1. VACCINATIONS IN PREGNANCY
Vivien Brown MDCM, CCFP, FCFP, NCMP
Past President, Federation of Medical Women of Canada
Board Member, Immunize Canada
Assistant Professor, University of Toronto

2. OBJECTIVES
Counsel pregnant women about the role of influenza and Tdap vaccines during pregnancy
Identify known barriers to uptake of vaccine during pregnancy
Discuss some future directions of immunizations during pregnancy

3. CLINICAL IMPORTANCE, KNOWN BENEFITS & SAFETY OF SELECT VACCINATIONS DURING PREGNANCY
Influenza and Pertussis

4. INFLUENZA Among the top 10 leading causes of death in Canada
Every season → 10 % of pregnant women diagnosed with influenza
↑ Hospitalization
1 per 1000 pregnant women
↑ Cardiopulmonary complications
↑ Death
H1N1 → 5% of deaths occured in pregnant women (1% of the population)

5. INFLUENZA Pregnancy complications from maternal influenza infection
↑ Stillbirth and neonatal death,
51% reduction in rate of stillbirth among women who received the influenza vaccine
↑ Preterm birth
↑ Low birth weight infants
↑ Spontaneous abortion

6. INFLUENZA VACCINE Recommended for all pregnant women
Primarily indicated for maternal benefits
30% reduction of febrile influenza-like illness
Infant benefits → important consideration
Infant < 6 months have the highest rate of pediatric influenza hospitalizations
No influenza vaccines are licensed for this vulnerable age-group

7. SAFETY OF INFLUENZA VACCINE IN PREGNANCY
Active studies of influenza immunization → no evidence of harm to mother or fetus
Overall sample size small, especially in 1st trimester
Passive surveillance of influenza immunization → no evidence of harm to mother or fetus
Decades of use
> 100,000 pregnant Canadian women
> 488,000 pregnant European women
Both adjuvated, unadjuvated and H1N1 vaccines
Live attenuated influenza vaccine (FluMistⓇ) not recommended → theoretical risk
Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for PHAC, Feb 2014.

8. BORDUTELLA PERTUSSIS Respiratory pathogen
First recognized in the middle ages → “the kink”
“Wooping cough”

9. BORDUTELLA PERTUSSIS One of the top 10 causes of childhood mortality
294,000 pediatric deaths per year, globally
Disproportionate burden of morality and morbidity
86% of pertussis-related deaths in infants < 4 months
Review of pertussis admissions in Manitoba (n=42) between
Proportion < 1.5y
100%
Admitted to ICU
33%
Required supplemental O2
60%
Required intubation and ventilation
26%
Mean length of intubation
6.3d (IQR 2-7d)
Death 0%
Wengiel M and Fanella S (2013) Can J Infect Dis Med Microbiol, 24(3):

10. BORDUTELLA PERTUSSIS Whole cell pertussis vaccine introduced in 1943
Incidence of pertussis dropped
156/100,000 (1940s) → 2/100,000 (2011)
Vaccine
Description
DTP/Whole Cell Pertussis Vaccine
No longer really used
Diptheria toxoid, tetanus toxoid and whole cell pertussis
Dtap
Acellular pertussis vaccine (also contains diptheria and tetanus antigens) → primary childhood vaccine series
Tdap
Acellular pertussis vaccine (also contains diptheria and tetanus antigens) → adolescent and adult booster

11. INCIDENCE OF LABORATORY-CONFIRMED PERTUSSIS BY AGE GROUP, ENGLAND AND WALES, 1998-2012
Incidence per 100,000 persons aged <3
250
200
150
100 50
Amirthalingam (2013) Euro Surveillance 18:pii=20587

12. BORDUTELLA PERTUSSIS IN CANADA: 2012
7x increase in national incidence
4800 cases nationally
104 hospitalizations (2-fold increase)
3 deaths (otherwise healthy)
Several Canadian jurisdictions
Incidence highest in infants
72.2 cases per 100,000 among infants < 4months

