Preventing Pertussis in Newborns with Tdap During Pregnancy

This article is based on the immunizations webinar, “Transplacental Partnerships: Immunity Building During Pregnancy and Beyond,” presented on May 22, 2018, by Dr Elias Kass, which is available for viewing via the Washington State Department of Health (with free continuing medical education credit available for those who qualify, through December 31, 2018). Hopefully this format is a bit more accessible for sharing than an hour-long webinar!

Pertussis (whooping cough)

When we’re talking about the Tdap vaccine in pregnancy, we are talking about our urgent desire to prevent pertussis in newborns. Pertussis is caused by a bacteria, Bordetella pertussis. It’s spread by respiratory droplets which are formed and propelled into the air during the long spasms of coughing. After the next victim inhales the droplets, the bacteria adhere to cells lining the nose, throat and upper respiratory tract. Once attached, the bacteria cause local tissue damage via several toxins (including tracheal cytotoxin, dermonecrotic toxin, and adenylate cyclase). This destructive process, with loss of the protective respiratory cells, is likely responsible for the cough. It’s also why pertussis is so difficult to treat: antibiotics can kill the bacteria and stop the spread to other people, but the damage done to the respiratory tissue by these toxins is already done.

One of the challenges with pertussis is that there’s a long incubation period of 1–3 weeks, and then a long stage that looks just like a regular cold, with runny nose and sneezing, so it’s hard to tell if it’s a cold or a big deal. Then there’s the coughing stage, which lasts up to 6 weeks, and then still many weeks of recovery, with the cough decreasing over time. This long-lasting cough earned pertussis the nickname “The 100-Day Cough.”

Infants generally skip the snotty phase and go right into coughing, rapid breathing, and apnea (abnormally long pauses in breathing, effectively lack of breathing). Because they’re spending so much time coughing and trying to breathe they don’t have time to eat.

Pertussis can be very complicated for young infants. Apnea is almost exclusively seen in babies under 6 months. They can get secondary pneumonias. They frequently vomit, though that’s not exclusive to young babies. They can have seizures.

Death is a pertussis complication that is seen almost exclusively in very young babies, especially those under 2 months, with babies under 1 month being especially vulnerable to this terrible outcome.

It’s also problematically common in these young babies. Figure 2 shows a chart from a study looking at immunization for pertussis during pregnancy. That top blue line is the incidence in babies under 3 months of age. The peak in 2012 is the height of the outbreak in England, and also when the immunization program was started, with the subsequent decline seen after introduction. You can see also that decline is much sharper in the babies under 3 months, who are the ones who really benefit from immunization during pregnancy.

Where are babies getting pertussis from? Mostly from the household, especially parents (50-55% of cases), siblings (up to 20% of cases), and grandparents (6-8%). Among infants and children hospitalized with initially unrecognized pertussis, 22 of 33 had a family member with laboratory-confirmed pertussis.

Prevention Strategies

It’s pretty clear that if the disease is killing babies in the first few months of life, waiting until they’re two months to start building their immunity with their own DTaP series is not a winning strategy.

In 2005, the Tdap vaccine was licensed. Before that, there actually wasn’t a pertussis booster vaccine. It was recommended to give Tdap before pregnancy or immediately postpartum. Cocooning was also recommended: vaccinating the people who will be in close contact with baby

By 2011 it was clear that this wasn’t sufficiently effective, and that Tdap during pregnancy would be significantly more effective. “Tdap vaccination during pregnancy could avert more infant cases and deaths at lower cost than postpartum vaccination, even when postpartum vaccination is combined with additional cocooning doses. Pregnancy dose vaccination is the preferred alternative to postpartum vaccination for preventing infant pertussis.” (Terranella et al, 2013)

This recommendation evolved a bit too. Initially (2011) it was only for people who hadn’t yet received a Tdap. Then because antibodies actually wane fairly quickly, Tdap was recommended in each pregnancy (2012). The issue of timing then becomes very important, because you want the levels to be highest at the time when the most antibody transfer is happening, but you don’t want to wait so long that baby is born before they receive the full benefit.

Transplacental Antibodies

How are antibodies exported to the fetus? Antigen-specific IgG antibodies begin to passively transfer to the fetus around 17 weeks, which means that they flow from high levels (parent side) to low levels (fetus side), much like a river. By 33 weeks, fetal and maternal levels are equal and active transfer begins, which is more like pumping water uphill. By 40 weeks, the fetus has more total IgG antibody than the gestational parent. If there are problems with the placenta, this transfer may not work as expected, and infections like HIV and malaria can also interfere with the transfer (Lindsey, Kampmann, & Jones, 2013).

This diagram (Figure 3) from a presentation by Dr Carol Baker at the NFID in 2014 shows where babies and kids get their antibodies from. Scenario A represents when antibodies are present in the mother’s bloodstream. She can’t give anything to the baby that she doesn’t have herself. Some of those antibodies are present because of infections in her past, and some are present because of vaccination during pregnancy or shortly before (depending on the disease and vaccination). The purple line represents IgG transported across the placenta – if those antibodies are present in the mom’s bloodstream — with the highest levels present in the baby right at birth and decreasing over time. The blue line that surges upwards next represents IgA expressed in the breastmilk, with a decrease secondary to when the baby stops breastfeeding.

