Results (
Thai) 2:
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Infant outcome
Five neonatal outcomes are summarised in Table 3. The
stillbirth rate was lower after maternal vaccination than
among the two control groups. This was also seen for
the rate of preterm birth and low birthweight but not
for SGA or for congenital malformations registered in
the Medical Birth Register. When the analysis of congenital
malformations was repeated restricted to vaccinations
between weeks 1 and 9, still no increased risk was seen
(OR 0.93, 95% CI 0.81–1.22, based on 54 malformed
infants among 1729 exposed infants).
When the analysis was repeated comparing vaccinated
women with women who had given birth during 2009 but
before 1 May (when influenza reached Sweden), a similar
OR was obtained.
When an analysis was made restricted to women with
known vaccination week and with comparisons with
nonvaccinated women who were still pregnant in that
week, all ORs increased and were no longer significantly
<1.0. For stillbirths the OR = 0.95 (95% CI 0.69–1.22).
for preterm birth among singletons OR = 0.96 (95% CI
0.88–1.05), for low birthweight in singletons OR = 0.96
(95% CI 0.87–1.07), and for SGA OR = 1.05 (95% CI
0.94–1.18). When the data were divided into three
groups according to the timing of vaccination, an effect
on the risk of preterm birth was seen only when vaccination
was made after week 26 (Table 4). The preterm rates in the three groups differed significantly (chi-square
for 2 df 13.8, P = 0.001).
In counties with a high registered vaccination rate
(>10%), the OR for preterm birth was 0.84 (95% CI 0.76–
0.94) and in counties with a low registered vaccination rate
(<10%) the OR was 0.93 (95% CI 0.79–1.12).
Among all women who were vaccinated during pregnancy
between weeks 27 and 36, 89% gave birth during the period
November 2009 to February 2010. These 4 months show the
highest rates of preterm birth in the population (around
5.4%, yearly average 4.9%) and when the rate of preterm
birth among vaccinated women was studied with a restriction
to these 4 months, the OR was even lower: 0.54 (95%
CI 0.45–0.65) when compared with nonvaccinated women.
The diagnoses among the 201 malformed infants identified
from the data ascertained from multiple health
registers (see Methods) are shown in Supplementary material,
Table S1 The distribution of malformations shows no unusual feature but there are five infants with orofacial
clefts, the mothers of three of these children were vaccinated
during weeks 7–9, which is when the face is formed,
the other two during week 11. The mothers of the infants
with oesophageal or ilial atresia were vaccinated during
weeks 8–9, slightly late for a causal association.
Risk analyses for subgroups of malformations identified
no statistically significant excess risk (Table 5). The highest
estimate concerned ventricular and atrial septum defects
but this estimate was also far from statistically significant.
Most infants (84%, n = 2643) exposed in the first trimester
to maternal Pandemrix vaccination were born during
May to July 2010. The risk for a ‘relatively severe malformation’
among these infants was 0.88 (95% CI 0.72–1.09).
After exclusion from the analysis of women who were
born outside Sweden, only small changes in OR estimates
occurred but the low OR for stillbirths when compared
with women belonging to the prevaccination group lost
statistical significance.
Discussion
This is one of the largest published studies of delivery outcome
after vaccination against H1N1 during pregnancy.
Most previous publications are based on much smaller samples.
Among 130 pregnancies in a Scottish study, there were
four miscarriages and six possible congenital malformations.
2 A French study identified 569 pregnant women who
were vaccinated with a nonadjuvant H1N1 vaccine (Panenza,
Sanofi Pasteur, Lyon, France) and found no adverse effects.3
A US prospective study of 261 pregnancies where vaccination
for an AS03-adjuvant split virion H1N1 had been performed
found a normal delivery outcome.4 A Taiwan study
analysed 198 pregnancies (202 infants) where the women
had been vaccinated with an adjuvant-free vaccine (Adim-
Flu-S, Adimmune Corp., Tanzih Township, Taiwan) without
finding any signs of adverse pregnancy effects.5
Only one vaccine had been used in our study, Pandemrix,
and the results may not be relevant for other vaccines.
Pandemrix contains both an adjuvant (squalene) and a preservative
(thiomersale).
The advantage with this study is, in addition to the large
number of women, the use of health registers which makes
it possible to study characteristics of the vaccinated women
and adjust for putative confounders, and to ascertain outcome
in an unbiased way.
