Penta is associated with an increased female-male mortality ratio: cohort study from Bangladesh

Human Vaccines and Immunotherapeutics, Volume 17, No. 1, Year 2021

Interpretation

Diphtheria-tetanus-pertussis (DTP) vaccine may be associated with excess female deaths. There are few studies of possible nonspecific effects of the DTP-containing vaccine Penta (DTP-hepatitis B-Haemophilus influenzae type b). We therefore investigated whether Penta vaccinations were associated with excess female deaths in rural Bangladesh. Between June 29, 2011 and April 20, 2016, we examined the mortality rates of 7644 children followed between 6 weeks and 9 months of age. We analyzed mortality using crude mortality rate ratio (MRR) and age-adjusted MRR (aMRR) from a Cox proportional hazards model. Mortality was analyzed according to sex, number of doses of Penta, and the order in which BCG and Penta were administered. During follow-up, 43 children died. For children who were only BCG vaccinated (BCG-only), the adjusted F/M MRR was 0.47 (0.09–2.48). However, among children who had Penta as their most recent vaccination, the adjusted F/M MRR was 9.91 (1.16–84.44). Hence, the adjusted F/M MRR differed significantly for BCG-only and for Penta as the most recent administered vaccination. Although the mortality rate was low in rural Bangladesh, there was a marked difference between adjusted F/M MRR’s for children vaccinated with BCG-only compared with children where Penta was the most recent administered vaccination. Although usually ascribed to differential treatment and access to care, DTP-containing vaccines may be part of the explanation for the excessive female mortality reported in some regions. International Center for Diarrheal Diseases Research, Bangladesh (icddr,b) runs a Health and Demographic Surveillance System (HDSS) in Chakaria. The HDSS covers a population of 90,000 individuals living in 16,000 households in 49 villages. All households are visited every three months to enquire about marriages, pregnancies, births, migrations, and deaths. The expanded program on immunization (EPI) provides services in the HDSS areas through 95 EPI outreach centers. Vaccines are given as recommended by WHO: BCG at birth, Penta and Oral polio vaccine (OPV) in three doses at 6, 10, and 14 weeks of age, followed by MV at 9 months of age. Information on vital status and vaccinations of children below 3 years of age was collected during household visits every 3 months. Lower respiratory infection (LRI) and diarrhea are the leading causes of morbidity and under-5 mortality for children in the Chakaria HDSS area.18,19 BCG is protective against disseminated TB in childhood and the single shot of Penta provides protection to children from five life-threatening diseases: diphtheria, pertussis (whooping cough), tetanus, hepatitis B, and haemophilus influenzae Type b (Hib). The incidence of these vaccine preventable infections is low among children below five years of age in Chakaria. During 2010–2012, only 2 pertussis, 8 meningitis, and 2 measles infection related deaths were reported among children less than five years of age. Hence, the mortality rates per 100,000 person-years (MR) were 7 for pertussis, 29 for meningitis, and 7 for measles infection among children less than five years of age.19 It should be noted that studies have reported that females are neglected in seeking medical care among under-five children,20,21 even for free immunization22. The study was conducted between June 29, 2011 and April 20, 2016. Children were categorized according to the sequence in which they received BCG and Penta vaccines. We defined 11 mutually exclusive vaccine-sequence categories (Group I–XI) of children’s hitherto administered BCG and Penta vaccinations. Vaccination sequences could be initiated in three ways: (1) the WHO recommended schedule: BCG-first and then three doses of Penta denoted Penta1-3 (Group I–IV); (2) BCG+Penta1 administered simultaneously first and then Penta2-3 (Group V–VII); and (3) Penta1-first followed by Penta2-3 with BCG administered together with Penta2 or Penta3 (Group VIII–XI). In addition, we defined the two categories “documented no vaccination” (unvaccinated) and “have card but not seen” when the family reported possession of vaccination card but was unable to show card to the interviewer. We furthermore focused on three broader, still mutually exclusive groups: BCG-only (Group I), Penta-vaccinated, i.e., Penta as the most recent administered vaccination (Group II–IV and VI–X), and “documented no vaccination.” Children who had only received “BCG and Penta1 simultaneously” (Group V) and the children who received “Penta1 followed by BCG” (Group-XI) were not included in the Penta-vaccinated group. This was because receiving BCG and DTP simultaneously has been associated with decreased mortality.2,12,16 We also compared the mortality between children who started vaccination according to the WHO recommended schedule ((BCG-first-then-Penta) (Group I–IV)) and children who started their vaccination schedule with BCG and Penta administered simultaneously (Group V–VII). The pneumococcal vaccine (PCV) and inactivated polio vaccine (IPV) were introduced on March 21, 2015 in Chakaria and the IPV was administered with PCV3. Therefore, we restricted our study to children who were born before February 9, 2015. Information on vaccinations and deaths was collected retrospectively through trimonthly visits to each household. Vaccinations of dead children are likely to be underreported because parents tend not to keep the vaccine card of a deceased child; even if they do keep the card, they may be reluctant to show the card to the interviewer. In such situations, using retrospectively updated information likely misclassifies some vaccinated deceased children as unvaccinated, resulting in excess deaths in the unvaccinated group. Furthermore, vaccinated children who survive will contribute to a time-to-event analysis with risk-free survival time because they survived up to the next visit. Hence, using the retrospective updating approach to measure the effect of vaccination can introduce survival bias23–25 which can distort the estimated effect of vaccinations. We therefore used a “landmark approach”23–25 to measure the impact of vaccination status on mortality. Depending on the specific analysis reported, we define vaccination status as either the vaccination sequence administered hitherto or the most recent administered vaccination. In the landmark approach, the vaccination status is fixed from the household visit until the date of the next visit when the vaccination card is seen again. Vaccination status changes with visit; hence, children could, e.g., contribute with unvaccinated risk-time after the first visit and vaccinated risk-time after the second visit. We limited the study to children aged 6 weeks (Penta1 is scheduled at 6 weeks) to 9 months of age (MV is scheduled at 9 months of age). Children who were visited only once were excluded from the present study (N = 144; Figure 1) because we could not follow these children for mortality between 6 weeks and 9 months of age. Children with no information about vaccination status at any visit were also excluded (N = 30). Furthermore, we excluded children who were not born in the HDSS area (N = 110) because mothers could not accurately report date of birth and date of vaccinations. Flowchart of study population We used Cox proportional hazards models with age as the underlying time-scale to estimate adjusted MRRs (aMRR) of different hitherto administered vaccination sequences for both boys and girls. Children were followed from 6 weeks of age until migration, death, or 9 months of age, whichever occurred first. We included parity, maternal age, maternal education, season of birth, and village as potential confounders in the adjusted models. To assess the sex-differential effects of different sequences of BCG and Penta vaccinations on mortality, an interaction between sex and hitherto administered sequence of BCG and Penta were included in the adjusted Cox proportional hazards models. To test the sex-differential effects according to whether Penta1, Penta2, or Penta3 were the most recent administered vaccination, we conducted a log-rank test.

