I began writing this post almost two months ago when a study I had been waiting for almost a year came out – one looking for clinical, epidemiological (“real world”) evidence for “cocooning,” which I’ll explain in a moment. But now I’m kind of glad I didn’t finish it then because it’s perfect to combine with the study that just came out looking at the safety of the Tdap vaccine during pregnancy.
The Tdap is the adult booster for the tetanus-diphtheria-acellular pertussis vaccine. While the tetanus booster is important for everyone, it’s the pertussis, or whooping cough, protection that is a bigger issue at the moment because rates have been climbing in a big way over the past decade. I’ve written before about the reasons for that: primarily the waning effectiveness of the vaccine with some contribution from geographical clusters of low vaccination rates. I’ve also written about the insights we’ve gleaned from the “baboon study” which call into question how effective cocooning might be in preventing the littlest babies from catching the illness. And that’s all the more reason why both these studies are so important.
The most recent one, published in JAMA Nov. 12., looked at pregnancy and birth outcomes in women who received the Tdap during pregnancy. It offers reassuring conclusions: no increased risk of preterm birth or underweight babies occurred among mothers getting the prenatal Tdap, and no increased risk of high blood pressure in pregnancy among those getting the Tdap before 20 weeks of pregnancy. A moderately increased risk of the bacterial infection chorioamnionitis showed up in those getting the Tdap, which I’ll address in a bit, but with more than 120,000 participants in the study, it’s a large enough study to find these results reliable.
As I wrote over on Forbes today, the Tdap has been recommended by the CDC during between 27 and 36 weeks of every pregnancy – yes, *every* pregnancy, even back-to-back ones – since October 2012. The hope is that, since infants don’t receive their first DTaP vaccine to protect against pertussis until 2 months old, they will receive sufficient antibodies through the placenta during pregnancy to offer some protection in those first few months, especially since infants under 3 months old are at the highest risk for death from whooping cough. And indeed, as I noted on the Forbes piece, a small JAMA study earlier this year showed a much higher pertussis antibody concentration – an average five times higher – in babies whose mothers got the shot.
This recommendation replaced the one for postpartum Tdap vaccination, part of a “cocooning” strategy in which all the individuals who will be around an infant too young to be vaccinated – such as household members, caregivers and grandparents – get the Tdap booster. The concept is basically a micro version of herd immunity: reduce the risk that those around a baby will get sick and thereby reduce the risk that the baby will get sick.
The problem is that nearly all the studies looking at the effectiveness of cocooning has been based on mathematical models, not on real-life (epidemiological) evidence. The difference is that mathematical model evidence calculates how many cases *should* be prevented based on certain assumptions, including the assumption that a person who isn’t coughing doesn’t have pertussis and can’t transmit it to others. And the baboon study showed us that those assumptions cannot necessarily be made. (Caveat: the study was in baboons — we don’t *know* that that asymptomatic transmission occurs in humans too, but it’s something we have to consider as a possibility.)
For example, a study I wrote about a few years ago found mothers were almost four times more likely than other household members to transmit pertussis to their infants. The authors calculated a substantial theoretical drop in infant infections – cutting infant cases in half – if mothers were vaccinated. But this conclusion was based, again, on math models and assumptions.
Meanwhile, epidemiological evidence would show an actual reduction in disease cases from cocooning, something that’s been shown with other vaccines but not yet with pertussis. The only studies that came close were one finding that postpartum Tdap immunization didn’t reduce cases in infants (ie, the cocooning wasn’t working if just mothers were vaccinated) and one last year that found indirect evidence that adolescent boosters moderately reduced infant pertussis hospitalization, though these findings speak more to herd immunity than to cocooning.
So, the big question – especially after the baboon study – is whether cocooning is effective in protecting infants from pertussis. And the study in Pediatrics in September began to give us the first glimmer of an answer: cocooning is not futile, but its effectiveness appears much more limited than hoped.
The study was a case-control study: they looked at the pertussis cases in children under 4 months old in New South Wales, Australia between April 2009 and March 2011 and then matched them to infants who did not catch pertussis, each with a matching birthday and area of residence. They were able to identify 217 infants with pertussis and matched them to 585 control infants. Then they asked all the parents about whether they had received the Tdap booster at least four weeks before the babies began sick with pertussis. (Although this part was based on parent report, which means they may not remember correctly, the researchers double-checked a subset of these with medical records.)
At first glance, the results appear to support cocooning as a strategy that would cut infant risk of pertussis infection. While only 22% of the sick infants’ mothers had received the Tdap, 32% of the healthy infants’ mothers did. Meanwhile, 20% of sick infants’ fathers had gotten the Tdap, compared to 31% of the healthy infants’ fathers.
But there are a few problems with taking these numbers at face value. One confounding factor is that the households with a sick infant were more likely to have an older child in the home (81% of sick babies’ homes compared to 62% of healthy babies’ homes), and we already knew older children were a significant source of transmitting infections. (The proportion of older children who had received at least three doses of a pertussis vaccine and gotten the 4- or 5-year-old booster were about the same in sick and healthy babies’ homes.)
After the authors took into account parents’ education, health care access and siblings in the home, they determined that having both parents vaccinated reduced the risk of pertussis in their newborn by 51%, or cut it in half. When they calculated it for mothers only – independent from the fathers’ vaccination status – the drop in risk was similar at 48%.
