Neil S. Silverman, MD Center for Fetal Medicine & Women s Ultrasound, LA Clinical Professor, Dept. of Obstetrics and Gynecology Division of

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1 Neil S. Silverman, MD Center for Fetal Medicine & Women s Ultrasound, LA Clinical Professor, Dept. of Obstetrics and Gynecology Division of Maternal-Fetal Medicine David Geffen School of Medicine at UCLA

2 Vaccine Importance and Strategies Children have benefited the most from vaccines in terms of declines in disability and death, primarily because vaccination programs are generally targeted to children In 1994, reported that 50,000-70,000 adults compared to 500 children died each year from vaccine-preventable illnesses (Fedson D, JAMA 1994) More than 50% of cases of significant vaccine-preventable illnesses reported to the CDC in 2004 occurred in individuals > 15 years old Many of the most vulnerable adults are seen in practices that provide health care to women Immunization services have not historically been part of obgyn care Need to address benefit of vaccination both for women and for the long-term health of their children

3 Vaccination: Key Areas Influenza (focus on pregnancy and HCWs) Tdap (tetanus, diphtheria, pertussis) Physician protection/liability Inadvertent vaccination Side effects/complications

4 Influenza

5 Influenza and Pregnancy Increased morbidity/hospitalization rates for pregnant women in every trimester compared to rates in nonpregnant persons (Dodds L et al, CMAJ 2007) When no comorbidities: risk ratio 1.7 (1 st tri) 5.1 (3 rd tri) With comorbidities: risk ratio 2.9 (1 st tri) 7.9 (3 rd tri) Increased risks of maternal deaths reported in pan-epidemics (CDC 2007) Newer live-attenuated nasal flu vaccine should not be given in pregnancy, or in those > 65 years old (GYN) Demonstrated benefit for mothers and newborns Immunization with the trivalent inactivated flu vaccine (TIV) is recommended for all pregnant women (ACOG CO #608, Sept 2014; CDC 2013)

6 Neonatal Benefits of Maternal Influenza Vaccination Flu vaccine not recommended for children < 6 months of age Pregnant women have been shown to have protective levels of anti-influenza antibodies after vaccination (Munoz FM, AJOG 2005) Passive transfer of antibodies that might provide protection from vaccinated women to neonates has been reported (Englund JA et al, J Infect Dis 1993; Reumen PD et al, Ped Infect Dis J 1987) Retrospective clinic-based study in showed (nonsignificant) trend toward fewer episodes of newborn respiratory illness among newborns of vaccinated pregnant women (Black SB,Am J Perinatol 2004)

7 Neonatal Benefits of Maternal Influenza Vaccination (2) Randomized study of flu vaccine during pregnancy to assess neonatal impact: NEJM, Sept 2008, Zaman K, et al 340 women received either flu vaccine or pneumococcal vaccine (Hopkins study group in Bangladesh) 63% lower risk of lab-confirmed neonatal influenza in children of vaccinated moms, up to 6 months of age 1 st study to definitively show benefit to women and children

8 Zaman K et al, NEJM 2008

9 Influenza Vaccination of Pregnant Women and Protection of their Infants (2014) Report on 2 double-blind R-PC trials of trivalent influenza vaccine in pregnant women with and without HIV infection Study cohorts: 2116 pregnant women without and 194 pregnant women with HIV infection (South Africa) At 1 month after vaccination, seroconversion rates and rates of antibody titers were significantly higher for vaccine recipients vs placebo in both cohorts (90-97% vs 25-44%) Vaccine efficacy (placebo vs vaccine) HIV-uninfected women/infants: 3.6% infection rate vs 1.9% HIV-infected women: 17% infected vs 7.0% Madhi SA, et al. NEJM, Sept 2014

10 Kaplan Meier Estimates of Percentages of Confirmed Cases of Influenza According to Cohort and Study Group. Madhi SA et al. N Engl J Med 2014;371:

11 So..why aren t more pregnant women vaccinated against influenza? Lack of information Variability in flu severity year-to-year Current flu season ending: mildest in CA in recent years Short memory syndrome Concerns over risk for pregnancy Provider interest: concerns over reimbursement, litigation Confusion over recommendations

12 Recommendations of ACIP for Maternal Influenza Vaccination : Any stage of pregnancy : HR conditions, any gestational age : No mention of maternal immunization : Pregnancy not an indication : No evidence to document influenza a risk : Evaluate pregnant as non-pregnant : Vaccinate HR pregnant women : Vaccinate HR pregnant women in any age : HR at any gestational age; others 3 rd trimester : HR at any time, other in 2 nd and 3 rd trimester : Women pregnant during influenza season at any trimester