AI Digest

Study Justification:

The study aimed to investigate whether the Penta vaccine, which contains diphtheria-tetanus-pertussis (DTP) and other components, is associated with excess female deaths in rural Bangladesh. This is important because previous studies have suggested that the DTP vaccine may be linked to higher mortality rates among females. Understanding the potential nonspecific effects of the Penta vaccine is crucial for improving vaccination strategies and reducing gender disparities in mortality.

Study Highlights:

– The study analyzed the mortality rates of 7644 children in rural Bangladesh between 6 weeks and 9 months of age.
– Mortality rates were compared based on the sex of the children, the number of doses of Penta vaccine received, and the order in which BCG and Penta vaccines were administered.
– Among children who had Penta as their most recent vaccination, there was a significantly higher female-male mortality ratio compared to children who were only BCG vaccinated.
– The findings suggest that DTP-containing vaccines, such as Penta, may contribute to the excessive female mortality reported in some regions.

Recommendations for Lay Readers:

– The study findings indicate a potential association between the Penta vaccine and higher mortality rates among females in rural Bangladesh.
– Further research is needed to confirm these findings and understand the underlying mechanisms.
– Policymakers and healthcare providers should consider the potential gender-specific effects of vaccines when designing vaccination programs.
– Efforts should be made to ensure equal access to healthcare and vaccination services for both males and females.

Recommendations for Policy Makers:

– The study highlights the need to investigate and address the potential gender-specific effects of vaccines, particularly the DTP-containing Penta vaccine.
– Vaccine policies and strategies should be reviewed to ensure they do not contribute to gender disparities in mortality.
– Further research should be conducted to understand the reasons behind the observed gender differences and develop interventions to mitigate any negative effects.
– Collaboration between health authorities, researchers, and vaccine manufacturers is essential to monitor and improve the safety and effectiveness of vaccines.

Key Role Players:

– Researchers and epidemiologists to conduct further studies and analyze data on vaccine safety and gender-specific effects.
– Health authorities and policymakers to review and update vaccination policies based on research findings.
– Healthcare providers to ensure equal access to vaccination services for all children, regardless of gender.
– Community leaders and educators to raise awareness about the importance of vaccination and address any concerns or misconceptions.