The study has not identified all vaccinated women.
When comparisons are made with deliveries that occurred
after the start of the mass vaccination (October 2009),
some women who are regarded as nonvaccinated will in
fact have been vaccinated. This will bias the estimated ORs
towards unity, which was also seen when the OR for preterm
birth was compared between counties with a high (OR = 0.84) and a low (OR = 0.93) registered vaccination rate. To avoid this fallacy, we also made comparisons with
women who had given birth during 2009 before October
and therefore were most certainly not vaccinated for H1N1
influenza during pregnancy. Some may have had vaccination
for seasonal influenza, however. The estimated two
ORs were in most instances similar even though a tendency
can be seen that the ORs based on comparisons with ‘nonvaccinated’
women deviate slightly more from 1.0 than the
ORs based on comparisons with women delivered before
October 2009.
We found no effect on congenital malformation rate
after vaccination and the low stillbirth rate after vaccination
could be random but agrees with the results in a
recent Danish study.7 The risk of preterm birth (and therefore
also of low birthweight) is significantly lower than 1.0
after vaccination during pregnancy. This analysis was
restricted to deliveries where the vaccination had been
made before 37 weeks of gestation because if made later, it
could not cause a preterm delivery. No effect was seen on
intrauterine growth restriction or SGA. Further analyses
showed that the effect of the vaccination on preterm birth
was only seen when it was given after 26 weeks of gestation
and that it was not the result of the temporal pattern of
vaccinations, which could have confounded the analysis. A
similar effect was seen in a study of maternal influenza
immunisation (not against H1N1) with an OR of the same
order of magnitude as that found by us.14
Different alternative explanations can be discussed for
the finding of a better than expected delivery outcome after
vaccination with regard to preterm birth and low birthweight.
It could be an effect of uncontrolled confounding,
for instance, from socio-economic conditions. It could be
that a high socio-economic standard increased the probability
of vaccination and decreased the probability of preterm
birth. Two facts speak against this explanation. One is
that practically no association was seen between maternal
smoking and vaccination rate, and maternal smoking is in
Sweden today strongly associated with a less advantageous
socio-economic level. The second fact is that the effect on
preterm birth was only seen when vaccination was performed
after 26 weeks of gestation. Had the effect been a
result of undetected confounding by socio-economic
factors, one would expect similar effects of vaccination
irrespective of the timing during pregnancy.
Another explanation of the ‘protective’ effect of vaccination
could be that vaccination had been avoided in pregnancies
showing pathological features, which could favour
preterm birth. One such mechanism could be pre-eclampsia,
but pre-eclampsia was not associated with a low vaccination
rate. The only maternal morbidity that was
associated with a reduced vaccination rate was pre-existing
(but not gestational) diabetes. On the other hand, chronic
lung disease was (as expected) associated with a somewhat
increased vaccination rate but maternal asthma, if anything,
increases the risk for preterm birth.15
Some women will have had influenza during pregnancy,
mainly those who had not been vaccinated. If maternal
influenza increased the risk for preterm birth, it could
explain the significantly low risk after vaccination when
comparison was made with nonvaccinated women who
gave birth after September 2009. Also, among women who
gave birth during 2009 before October 2009 influenza may
have occurred. When the analysis was repeated comparing
vaccinated women with women who had given birth before
May 2009 (when the H1N1 influenza reached Sweden), the
same low OR was found, however.
A direct effect of the vaccination must be considered.
One possibility is that the immune reaction induced by the
vaccination somehow reduced the risk for rejection of the
fetus. A substantial part of noniatrogenic preterm deliveries
are associated with signs of anti-fetal rejection.16 This
would agree with the fact that a protective effect is only
seen towards the end of the pregnancy (after 26 weeks of
gestation) but this mechanism of action is speculative.
Inflammatory responses to trivalent influenza vaccine
among pregnant women have been described that were
suggested to be beneficial for pregnancy outcome.17
The observed effect could, however, also be obtained if
vaccination before 22 weeks of gestation increased the risk
for spontaneous abortion in pregnancies that were at risk for
preterm birth (and stillbirth), e.g. as the result of placental
insufficiency. This is an unlikely explanation as vaccination
before week 27 did not seem to affect preterm rates.
The number of women who were vaccinated before the
end of the first trimester was only somewhat more than
3000 but among their infants no indication was noted of
an increased risk for a congenital malformation. This
observation is limited by the absence of data
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