. 2016 Dec 9;110(10):570–581. doi: 10.1093/trstmh/trw073

Table 1.

Mortality rates and mortality rate ratios (MRR) for DTP-vaccinated and DTP-unvaccinated females; DTP as most recent vaccine and before MV (Hypothesis 1)

Study used in SAGE review¹⁷; period; age group; length of follow-up (FU); and vaccine comparison	Mortality rate per 1000 person-years (deaths/person-years) or case fatality % (deaths/cases)		MRR DTP vaccinated vs DTP-unvaccinated females	Comments; adjustments; vaccine during FU	Bias index, i.e. MRR for unvaccinated vs vaccinated children (95% CI)
Included studies	DTP-vaccinated females	DTP-unvaccinated females
Studies in which most or all DTP-unvaccinated had received BCG
In SAGE analysis: Guinea-Bissau II² 1990–96; children aged 0–6 and followed for 6 months; DTP1 (mostly after BCG) vs BCG or unvaccinated	Also BCG 4.1% (28/680)^a Only DTP 18.2% (2/11)	BCG-vaccinated 2.0 (11/544)^a Unvaccinated 4.0 (38/943)	2.31 (1.16–4.59)^a,b	Non-vaccinated likely to receive DTP during FU. Estimates similar when follow-up was censored at 9 months. VAS not given. Adjusted – see paper.	1.35 (1.0–1.9).
Excluded in SAGE analysis: Guinea-Bissau V⁴⁰ 1990–1996; Hospital case fatality; children aged 1.5–8 mo; DTP1-3 (mostly after BCG) vs BCG	17.8% (35/197)^a	BCG 12.1% (4/33)^a	1.47 (0.56–3.85)	No vaccine during FU. VAS not given.	Vaccination status defined by card at entry; hence, no unvaccinated^I
In SAGE analysis: Senegal I²⁴ 1997–2001; age 0–24 mo; DTP1 after BCG vs BCG (Table 1)	130 (10/77.0)^a	75 (162/2160.8)^a	3.55 (0.92-17.57)^b	Vaccination coverage low so other vaccines during FU were unlikely. Females with BCG=DTP1 excluded. VAS not given. Adjustment: Age, season, health centre.	1.48 (1.2–1.8).
Excluded in SAGE analysis: Guinea-Bissau IV²⁵ Case fatality during 3 months of war (1998), 1.5–6 months; DTP1-3 vs no DTP (mostly BCG vaccinated)	6.1% (14/228)^a	2.9% (1/35)^a	2.33 (0.14–39.17)^b	Vaccine unlikely during FU due to war. VAS not given.	0.67 (0.1–5.4)^II
In SAGE analysis: Malawi²⁶ 1995–1997; mortality between 1 week and 8 months; monthly anthropometrics; only children present; DTP1 (mostly after BCG) vs no DTP (BCG vaccinated)	198 (10/50.4)	No DTP 87 (6/68.9)	5.44 (0.88-33.7)^a,b	Vaccines unlikely during FU with one month FU. Adjusted age, HIV status of mother VAS probably not given.	1.45 (0.7–3.2).