Cost Items for Planning Recommendations:

– Research funding for conducting further studies on vaccine safety and gender-specific effects.
– Budget allocation for monitoring and surveillance systems to track vaccination coverage and adverse events.
– Resources for training healthcare providers on gender-sensitive vaccination practices.
– Investments in community engagement and education programs to promote vaccination and address vaccine hesitancy.
– Support for the development and implementation of targeted interventions to reduce gender disparities in healthcare access and outcomes.

Strength of Evidence

The strength of evidence for this abstract is 8 out of 10.
The evidence in the abstract is strong, but there are some areas for improvement. The study design is a cohort study, which is a robust method for investigating associations. The study population is large, with 7644 children included. The mortality rates were analyzed using a Cox proportional hazards model, which is appropriate for this type of analysis. The adjusted mortality rate ratio (MRR) for children who had Penta as their most recent vaccination compared to BCG-only vaccinated children was 9.91 (1.16–84.44), indicating a significant difference. However, there are a few areas that could be improved. First, the abstract does not provide information on potential confounders that were adjusted for in the analysis. Including information on the variables adjusted for would strengthen the evidence. Second, the abstract does not mention any limitations of the study, such as potential biases or sources of error. Including a discussion of limitations would provide a more balanced assessment of the evidence. Finally, the abstract does not mention any implications or recommendations based on the findings. Providing actionable steps for further research or public health interventions would enhance the usefulness of the evidence.

Abstract

International Center for Diarrheal Diseases Research, Bangladesh (icddr,b) runs a Health and Demographic Surveillance System (HDSS) in Chakaria. The HDSS covers a population of 90,000 individuals living in 16,000 households in 49 villages. All households are visited every three months to enquire about marriages, pregnancies, births, migrations, and deaths. The expanded program on immunization (EPI) provides services in the HDSS areas through 95 EPI outreach centers. Vaccines are given as recommended by WHO: BCG at birth, Penta and Oral polio vaccine (OPV) in three doses at 6, 10, and 14 weeks of age, followed by MV at 9 months of age. Information on vital status and vaccinations of children below 3 years of age was collected during household visits every 3 months. Lower respiratory infection (LRI) and diarrhea are the leading causes of morbidity and under-5 mortality for children in the Chakaria HDSS area.18,19 BCG is protective against disseminated TB in childhood and the single shot of Penta provides protection to children from five life-threatening diseases: diphtheria, pertussis (whooping cough), tetanus, hepatitis B, and haemophilus influenzae Type b (Hib). The incidence of these vaccine preventable infections is low among children below five years of age in Chakaria. During 2010–2012, only 2 pertussis, 8 meningitis, and 2 measles infection related deaths were reported among children less than five years of age. Hence, the mortality rates per 100,000 person-years (MR) were 7 for pertussis, 29 for meningitis, and 7 for measles infection among children less than five years of age.19 It should be noted that studies have reported that females are neglected in seeking medical care among under-five children,20,21 even for free immunization22. The study was conducted between June 29, 2011 and April 20, 2016. Children were categorized according to the sequence in which they received BCG and Penta vaccines. We defined 11 mutually exclusive vaccine-sequence categories (Group I–XI) of children’s hitherto administered BCG and Penta vaccinations. Vaccination sequences could be initiated in three ways: (1) the WHO recommended schedule: BCG-first and then three doses of Penta denoted Penta1-3 (Group I–IV); (2) BCG+Penta1 administered simultaneously first and then Penta2-3 (Group V–VII); and (3) Penta1-first followed by Penta2-3 with BCG administered together with Penta2 or Penta3 (Group VIII–XI). In addition, we defined the two categories “documented no vaccination” (unvaccinated) and “have card but not seen” when the family reported possession of vaccination card but was unable to show card to the interviewer. We furthermore focused on three broader, still mutually exclusive groups: BCG-only (Group I), Penta-vaccinated, i.e., Penta as the most recent administered vaccination (Group II–IV and VI–X), and “documented no vaccination.” Children who had only received “BCG and Penta1 simultaneously” (Group V) and the children who received “Penta1 followed by BCG” (Group-XI) were not included in the Penta-vaccinated group. This was because receiving BCG and DTP simultaneously has been associated with decreased mortality.2,12,16 We also compared the mortality between children who started vaccination according to the WHO recommended schedule ((BCG-first-then-Penta) (Group I–IV)) and children who started their vaccination schedule with BCG and Penta administered simultaneously (Group V–VII). The pneumococcal vaccine (PCV) and inactivated polio vaccine (IPV) were introduced on March 21, 2015 in Chakaria and the IPV was administered with PCV3. Therefore, we restricted our study to children who were born before February 9, 2015. Information on vaccinations and deaths was collected retrospectively through trimonthly visits to each household. Vaccinations of dead children are likely to be underreported because parents tend not to keep the vaccine card of a deceased child; even if they do keep the card, they may be reluctant to show the card to the interviewer. In such situations, using retrospectively updated information likely misclassifies some vaccinated deceased children as unvaccinated, resulting in excess deaths in the unvaccinated group. Furthermore, vaccinated children who survive will contribute to a time-to-event analysis with risk-free survival time because they survived up to the next visit. Hence, using the retrospective updating approach to measure the effect of vaccination can introduce survival bias23–25 which can distort the estimated effect of vaccinations. We therefore used a “landmark approach”23–25 to measure the impact of vaccination status on mortality. Depending on the specific analysis reported, we define vaccination status as either the vaccination sequence administered hitherto or the most recent administered vaccination. In the landmark approach, the vaccination status is fixed from the household visit until the date of the next visit when the vaccination card is seen again. Vaccination status changes with visit; hence, children could, e.g., contribute with unvaccinated risk-time after the first visit and vaccinated risk-time after the second visit. We limited the study to children aged 6 weeks (Penta1 is scheduled at 6 weeks) to 9 months of age (MV is scheduled at 9 months of age). Children who were visited only once were excluded from the present study (N = 144; Figure 1) because we could not follow these children for mortality between 6 weeks and 9 months of age. Children with no information about vaccination status at any visit were also excluded (N = 30). Furthermore, we excluded children who were not born in the HDSS area (N = 110) because mothers could not accurately report date of birth and date of vaccinations. Flowchart of study population We used Cox proportional hazards models with age as the underlying time-scale to estimate adjusted MRRs (aMRR) of different hitherto administered vaccination sequences for both boys and girls. Children were followed from 6 weeks of age until migration, death, or 9 months of age, whichever occurred first. We included parity, maternal age, maternal education, season of birth, and village as potential confounders in the adjusted models. To assess the sex-differential effects of different sequences of BCG and Penta vaccinations on mortality, an interaction between sex and hitherto administered sequence of BCG and Penta were included in the adjusted Cox proportional hazards models. To test the sex-differential effects according to whether Penta1, Penta2, or Penta3 were the most recent administered vaccination, we conducted a log-rank test.

