of HPV• Cervical and Vaginal HPV are the most commonsexually transmitted disease• Estimated 6.2 million women and men infectedin US annually• 74% in ages 15-24; Lifetime risk = 50%• Infection with oncogenic HPV types (especially 16and 18) is most significant risk factor fordeveloping cervical cancer• Approx 4000 women die annually• <strong>Vaccines</strong> reduces Cervical intraepithelialneoplasia (CIN) > 90%

Human Papillomavirus (HPV) Vaccine• HPV vaccine significantly reduces HPV infection andsubsequent cancer changes (cervical and anal);• Inactive vaccine; 3 injections over 6 months• Quadrivalent (Gardisil 6,11,16,18) and Bivalent(Cervarix 16,18); Approved for females ages 9-26• Routine vaccination against HPV is recommended for allgirls 11-12 years of age. Can be started in age 9• “Catch-up” vaccination recommended for females 13-26 years.• ACIP recommends all 11-12 year-old males getvaccinated against HPV (October 25, 2011): protectsagainst 90% warts

COMBINED HEPATITIS A andHEPATITIS B VACCINE• Twinrix®• Contains inactive heptitis A virus and recombinanthepatitis B surface antigen• Indications• Chronic liver disease; Illicit drug user; Men who have sexwith men; Recipients of therapeutic blood products;Travelers to areas of endemicity• Primary vaccination: 3 does (0.1.6-month schedule)• Accelerated Dosing: A series of 4 doses (1mL each) given on days 0, 7, and 21 to 30followed by a booster dose at month 12.

MENINGOCOCCAL VACCINE• Vaccine characteristics• Inactive vaccine• Polysaccharide Quadrivalent-serogroupsA, C, Y, W-135• Quadrivalent Conjugate vaccine (Menactra)• Same serogroups; approved for ages 2-54• Better and Longer immunity• Indications(somewhat controversial)• College freshman(recommended by Am Coll of HealthAssoc; not yet routinely recommended by CDC)• NOW Recommended by CDC with booster dose oftetravalent meningococcal vaccine should be routinelyadministered to adolescents 5 years after the first doseis given at ages 11 through 13 years (ACIP Oct 28,2010)• Travelers to high risk areas

HEPATITIS B VACCINE• New Recommendation by Advisory Committeeon Immunization Practices (Nov 2011)• Hepatitis B vaccine recommended now for all patientswith diabetes ages < 60 years• Reflects new information that adults with diabetes < 60years of age are twice as likely to get hepatitis B andmay experience greater morbidity and mortality.• Some feedback:• WHY NOT UNIVERSAL (including age >60)

Adult vaccines: Retail cost• Pneumocovax-approx $60• Prevnar 13-approx $120• Gardasil – for the series of 3 shots - $429.20• Zostavax – for one shot - $185.15• Adacel – for one shot - $46.76• Recombivax HB – for series of 3 shots - $198.09• Havrix – for series of 2 shots - $107.18

The wars of the world: Saving livesthrough vaccinationDW Kimberlin Inf Dis News. Aug 1, 2011• It’s been a hard week. The infectious diseases ward of our hospital isso full that we have to put many children who normally would be inisolation wings on regular floors. The 3-year-old with smallpox diedearly this morning, and the three infants on the ventilator withmeasles pneumonia are not far behind.• Although there is not much more to do for them, the house staff isconsistently over their duty hours because of the sheer number ofother children in the hospital. The easiest way to tell the dozenchildren with bacterial meningitis apart is that the eight withHaemophilus influenza type b meningitis have seizures that areeasier to control than the two with pneumococcal central nervoussystem infection. Of course, the two with meningococcus are easilydistinguished by their amputations. The one bit of good news is thatit is not summertime, so at least we do not have to deal with polioyet. You’d think that in the year 2011 something could be done toprevent this.

The wars of the world: Saving livesthrough vaccinationDW Kimberlin Inf Dis News. Aug 1, 2011• Without the safe and effective vaccines that wetoo often take for granted now, more than 300million who lived full and rewarding lives duringthe 20th century would have died prematurelyof a vaccine-preventable disease. Compare thiswith the 160 million estimated to have beenkilled in all wars combined during the samecentury. Stated another way, vaccines savedtwice as many lives as were lost in war duringthe most destructive 100 years in humanhistory.

The wars of the world: Saving livesthrough vaccinationDW Kimberlin Inf Dis News. Aug 1, 2011• With this as background, it is incredible to me that anyone woulddeliberately refuse the protections that previous generations wouldhave given their eye teeth to have had. I am certain that today’svaccine refusers love their children just as much as parents did in prioreras. So why would so many people willingly leave their children at realrisk for lifelong disability or death when there is a way to prevent it?• I believe that in most situations, it comes down to a misperception ofwhat the risks really are, and this misperception is aggravated by theonslaught of (mis)information that is available at the click of a mouse.• Measles vaccine does not cause autism, nor does it produceinflammatory bowel disease. In 2011, though, measles virus has killed12 children in France and left six with permanent brain damage. Is itmore dangerous to have your child vaccinated against measles or totake him to France for a wonderful family vacation?

Vaccine Messages• Clear and unambiguous• <strong>Vaccines</strong> have highbenefit/risk ratio• SAFE• Anti-vaccine groups harmfulto public healthGA Poland 2011

Supplemental Slides

Which vaccines are appropriate forElena (40 y/o woman)?Tetanus, diphtheria, and acellular pertussis (Tdap);influenza; and pneumococcal vaccines areappropriate for Elena. Because she does not recallreceiving the 3-dose primary vaccination series with Tdcontainingvaccine, Elena should begin the series of 1 dose ofTdap and 2 doses of Td. She should also receive the annualinfluenza vaccine. (Because of her asthma, Elena shouldreceive the trivalent inactivated vaccine [TIV] rather than thelive attenuated influenza vaccine [LAIV].) Elena's asthma isan indication for her to receive pneumococcal vaccine.

Which vaccines are appropriate forArthur (65 y/o male?Arthur's age (65 years), emphysema, and diabetesare indications for 4 vaccines. Influenza,pneumococcal, and Tdap are priorities givenArthur's lung disease. He recalls getting a tetanusbooster several years ago after an injury, so heneeds only Tdap, and not the catch-up Td series.

What should 30 y/o pregnantfemale receive?She should receive the seasonal influenza andTdap vaccines. Because pregnancy is acontraindication for LAIV, She should receive anage-appropriate TIV for influenza. ACIPrecommends that pregnant women who have neverreceived the Tdap vaccine should be vaccinatedduring the second trimester (after 20 weeksgestation) or during the third trimester. If Tdap isindicated but not administered during pregnancy, itshould be given in the immediate postpartumperiod.