13. SOURCE OF INFANT INFECTION?
Infections in adults are common.
Household contacts are the major source of infection.
Unvaccinated adolescents and adults
Remotely vaccinated adolescents and adults
Adult cases are not suspected, detected or reported
Either Parent
52-58%
Sibling
16-43%
Non-household contact
4-22%
Wiley et al (2013) Vaccine 13:

14. MATERNAL VACCINATION
Newborn antibody levels stratified whether mothers Tdap
Outcome
Antibodies
Mother did not receive Tdap, mean (SEM) n=52
Mother received Tdap, mean (SEM) n=52
P valueª
Dipheria
0.571 (0.157)
1.970 (0.291)
< .001
Tetanus
4.237 (1.381)
9.015 (0.981)
.004 PT
(1.796)
(2.768)
FHA
(4.022)
(21.664)
.002
PRN
(5.765)
(56.435)
FIM 2/3
82.83 (14.585)
( )
FHA, filamentous hemagglutinin; FIM, fimbriae; PRN, pertactin; PT, pertussis toxin; TdaP, tetanus, reduced diphtheria, and acellular pertussis antigens vaccine.
ª Significant at .05 level.
Gall. Effect of maternal immunization with Tdap. Am J Obstet Gynecol 2011.
Gall Sa, Myers J, Pichichero M (2011) AJOG, 204:344.e1-5.

15. EFFICIANCY OF MATERNAL VACCINATION
A Case-Control Study to Estimate the effectiveness of Maternal Pertussis Vaccination in Protecting Newborn Infants in England and Wales,
Gavin Dabrera₁₂₃, Gayatri Amirthalinga₃, Nick Andrews₄, Helen Campbell₃, Sonia Ribeiro₃, Edna Kara₃, Norman K. Fry₅, and Mary Ramsay₃
Cases
Controls
Total
No.
History of Maternal Pertussis Vaccination, No. (%)
Total No.
Unadjusted VE, % (95% CI)
Adjusted VEª, % (95% CI) 58
10 (17) 55
39 (71)
91 (77-97)
93 (81-97)
Dabrera (2015) CID 60(3): Amirthalingam et al (2014) Lancet, 384: 1521 – 1528.

16. EFFECTIVENESS OF VACCINCATION DURING PREGNANCY TO PREVENT INFANT PERTUSSIS
Cohort study of 148,981 infants born at Kaiser Permanente Northern California
Maternal Tdap > 8d prior to delivery
Maternal Tdap post-partum
No Maternal Tdap
Followed for first year of life for estimates of vaccine efficacy of maternal Tdap vaccination
2 months
12 months
Cases of pertussis defined by PCR detection of B. pertussis
Baxter et al. Pediatrics; 2017, 139(5):e c

17. EFFECTIVENESS OF VACCINCATION DURING PREGNANCY TO PREVENT INFANT PERTUSSIS
Year
2006
2007
2008
2009
2010
Births
30.715
32.569
31.536
31.307
30.465
Tdap Pregnancy 42
137
194
502
3634
Tdap Postpartum
186
983
2951
7604
9653
2011
2012
2013
2014
2015
31.255
32.066
31.743
32.869
34.777
7197
5334
13.953
26.294
30.395
7455
5355
3824
1553
609
Baxter et al. Pediatrics; 2017, 139(5):e c

18. SAFE IN PREGNANCY AND Q2Y
Comprehensive review in most recent NACI guidelines
Safety data of Tdap for pregnant women and the fetus are available:
Several small studies and not RCT data
US Vaccine Adverse Event Report System (VAERS)
UK Clinical Practice Research Datalink (CPRD)
Pharmaceutical registries (GSK and Sanofi Pasteur)
Retrospective data from mass vaccination campaign of HCW provides evidence of vaccine safety with short internal with last vaccination (<2y)
Kharbanda et al (2014) JAMA, 312(18):