If the mother does not have antibodies to give – scenario B – then nothing is transported to the baby across the placenta, and nothing is expressed through the milk. This is a tremendous simplification: everyone has some antibodies, unless they have a profound immunodeficiency, so here we are interested in specific antibodies to specific diseases, like pertussis and influenza. If antibodies to neutralize those diseases are not present in the mother’s blood, then the child then needs to wait until the yellow curves — the first yellow curve represents the immunity a baby builds in response to their own vaccines, and the second yellow curve represents the immunity a child builds over time as a result of exposure to the diseases themselves. You can already see where the gaps are when any of the lines are missing, and certainly without the purple line, that baby is left exposed for a long time. There are antibodies in breastmilk that protect against primarily gastrointestinal diseases (and some respiratory diseases), but they do not protect against pertussis, so without transplacental antibody, baby remains vulnerable to pertussis until she receives her primary DTaP series.

The current ACIP recommendation was issued in 2012, which is for Tdap in each pregnancy, at 27-36 weeks gestation. The vaccine takes 2 weeks to produce protective levels of antibody, so you want to be sure you’ve gotten your levels as high as possible before baby is born. This is an off-label use (because the label has not been updated, not because there is a problem with using it). Because the Tdap is boosting pre-existing immunity to pertussis (from a childhood vaccine series or infection), one dose of the booster is enough to drive up antibody levels high enough to be transferred through the placenta.

Figure 4 shows the difference in antibody transfer even within the recommended 27-36 week range, with the highest newborn levels found in people who were immunized at 27-30+6, and the lowest in people who were not immunized (Abu Raya et al., 2014).

Timing is always tricky though because you’re never sure who’s going to deliver when, and you don’t want to miss an opportunity to get preterm babies protection. Eberhardt has published two studies suggesting that there may be good antibody transfer for preterm infants who received Tdap in the second trimester (Eberhardt et al., 2016, 2017).

What about Tdap before pregnancy?

But can’t you avoid this whole vaccines-during-pregnancy issue if you get Tdap before pregnancy? Or if you’ve had Tdap in the past? Unfortunately, Tdap before pregnancy does not confer sufficient protection – the antibodies wane too quickly and so they’re not there to be transported to the fetus. Healy demonstrates that timing matters: “Infants of mothers immunized preconception or in early pregnancy have insufficient pertussis-specific antibodies to protect against infection. Maternal immunization during the third trimester, immunization of other infant contacts, and reimmunization during subsequent pregnancies may be necessary.” (Healy, Rench, & Baker, 2013)

Does it work?

So, does it work? Yes. At this point we have multiple studies showing very consistent results, all over 90%, whether it’s effectiveness against lab-confirmed pertussis, hospitalizations from pertussis, or infant death.

• Vaccine effectiveness against lab confirmed pertussis in babies under 3 months: 91% (95% CI 84 to 95) (Amirthalingam, 2014)
• Vaccine effectiveness in babies under 8 weeks: 93% (Dabrera, 2015)
• Vaccine effectiveness against laboratory-confirmed pertussis has been sustained >90% in the 3 years following its introduction (Amirthalingam, 2016)
• Vaccine effectiveness against infant deaths was estimated at 95% (95% confidence interval, 79%–100%).  (Amirthalingam, 2016)
• Infants with pertussis whose mothers received Tdap during pregnancy had significantly lower risk of hospitalization and ICU admission and shorter hospital stays (emphasis mine). Prenatal Tdap vaccination is a critical strategy for reducing the morbidity and mortality from pertussis. (Winter, Cherry, & Harriman, 2016)
• Vaccine effectiveness for Tdap administered during the third trimester of pregnancy was 77.7% (95% confidence interval [CI], 48.3%–90.4%); vaccine effectiveness increased to 90.5% (95% CI, 65.2%–97.4%) against hospitalized cases. (Skoff et al., n.d.)

A huge study of 675,167 mother–infant pairs showed a rate of pertussis 43% lower in babies whose whose mothers received prenatal Tdap (hazard ratio=0.57, 95% CI=0.35, 0.92). Interestingly (but not surprisingly), infants whose mothers received Tdap at <27 weeks of gestation did not experience reductions in pertussis rates, underscoring the importance of getting the timing right. (Becker-Dreps et al., 2018)

Another timing study comparing receiving vaccine while pregnant vs immediately after delivery, found “Tdap vaccination during 27-36 weeks gestation was 85% more effective than postpartum vaccination at preventing pertussis in infants <8 weeks of age.” (Winter et al., 2016)

Is it safe?

We know the vaccine works, as studies consistently show fewer severe illnesses, fewer admissions, fewer ICU admissions, fewer deaths. The next question is always, as it should be, is this safe? Is it safe during pregnancy, and is it safe to get during each pregnancy?