13 Are we barriers to vaccination during pregnancy? Prospective survey study during 3 months of flu season Among responding women, only 22% reported discussing flu vaccine with doctor, and only 8% were vaccinated More physicians said they discussed vaccine with patients than did patients say it was discussed (74% v 22%; p<0.01) Physicians were more likely to vaccinate if: Aware of CDC guidelines (RR 2.6; ) Gave vaccinations in their office (RR 1.2; ) Had received flu vaccine themselves (RR 1.9; ) Study demonstrated gaps in both groups understanding of benefit of vaccine for both pregnant women & newborns Silverman NS, Greif A. J Repro Med, Nov 2001

14 HCW Vaccinations Overall influenza coverage rate for season was 75.2% Coverage was > 90% for; 1. Physicians, regardless of work setting 2. HCW with employer vaccination requirement, regardless of work setting Majority of vaccinated HCWs (77.3%) reported receiving vaccine at work If vaccines not required at work: 80%: vaccine if free and on-site > 1 day 62%: vaccine if free and on-site only 1 day 49%: vaccine if not available on-site MMWR: Sept 19, 2014

16 MMWR, Sept 19, 2014

17 MMWR, Sept 19, 2014, Sept 19, 2014

21 Doctors ARE Covered: National Childhood Vaccine Injury Act Established by Congress in 1986 Began operation 1988 No-fault federal compensation program Alternative to tort system

22 NCVI Act Table of injury established for each vaccine Alleged injury must be on the table Financed by $0.75 tax per antigen and each tax must be passed by congress Time limits for inquiries

23 But this is a Childhood Vaccine Injury Act, right? Yes, but it covers all vaccines that are part of the childhood vaccination schedule, regardless of who s getting them e.g.: Influenza, hepatitis B, varicella, tetanus Requires health-care provider who administers VCIPcovered vaccines to record, either in an office log or the recipient s permanent medical record: Date of vaccine, manufacturer and lot #, name and title of person administering the vaccine Also requires reporting of adverse vaccination reactions to Vaccine Adverse Event Reporting System (VAERS) or

26 Influenza Antivirals and Pregnancy Issue initially arose with H1N1 (A strain), since it was susceptible, choice was between oseltamavir and zanamavir Both OK in pregnancy; rimantidine also OK, only IF susceptible Neuraminidase inhibitors usually also effective against B strains Oseltamavir, as a systemic agent, may be preferable Treat mother and, possibly, fetus: does cross placenta Treatment dose: 75 mg BID X 5 days Ideally, within 2 days after onset of symptoms Prophylactic dose: 75 mg daily X 10 days Exposure window: 7 days

27 BUT: Vaccination is ALWAYS better than treatment

28 Influenza Vaccine (MMWR, Aug 15, 2014) In June 2014, the ACIP voted on updated recommendations for use of trivalent seasonal influenza vaccine for the influenza season. Expanded vaccination recommendations for adults were established in 2009 to include all adults. Therefore, all people age 6 months and older are now recommended to receive annual influenza vaccination. The trivalent vaccine is identical to last year s: A/California/7/2009 (H1N1)-like, A/Texas/50/2012 (H3N2)- like, and B/Massachusetts/2/2012-like antigens. Recombinant trivalent vaccine available for persons with severe egg allergy (anaphylaxis): FluBlok. Nasal vaccine NOT an alternative. Quadrivalent vaccine also available but no CDC recommendation

29 Influenza Vaccine: Preparations and Preservatives Quadrivalent vaccine also available but no ACIP/CDC or ACOG recommendation or preference 1,2 Recombinant trivalent vaccine available for persons with severe egg allergy (anaphylaxis): FluBlok. (allergy no longer an excuse ) Thimerosal: a mercury-containing preservative used in multi-dose vials of the vaccine Thimerosal-free formulations are available, NO scientific evidence that thimerosal-containing vaccines result in adverse effects in newborns whose mothers got them during pregnancy 1 1. CDC/MMWR ACOG 2014

30 Pertussis and Tdap

31 Pertussis Epidemiology Pertussis is an endemic human disease that peaks every 3 to 5 years increasingly being reported in adolescents and adults; immunity wanes In 2005, ~60% of cases 11 years of age* Adolescents and adults serve as vectors of infection for non-immune infants, in whom disease is often quite severe Probably not a disease reservoir Prolonged carriage most likely does not occur *CDC. Pertussis Surveillance Report, Oct 14, Weeks 1-52 (final data)

32 Tetanus-Diphtheria-Pertussis Vaccines: New Considerations Tetanus booster recommendations have not changed: every 10 years, with pregnancy no exception (toxoid) DTP typically a childhood vaccine, with adults receiving Td boosters However, rates of pertussis infection have soared in US despite childhood vaccination Pertussis is highly contagious and spread easily by inhalation of respiratory droplets or aerosols Cases reported to CDC have doubled between 2003 and 2004, and are higher than any year since 1959 Adults and adolescents accounted for 67% of cases in 2006