19. CURRENT RECOMMENDATIONS AND UPTAKE OF MATERNAL IMMUNIZATIONS IN CANADA

20. INFLUENZA 2016-2017 NACI STATEMENT Recommended for all pregnant women
Adults and children with chronic medical conditions
People residing in a nursing or chronic care homes
People ≳ 65 years of age
Children 6-59 months
Aboriginal peoples
NACI (2016) Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine. PHAC, 2016

21. PERTUSSIS 2014 NACI STATEMENT
Universal immunization of pregnant women is not recommended given current epidemiology of pertussis in Canada
Depending on regional epidemiology, immunization with Tdap may be offered during pertussis outbreaks in women ≳ 26 weeks gestation, irrespective of their immunization status
If an adult dose of Tdap has not been given, pregnancy is an ideal time to evaluate vaccine history and give the adult dose
NACI (2014) Update on Pertussis Vaccination in Pregnancy. PHAC, Feb 2014.

22. BARRIERS TO IMMUNIZATION DURING PREGNANCY IN CANADA

23. PREGNANT WOMEN
BARRIERS TO
IMMUNIZATION
SYSTEM
ISSUES
HEALTH CARE
PROVIDERS

24. BARRIERS TO VACCINATION IN PREGNANCY
BARRIERS FOR HEALTH CARE PROVIDERS RECOMMENDING VACCINES
Lack of knowledge/education
Concerns of vaccine safety and insufficient testing in pregnancy
Misperceptions of risk of the disease and disease severity
Physician in solo practice
Ambiguous guidelines
Lack of time
Risk of blame if adverse event occurs
Inability to track vaccine status of their pregnant patients
Uncertainty of who bears responsibility for vaccination discussions
Not usual practice to vaccinate
MacDougall DM and Halperin SA (2016) Human Vaccines & Immunotherapeutics 12:4,

25. PROVIDERS IN 2004
40% → not aware of clinical importance of influenza for pregnant women
Factors associated with recommending the influenza vaccine to pregnant women:
Provider knowledge
Positive attitude toward the influenza vaccine
Increased phsycian age
Family phsycian
Personally been vaccinated OB FP
P-Value
Discuss
87%
97%
0.02
Recommend
70%
91%
0.002
Provide
13%
86%
<0.001
Tong, et al (2008) JOGC 30(5):

26. PROVIDERS IN 2015
Midwives were less likely to offer the influenza vaccine
Not allowed to administer the vaccine themselves in QC
Factors associated with recommending the influenza vaccine to pregnant women:
Older age
Higher numbers of follow-ups per year
Academic practice
Desjardins (2016) Poster Presentation SOGC Annual Meeting

27. IMPORTANCE OF PHYSICIAN DISCUSSIONS
Having had a physician discussion about the influenza vaccine was associated:
More frequent correct responses to knowledge questions
Annual receipt of the influenza vaccine
Positive attitudes toward influenza vaccination
Halperin (2011) Human Vaccines & Immunotherapeutics; 10(12):

28. BARRIERS TO VACCINATION IN PREGNANCY
BARRIERS FOR PREGNANT WOMEN RECEIVING VACCINES
Lack of recommendation to receive the vaccine
Perceived risk of disease and disease severity
Concern about vaccine effectiveness
Concern about vaccine safety
Time to get the vaccine
Fear of needles
Religion
Social family influences
Previous adverse reaction

29. BARRIERS TO VACCINATION IN PREGNANCY
SYSTEM BARRIERS
Reimbursement
Liability
Compliance with reporting
Access to care
Ineffective dissemination of information from clinics to patients
Cost of vaccine to patients
Cost of administering vaccines in clinic
Workload/lack of staff
Vaccine tracking

