Table 4.
Summary of findings table of GRADE-prioritised outcomes synthesised from 29 included observational studies that compared seasonal influenza vaccination (TIIV and or QIIV) to no vaccination
| Outcome no of participants (studies) |
Relative effect (95% CI) |
Anticipated absolute effects (95% CI) | Certainty | GRADE lay statement | ||
| Without seasonal influenza vaccine | With seasonal influenza vaccine | Difference | ||||
| Preterm birth (<37 completed weeks) No of participants: 152 476 (5 observational studies) |
HR 1.08 (0.89 to 1.30) |
Low baseline risk | ⨁〇〇〇 Very low*† |
The evidence is very uncertain about the effect of seasonal influenza vaccination during pregnancy on the risk of preterm birth <37 completed weeks. | ||
| 3.2% | 3.5% (2.9 to 4.2) |
0.3% more (0.3 fewer to 1 more) |
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| High baseline risk | ||||||
| 15.0% | 16.2% (13.5 to 19.4) |
1.2% more (1.5 fewer to 4.4 more) |
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| Spontaneous abortion (<20 gestational weeks) No of participants: 1900 (2 observational studies) |
HR 0.77 (0.31 to 1.89) |
Moderate baseline risk | ⨁〇〇〇 Very low‡§¶ |
Seasonal influenza vaccination during pregnancy may reduce spontaneous abortion <20 gestational weeks, but the evidence is very uncertain. | ||
| 5.0% | 3.9% (1.6 to 9.2) |
1.1% fewer (3.4 fewer to 4.2 more) |
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| Stillbirths (≥ 18–22 gestational weeks or ≥500 g) No of participants: 71 602 (2 observational studies) |
Regan et al, 2016,97 reported an adjusted HR=0.49 (0.29 to 0.84) in 58 008 pregnancies (5076 exposed and 52 932 unexposed) in a cohort study evaluating influenza vaccination at any trimester of pregnancy. In a case–control study evaluating influenza vaccination at any trimester, Panagiotakopoulos et al,116 2020 found an aOR=0.98 (0.82 to 1.18) among 1475 cases and 12 119 controls. These two studies could not be pooled due to extremely high heterogeneity (I2=82.85). | ⨁〇〇〇 Very low** |
The evidence is very uncertain about the effect of seasonal influenza vaccine during pregnancy on the risk of stillbirth ≥18–22 gestational weeks or ≥500 g. | |||
| Small-for-gestational-age birth (<10th percentile) No of participants: 297 424 (11 observational studies) |
RR 0.99 (0.95 to 1.04) |
Low baseline risk | ⨁〇〇〇 Very low†† |
Seasonal influenza vaccination during pregnancy may have little to no effect on the risk of small-for-gestational-age birth (<10th percentile for gestational age and sex of a valid reference control group), but the evidence is very uncertain. | ||
| 3.7% | 3.7% (3.5 to 3.8) |
0.0% fewer (0.2 fewer to 0.1 more) |
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| Moderate baseline risk | ||||||
| 6.0% | 5.9% (5.7 to 6.2) |
0.1% fewer (0.3 fewer to 0.2 more) |
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| High baseline risk | ||||||
| 13.6% | 13.5% (12.9 to 14.1) |
0.1% fewer (0.7 fewer to 0.5 more) |
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| Congenital anomalies from birth to 6 months of age No of participants: 4277 (one observational study) |
Single case–control study reporting adjusted findings from 2866 cases and 1411 controls, indicating no significant effect of TIIV on congenital anomalies up to 6 months of age (aOR=1.01 (0.85 to 1.21)). | ⨁〇〇〇 Very low‡‡ |
The evidence is very uncertain about the effects of seasonal influenza vaccination during the first trimester of pregnancy on the risk of congenital anomalies identified at birth or up to six months of age. | |||
| Congenital anomalies from birth to discharge No of participants: 1207 (1 observational study) |
Single cohort study found an aRR=0.33 (0.04 to 2.73), with 2 events in 141 vaccinated pregnancies and 21 events in 1066 unvaccinated pregnancies. | ⨁〇〇〇 Very low§§ |
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| Maternal serious non-obstetrical adverse events: events unrelated to pregnancy causing hospitalisation No of participants: 1051 (1 observational study) |
Single study Munoz et al,88 2005 found no apparent difference in risk between TIIV vaccinated (2 in 225) and unvaccinated women (3 in 826). | ⨁〇〇〇 Very low¶¶ |
The evidence is very uncertain regarding the effect of seasonal influenza vaccination during pregnancy on hospitalisation events within 42 days and non-obstetric SAEs, generally, for an undetermined time after vaccination. | |||
| Maternal serious non-obstetrical adverse events: not defined and time of follow-up not reported No of participants: 346 (one observational study) |
No events found in a single study Singh et al,103 2019 of 288 TIIV vaccinated and 58 unvaccinated women. | ⨁〇〇〇 Very low¶¶***††† |
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| Maternal serious non-obstetrical adverse events: inpatient Guillain-Barré syndrome No of participants: 223 898 (1 observational study) |
Single study Nordin et al,95 2013 found no significant difference between TIIV vaccinated (0 in 75 906) and unvaccinated women (1 in 147 992) (p=0.34). | ⨁〇〇〇 Very low††† |
Seasonal influenza vaccine may have little to no effect on maternal serious non-obstetrical adverse events (inpatient Guillain-Barré syndrome), but the evidence is very uncertain. | |||
GRADE working group grades of evidence: High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: ur confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
*Four of five studies scored ≥7 and the fourth scored 6; however, there were concerns regarding the representativeness of the exposed cohort (selection bias) in four studies, the adequacy of follow-up in two studies, and assessment of the exposure in one study and assessment of the outcome in two studies.
†The 95% CIs of the most heavily weighted study does not encompass the effect estimates of the three moderately weighted studies.
‡The total sample size met the criteria for optimal information size, but the total number of events did not.
§There were concerns regarding selection bias in both of the included studies.
¶Initial postpandemic study found significantly increased risk, whereas no other study found significant effects.
**Neither of the CIs of the two studies contains the other’s effect estimate.
††The p value of the Q estimate for the meta-analysis was >0.05 and two heavily weighted studies were consistent; however, most of the minimally weighted studies had point estimates that did not fall within all other confidence intervals.
‡‡Serious ROB due to inadequate case definition, the unclear representativeness of the cases and unclear non-response rate.
§§Concerns regarding biases related to selection and outcome assessment.
¶¶Total sample size is much lower than the optimal information size for the control group risk.
***Potential serious bias due to lack of reporting of follow-up time and follow-up methods in unvaccinated group, leading to potential bias for the following domains: ‘Could outcome be present at the start of study for unvaccinated women?,’ ‘Was follow-up time long enough for outcome to occur?’ and ‘Were unvaccinated women followed adequately?’.
†††Although country/countries of conduct was/were low income to middle income, the outcome shouldn't be substantially different in the Canadian context.
aOR, adjusted OR; aRR, adjusted risk ratio; GRADE, Grading of Recommendations, Assessment, Development and Evaluation; QIIV, trivalent inactivated influenza vaccine; SAE, serious adverse event; TIIV, trivalent inactivated influenza vaccine.