33 Why here? Why now? Pertussis cyclical Epidemics occur every 3-5 yrs when enough susceptible people accumulate in population to sustain widespread transmission Last US epidemic in 2005 (nationwide) Susceptible people increase in population due to New birth cohorts of unvaccinated infants Waning population immunity from vaccine or disease (and less chance for boosting opportunities) Parental choice not to vaccinate children, etc.? Unclear why California most affected state so far Speculation: may have less population immunity than other states because (until recently) one of only 11 states not having requirement that all middle school students receive Tdap Courtesy of Kathleen Harriman, California Dept of Public Health

36 Why the New Pertussis-containing Vaccines? Newer vaccine is an acellular pertussis-containing preparation (Tdap): presumed better and more durable immunogenicity Approved in 2005 for individuals years of age Compensates for waning immunity (5-10 yrs) from old vaccine DTaP is similar vaccine in pediatric formulation, with 3-5 X as much diphtheria component Higher amount of pertussis component also is pediatric preparation Upper case D for pediatric formulation, lower case d for adult formulation (same for P vs p ) Tetanus components equivalent

37 Pertussis: Common Questions (1) A child or adult who has had pertussis can (uncommonly) get the disease again, so vaccination is recommended Reinfection may present as persistent cough rather than typical pertussis After a tetanus-prone injury, in an adult whose last booster was > 2 years ago? Give Tdap, not Td or tetanus toxoid (TT) alone (can give Td only if prior Tdap can be documented) Age no excuse: TT became available in 1938, routinely used in 1944 No documentation assume to be unimmunized

38 Pertussis: Common Questions (2) Tdap can be given at same visit as other vaccines Different site, using a separate syringe (don t mix) Mixed clinic setting (peds/adult) and an adult got DtaP in error instead of Tdap No harm to adult Age limitations? Both current commercially available Tdap formulations are licensed for ages 11 and up. Recent ACIP/CDC recommendations (June 2011): approved for ages > 65

39 New Tdap Urgency: CA Outbreak Largest pertussis outbreak in 65 years in CA in cases statewide; 304 cases through same time in infant deaths Studies have shown that household contacts, most often mothers, are the most common source of pertussis in infants (Wendleboe AM, Ped Infect Dis J, 2009) CA Dept. of Public Health, CDC, and CA-ACOG endorsed vaccinating women during pregnancy At least 2 weeks before contact with young infants Household contacts are also to be vaccinated Health-care personnel and childcare workers also need to be vaccinated

41 ACIP Pertussis Recommendations October 2010 No interval necessary between Td and Tdap (Previously: 2-year interval recommended) Tdap for adults 65 years of age with infant contact One dose Tdap for un-/under-immunized children 7-10 years of age February 2011 All healthcare personnel (HCP) who have not received Tdap should receive ASAP Healthcare facilities should take steps to encourage Tdap, including providing at no cost

43 How to Best Protect the Infant Tdap during Pregnancy! Gall SA, AJOG 2011;204;334.e1-5.

44 Tdap during Pregnancy: Safety and Immunogenicity Randomized clinical trial evaluating Tdap during pregnancy or postpartum Significantly higher pertussis antibodies if Tdap given during pregnancy compared to postpartum in both women and in their infants at birth (p< 0.001) No increased risk in serious adverse events in women or infants, other than injection site reactions in women Pertussis antibodies in newborns did not alter infant responses to Dtap vaccine in infancy Munoz FM, et al. JAMA, May 2014

46 Pertussis Recommendations Current Landscape All health care personnel All adults, adolescents After wound (instead of Td) 7-10 yo, if not completely immunized Cocooning including GRANDPARENTS Antepartum 2 nd or 3 rd trimester If not antepartum, give postpartum

47 Other Vaccines & Issues

48 Inadvertent vaccinations Issue arises when a live attenuated vaccine (MMR or varicella) is administered to a women whose early pregnancy was undiagnosed Rubella Congenital rubella syndrome (CRS) reported with rubella infection in any trimester However, no proven vaccine-caused cases of CRS in either the US or UK registries with current RA27/3 vaccine (MMWR, RR-8, 1998) Varicella Nonpregnant women who are vaccinate are counseled to avoid pregnancy for 1 month (MMWR, RR-11, 1996) Current Varivax registry data report no attributable cases of congenital varicella syndrome Varicella or rubella vaccination during early pregnancy should not be regarded as reasons to terminate pregnancy (MMWR, RR-15, 2006)

50 Outreach to Ob-Gyns

51 Visit our Website:

Neil S. Silverman, MD Clinical Professor, Obstetrics and Gynecology David Geffen School of Medicine at UCLA Chair, ACOG Committee on Obstetric

Neil S. Silverman, MD Clinical Professor, Obstetrics and Gynecology David Geffen School of Medicine at UCLA Chair, ACOG Committee on Obstetric Practice Bulletins Vaccine Importance and Strategies Children