30. WHAT’S ON THE HORIZON FOR MATERNAL IMMUNIZATION?

31. GROUP B STREPTOCOCCUS (GBS)
Colonization ~ 1/5 pregnant women
Several recently published vaccine trials
Monovalent and trivalent polysaccharide conjugate vaccines of serotypes la,lb,lll
There are major serotypes causing infant GBS in Europe/North America
RCT of trivalent conjugate vaccine in Belgium and Canada, 86 women/infants
Vaccine was immunogenic and safe with good Ab titers in mothers/infants and no safety concerns

32. RESPIRATORY SYNCYTIAL VIRUS
Leading cause of viral acute LRTI
Lead to high morbidity in infants < 6 mos
In different studies: 2-3% of all neonatal deaths due to RSV
20% of hospitalizations in children < 5 due to RSV during winter months
Vaccine in pregnant could over neonatal protection

33. CONCLUSIONS
Influenza vaccine is universally recommended during pregnancy
Maternal health
Fetal health
Infant Health
Tdap during pregnancy is safe and likely reduces the incidence of pertussis among young infants
Canadian recommendations → under review
Barriers at the level of the patient, provider and system
This issue is not going to go away
GBS vaccine trials
RSV vaccine trials

34. Vaccination In Pregnancy: What You Need to Know
Household and close neonatal contacts
Vaccinate all
Promote safety cocoon for upcoming newborn
Influenza
Consider Oseltamivir 75mg BID x 5 days
Tetanus, Diptheria, Pertussis ( CDC)
Vaccinate All :
in 3rd trimester
Provides passive immunity. Most deaths from whooping cough are in those babies too young to receive vaccination.
Pneumococcus
Vaccinate if High Risk
Zika
Vaccination in development.
Recommend mosquito protection, barrier protection
Hep A
No apparent risk
Use in high risk situation only
Hep B
Vaccinate
Recommended for pregnant women at risk, no apparent fetal risk
Japanese Encephalitis
No safety data
Only provide if benefit >risk (travel to high endemic area)
Rabies
No indication of fetal effects
Provide post-exposure prophylaxis
Tdap
Risk Dependent
Typhoid
Risk dependent
Consider provision in high risk cases
HPV
Not routine
No evidence
Meales, mumps, rubella
No known effects but theoretical risk of PTL, LBW
Typhoid Oral
Use inactivated only
Varicella
If mother exposed, consider immunoglobulin.
Yellow Fever
Exposed fetuses have shown no complications

35. Quick Facts
1.Are the Vaccines Safe: Yes, inactivated viral, bacterial and toxoid vaccines can be used safely in pregnancy. The most common reactions are local erythema or swelling
2. If women receive a live or live-attenuated vaccination or otherwise in pregnancy they should not be counseled to terminate the pregnancy due to teratogenic risk
3. Live Vaccines in Pregnancy only present a theoretical risk to the fetus. They are not contraindicated if woman is at high risk of exposure. A discussion of the risk and benefit should occur. For instance a study of 304 women exposed to yellow fever immunization did not show increase in major fetal malformation.
4. Can I breastfeed? Women who are immunized can still breastfeed. This includes passive-active, live and non-live vaccinations.
 5. If a non-pregnant woman receives a live or live-attenuated vaccination, she should delay pregnancy for 4 weeks.
6. Household contacts can be safely vaccinated and in fact should be vaccinated to promote a cocoon immunization effect similar to herd immunity.
7. The following are not contraindications to vaccination:
Breastfeeding, low grade fever, autoimmune disorder, household contact with pregnant women, prior reaction to immunization, personal history of allergies or anaphylaxis to egg protein/neomycin/streptomycin, positive TB skin test. 

36. Acknowledgements
Dr. Mark Yudin and Dr. Vanessa Poliquin for their work on this presentation originally given at the SOGC meetings June 2017 Dr. Pam Liao and Dr. Pretty Verma for their work on the “Cocoon Effect, Evaluating Vaccine in Pregnancy”