As part of the recommendation to give Tdap in each pregnancy, the existing data available about standard interval (receiving a second dose 5 or 10 years after the first) and “short interval” administration (less than 2 years between doses) administration was reviewed. No problems were noted with even short interval repeat administration (“Updated Recommendations for Use of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccine (Tdap) in Pregnant Women — Advisory Committee on Immunization Practices (ACIP), 2012,” 2013). Given the recommendation has been in place for 6 years now, we would expect problems with short interval dosing to have become obvious if they were going to exist.

A UK study from 2014 looking at the safety of Tdap during pregnancy showed no increased risk of a long list of complications, including stillbirth, maternal or neonatal death, pre-eclampsia or eclampsia, hemorrhage, fetal distress, uterine rupture, placental problems, mode of delivery, low birth weight, or neonatal kidney problems. “In women given pertussis vaccination in the third trimester, there is no evidence of an increased risk of any of an extensive predefined list of adverse events related to pregnancy. In particular, there was no evidence of an increased risk of stillbirth.” (Donegan, King, & Bryan, 2014)

A 2018 study of a whopping 410,000 births showed no association between pregnancy Tdap or flu vaccine and infant hospitalization or death. “We found no association between vaccination during pregnancy and risk of infant hospitalization or death in the first 6 months of life. These findings support the safety of current recommendations for influenza and Tdap vaccination during pregnancy.” (Sukumaran et al., 2018)

Summary

In summary, Tdap matters because pertussis kills very young babies, and immunizing during pregnancy allows babies to be “pre-stocked” with protective antibodies to protect them during their most vulnerable time. Receiving Tdap during pregnancy is a safe and highly effective way to provide this protection.

This is a huge opportunity to confer protection at a time when it really matters!

 

 

References

Abu Raya, B., Srugo, I., Kessel, A., Peterman, M., Bader, D., Gonen, R., & Bamberger, E. (2014). The effect of timing of maternal tetanus, diphtheria, and acellular pertussis (Tdap) immunization during pregnancy on newborn pertussis antibody levels – a prospective study. Vaccine, 32(44), 5787–5793. https://doi.org/10.1016/j.vaccine.2014.08.038

Becker-Dreps, S., Butler, A. M., McGrath, L. J., Boggess, K. A., Weber, D. J., Li, D., … Layton, J. B. (2018). Effectiveness of Prenatal Tetanus, Diphtheria, Acellular Pertussis Vaccination in the Prevention of Infant Pertussis in the U.S. American Journal of Preventive Medicine. https://doi.org/10.1016/j.amepre.2018.04.013

Donegan, K., King, B., & Bryan, P. (2014). Safety of pertussis vaccination in pregnant women in UK: observational study. BMJ (Clinical Research Ed.), 349, g4219.

Eberhardt, C. S., Blanchard-Rohner, G., Lemaître, B., Boukrid, M., Combescure, C., Othenin-Girard, V., … Siegrist, C.-A. (2016). Maternal Immunization Earlier in Pregnancy Maximizes Antibody Transfer and Expected Infant Seropositivity Against Pertussis. Clinical Infectious Diseases, 62(7), 829–836. https://doi.org/10.1093/cid/ciw027

Eberhardt, C. S., Blanchard-Rohner, G., Lemaître, B., Combescure, C., Othenin-Girard, V., Chilin, A., … Siegrist, C.-A. (2017). Pertussis Antibody Transfer to Preterm Neonates After Second- Versus Third-Trimester Maternal Immunization. Clinical Infectious Diseases, 64(8), 1129–1132. https://doi.org/10.1093/cid/cix046

Healy, C. M., Rench, M. A., & Baker, C. J. (2013). Importance of timing of maternal combined tetanus, diphtheria, and acellular pertussis (Tdap) immunization and protection of young infants. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 56(4), 539–544. https://doi.org/10.1093/cid/cis923

Lindsey, B., Kampmann, B., & Jones, C. (2013). Maternal immunization as a strategy to decrease susceptibility to infection in newborn infants. Current Opinion in Infectious Diseases, 26(3), 248–253. https://doi.org/10.1097/QCO.0b013e3283607a58

Skoff, T. H., Blain, A. E., Watt, J., Scherzinger, K., McMahon, M., Zansky, S. M., … Martin, S. W. (n.d.). Impact of the US Maternal Tetanus, Diphtheria, and Acellular Pertussis Vaccination Program on Preventing Pertussis in Infants <2 Months of Age: A Case-Control Evaluation. Clinical Infectious Diseases. https://doi.org/10.1093/cid/cix724

Sukumaran, L., McCarthy, N. L., Kharbanda, E. O., Vazquez-Benitez, G., Lipkind, H. S., Jackson, L., … Weintraub, E. S. (2018). Infant Hospitalizations and Mortality After Maternal Vaccination. Pediatrics, e20173310. https://doi.org/10.1542/peds.2017-3310

Updated Recommendations for Use of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccine (Tdap) in Pregnant Women — Advisory Committee on Immunization Practices (ACIP), 2012. (2013). MMWR, 62(07), 131–135.

Winter, K., Cherry, J. D., & Harriman, K. (2016). Effectiveness of prenatal Tdap vaccination on pertussis severity in infants. Clinical Infectious Diseases, ciw633. https://doi.org/10.1093/cid/ciw633