In SAGE analysis: Guinea-Bissau III²⁷ 2004–2008; LBW cohort; vaccination status at 2 month FU to 6 month^c DTP1-2 after BCG vs BCG	115 (13/113.3)^a	BCG 34 (2/58.1)^a	7.18 (1.53–33.7)^a,b	Only BCG-arm of study with BCG first and then DTP. DTP unvaccinated children likely to receive DTP during FU. Some may have received NVAS. Adjusted age, MUAC.	1.45 (0.7–3.2).
In SAGE analysis: India II⁶ 1998–2001; 1 week to 5 months; NVAS trial DTP and BCG vs BCG			2.52 (1.04–6.09)^b	A few may have received BCG and DTP simultaneously. SAGE used the estimate for all children (both NVAS and placebo recipients). If restricted to placebo recipients the MRR was 3.15 (0.95–10.46). Since the difference is small we have maintained estimate used by SAGE.	1.38 (0.8–2.3).
Excluded studies
Studies in which DTP-unvaccinated had mostly not received BCG
In SAGE analysis: Guinea-Bissau²³ 1984–87: age 2–8 mo; FU 6 mo; DTP1-3 versus unvaccinated (few BCG vaccinated)	126 (27/215.0)	NA	2.34 (1.04-5.27)^a,b	Controls were unvaccinated. Not likely to receive other vaccines during FU. Adjustment: age, sex, season, BCG, region, period, BCG. VAS not given.	0.49 (0.3–0.9)^III
Studies in which most or all DTP–unvaccinated had received BCG
In SAGE analysis: Bangladesh I^8,31 1985–1999; 6 weeks to 8 months DTP after BCG vs BCG only	31 (13/416)^a	77 (34/440)^a	0.36 (0.18–0.72)^a		3.40 (2.9–3.9)^I,V
In SAGE analysis: Burkina Faso⁷ 1985–1993; vaccination status at first visit and 6 months FU DTP and BCG vs BCG only	51 (15/295)^a	64 (16/251)^a	0.81 (0.39–1.66)		2.29 (1.7–3.0)^V
In SAGE analysis: Papua New Guinea⁴ 1989–1994; 4 weeks to 5 months DTP after BCG vs BCG only	13 (4/309)^a	26 (4/155)^a	0.50 (0.13–2.01)		7.52 (5.2–11.0)^V,I Very high mortality in unvaccinated.
Excluded in SAGE analysis: India I²¹ 2006–2011; 6 weeks to 8 months; DTP after BCG vs BCG only	29 (73/2523)^a	78 (19/245)^a	0.37 (0.22–0.62)		6.82 (4.4–10.5). Very high mortality in unvaccinated.
Excluded in SAGE analysis: Philippines²² 1988–1991; 0–30 months BCG+DTP vs BCG only	Data not presented in paper		0.96 (0.26–5.15)		MRR(unvaccinated/vaccinated) could not be calculated because the study only included children who had received BCG 63% received BCG and DTP simultaneously so this study did not compare DTP after BCG versus BCG.