But here’s where the bigger confounder is: when they asked mothers whether they got the Tdap, that included getting it both before AND after pregnancy. In other words, boosters before becoming pregnant and postpartum boosters are combined. Since we already know babies whose mothers got a prenatal booster have up to five times more antibodies against pertussis than those who didn’t, it’s reasonable to presume that a mom who got a booster shortly before getting pregnant might have passed along more antibodies as well, so combining these into “all mothers who got the vaccine” is problematic.
And when the authors calculated how much fathers’ vaccinations reduced the baby’s risk of pertussis – disentangled from the mothers’ vaccination status – it only reduced the risk by 5%. So, yes, cocooning does help, but with fathers at least, it doesn’t help much. When the researchers calculated the drop in babies’ pertussis risk among mothers who got their booster pre-pregnancy, it was a 58% reduction, which isn’t far off from the 48% overall.
The fact that a mother’s pre-pregnancy Tdap has a bigger reduction than mothers’ boosters at any time (before or after pregnancy) means it offers added protection, which means that postpartum vaccination – cocooning from the mother – does also provide some protection. But I’ll bet if we removed pre-pregnancy boosters from the analysis (they didn’t have enough numbers to do this), the protective effect from a postpartum Tdap alone isn’t terribly high.
I reached out to the senior author of this study, Peter McIntyre at the University of Sydney, and he confirmed what I was seeing in this study: “We found a statistically significant reduction in pertussis risk when both parents of controls had received a Tdap dose at least one month prior to disease onset in the matched case,” he wrote to me, but this included “some mothers who were actually vaccinated before the current pregnancy, so how much of the protective effect we demonstrated is actually due to mothers who had Tdap in the last few years still having higher antibodies and passing these on to their baby – as opposed to mothers receiving vaccine after pregnancy but more than one month prior to baby being exposed (ie from reduced transmission) – is uncertain. We did not have large enough numbers to tease these two potential factors.”
He also pointed out that cocooning is looking increasingly unattractive as a policy action simply because it’s expensive and difficult to gain compliance: it requires lots of household contacts to get the booster. And he said something similar to what I’m showing here: cocooning “probably does do something but that realizing that benefit is challenging, and that it is very unlikely to add anything if mother has received vaccine in pregnancy.”
So, bottom line: if you can convince the others around your baby – dads, grandparents, other moms, nannies, etc. – to get the booster, then yes, it will help in providing a cocoon-like protective effect for your newborn, but that effectiveness has limits. The far more effective strategy (especially if combined with cocooning) is for the mother to follow CDC recommendations to get the prenatal Tdap.
And that brings us full circle to the other recent study, the one on the safety of the Tdap during pregnancy. So, let’s review what that one found in a bit more detail. It involved 123,494 live births at two California sites involved in the Vaccine Safety Datalink. Among mothers who got the Tdap during pregnancy, 6.3% had preterm delivery, compared to 7.8% among unvaccinated mothers. Further, 8.4% of vaccinated mothers and 8.3% of unvaccinated mothers had underweight (small-for-gestational-age) babies. There was no higher risk of preterm delivery, underweight babies or hypertensive disorders of pregnancy in vaccinated mothers.
However, 6.1% of vaccinated mothers and 5.5% of unvaccinated mothers had chorioamnionitis, a bacterial infection. These numbers are very similar, but there was a small (19% greater) increased risk for chorioamnionitis in vaccinated mothers. Does this mean the Tdap vaccine caused it? No. In fact, there is likely factor that could have accounted for this: 95% of the women with chorioamnionitis had an epidural, a risk factor for chorioamnionitis. But we don’t know how many of the women vaccinated or unvaccinated had an epidural (it wasn’t recorded), so the authors could not take epidural use into account.
The authors also note the results regarding chorioamnionitis “should be interpreted with caution because the magnitude of this risk was small, and we did not observe an increased risk of preterm birth, a major sequela [consequence] of chorioamnionitis.” They also write that they “are not aware of a biological mechanism for Tdap vaccination during pregnancy to increase a woman’s risk of developing clinical chorioamnionitis during delivery.” In other words, if the Tdap causes chorioamnionitis in some way, it’s unclear how that could occur.
What this study did not (and could not, with the data set they used) do was assess late-term miscarriage risk, but there is no evidence to date that that is a concern. [Updated:] In fact, a large observational study published this past July in BMJ Open (you can read the full study for free yourself) looked at wide range of pregnancy outcomes in more than 20,000 pregnant women who received the Tdap during pregnancy. That study found no increased risk of stillbirth in the two weeks after the vaccination or throughout the rest of the pregnancy in vaccinated women, compared to historical rates. There was also no evidence that vaccinated women gave birth earlier or had any increased risk of maternal death, newborn death, pre-eclampsia or eclampsia, hemorrhage, fetal distress, uterine rupture, placenta or vasa previa, C-section, low birth weight or neonatal kidney failure
Also, for those concerned about getting a Tdap in both pregnancies with only a short time in between, there is an increased risk of greater pain in the arm due to the tetanus toxoid and, in extremely rare cases, a risk of an Arthus reaction (which is very painful but goes away on its own; read more here), but there is no known additional risk. (For what it’s worth, I got the Tdap in May 2013, before I became pregnant, since I would be working in a postpartum unit, and then I got another in January 2014 when I was in my third trimester with my second son.)
So, the final word: cocooning with household contacts probably helps protect your newborn from pertussis. Getting the prenatal Tdap, which so far appears sufficiently safe, really helps.