DTP: diphtheria-tetanus-pertussis; FU: follow-up; LBW: low birth weight; MRR: mortality rate ratio; MUAC: mid-upper-arm-circumference; MV: measles vaccination; NA: not applicable; NVAS: neonatal vitamin A supplementation; SAGE: Strategic Advisory Group of Experts on Immunization; VAS: vitamin A supplementation.

The SAGE review had 16 studies of DTP; 5 studies mentioned in the table were excluded because they had survival and frailty bias with a bias index higher than 2.0; 4 studies, India,³⁰ Ghana,⁴⁴ Ghana⁴⁵ and Benin⁴⁶ had no information on sex. The Roman numerals are used when there are several studies from the same country; the same numerals have been used in a previous analysis of the SAGE review of DTP.¹⁹

^a Estimate or numbers are in the paper; & calculated by the person responsible for the data set.

^b Estimate reported in the SAGE review.¹⁷

^c Estimate for BCG is from a randomised comparison of BCG at birth versus BCG later (as currently recommended for LBW children). The estimate is only from the BCG at birth arm of the trial because most children in the control groups received BCG and DTP simultaneously or closely spaced.

I: Guinea-Bissau V was not included in the SAGE review. This study is not overlapping with any of the other studies included in the SAGE review. The bias index could not be assessed because all children had been vaccinated. The study included children sick enough to be admitted to hospital, so inclusion depended on degree of illness and not vaccination status. This is a strong version of a case-control study where the population is children admitted to hospital, so it is a far more robust design than the Benin case-control study that was included in the SAGE review. There is no reason to suspect that high-risk children who had received DTP or low-risk children who had not received DTP were more likely to be admitted. Note that community-based studies are also a sample because not all children are seen, and the reason for not being seen is often linked to vaccination status (for example, did not attend clinic or away travelling), whereas admission is very unlikely to have been linked to vaccination status in this study. We therefore included the study in our review. The hospital case fatality study included a few readmissions, as 6% (12/185) had been admitted more than once with DTP as their last vaccination; the similar figure is not reported for the BCG group. Hence, it was not possible to make the comparison for only the last admission. However, this is unlikely to have exaggerated the results as there were probably fewer readmissions with BCG as last vaccination because BCG-vaccinated children will become eligible for DTP-vaccination shortly after being discharged. Hence, the DTP/no-DTP estimate in this study is likely to be conservative.

II: Guinea-Bissau IV was not included in the SAGE review. This study is not overlapping with any of the other studies included in the SAGE review. The study has a bias index of only 0.7. Due to war in Guinea-Bissau in 1998, routine immunisation was suspended and DTP was not given when it was due. Whether a child received DTP or not depended on the war and not on factors that may be associated with the health of the child (such as attendance at clinic, or too ill to vaccinate) as in most cohort study or case-control study. This is not a typical cohort study, and many of the criteria used to assess bias in cohort studies do not apply. Virtually all children were vaccinated with BCG. We therefore included the study in our review.

III: This study was included in the SAGE review. However, since the DTP-unvaccinated children were mostly not BCG-vaccinated the study is not included in the testing of Hypothesis 1.

IV: In the Bangladesh study ‘unvaccinated’ was the default classification - no child was excluded for lack of information, and ‘unvaccinated’ was not verified by inspection of the vaccination card or interview. Consequently, children who were vaccinated and died may have been incorrectly coded as unvaccinated if vaccination was not documented before death (for example, because of travel). Similarly, some children who died after receiving DTP may not have had DTP vaccination registered, which would make mortality too high in the no-DTP group and too low in the DTP group. We have therefore not included the study in our review.

V: In Burkina Faso, when the vaccination card was not seen, the child was assumed to be unvaccinated; as in Bangladesh, children who had been given DTP and died may therefore have been incorrectly classified as unvaccinated. According to the authors 54% of follow-up time (72938 person-months) was assigned to unvaccinated, 11% (14238 person-months) to BCG, 3% (3411 person-months) and 33% (44515 person-months) to BCG and DTP (Table 3).⁵ Hence, a large proportion of children received DTP with BCG. First, administration with BCG is likely to reduce harm from DTP. Second, the hypothesis being tested is the effect of DTP given after BCG. Hence, mortality was over-estimated in the no-DTP group and under-estimated in the DTP group, and it is impossible to deduce who received DTP after BCG. We have therefore not included the study in our review.

VI: PNG study performed in Tari has extraordinarily high frailty bias (and perhaps survival bias), and this is reflected in its very high bias index of 7.5. The 1-5 month mortality rate in unvaccinated children was 233 per 1000 person-years, a staggeringly high rate for this community, compared to only 30.9 in vaccinated children. At the time of the study, infant (0-12 month) mortality in Tari was only 68 per 1000 live births,⁴ so 1-11 month mortality was probably around 34 per 1000 as approximately 50% of infant deaths are before 1 month of age in these circumstances. Frailty bias occurred in the PNG study because vaccines were given only at health centres⁴ and health centres were instructed not to vaccinate sick children. In addition, the SAGE review used an estimate from this study for DTP where, among children aged 1-5 months who got DTP (Table 3), only 69% got DTP after BCG (2185/3153); 22% (686/3153) got DTP before or with BCG - which biases the estimate in favour of DTP. BCG is purported (implausibly) to reduce infant mortality by 83% in this study. Frailty bias very strongly influenced the MRR for both BCG and DTP because both vaccinations were delayed in frail children. We have therefore not included the study in our review.