Materials

N/A

Innovations

Based on the information provided, it seems that the study is focused on investigating the potential association between Penta vaccinations and excess female deaths in rural Bangladesh. The study analyzes mortality rates of children who received different sequences of BCG and Penta vaccinations. The goal is to understand if there is a difference in mortality rates based on the vaccination sequence and whether this could contribute to the excessive female mortality reported in some regions.

In terms of potential innovations to improve access to maternal health, it is important to consider the findings of this study. If there is indeed an association between Penta vaccinations and excess female deaths, it highlights the need for further research and interventions to address this issue. Some potential recommendations for innovation could include:

1. Conducting further research: More studies should be conducted to confirm the findings of this study and understand the underlying reasons for the potential association between Penta vaccinations and excess female deaths. This could involve larger sample sizes, different populations, and more comprehensive data collection.

2. Vaccine safety monitoring: Implementing a robust vaccine safety monitoring system to closely monitor the potential adverse effects of Penta vaccinations, particularly in relation to gender-specific outcomes. This could involve regular surveillance, data collection, and analysis to identify any patterns or trends.

3. Gender-sensitive vaccination strategies: Developing vaccination strategies that take into account potential gender-specific effects. This could involve considering the timing and sequence of vaccinations, as well as any potential interactions with other factors that may contribute to gender disparities in health outcomes.

4. Improving access to maternal health services: Strengthening healthcare systems and infrastructure to ensure equitable access to maternal health services, including vaccinations. This could involve improving transportation, increasing the availability of healthcare facilities, and addressing cultural and social barriers that may prevent women from accessing these services.

5. Health education and awareness: Increasing awareness and education about maternal health, vaccinations, and potential gender-specific effects. This could involve community outreach programs, health campaigns, and targeted messaging to ensure that women and their families are informed and empowered to make informed decisions about their health.

It is important to note that these recommendations are based on the information provided in the study and should be further explored and evaluated in consultation with healthcare professionals, researchers, and policymakers.

AI Innovations Description

Based on the information provided, the recommendation to improve access to maternal health would be to conduct further research and investigation into the potential association between Penta vaccinations and excess female deaths. This would involve conducting comprehensive studies in different regions to determine if there is a consistent pattern of increased female mortality associated with the Penta vaccine. Additionally, it would be important to investigate the underlying factors contributing to this potential gender disparity, such as differential treatment and access to care for females. The findings from these studies can then be used to inform policy and programmatic interventions aimed at reducing maternal mortality and improving access to maternal health services.

AI Innovations Methodology

To improve access to maternal health, here are some potential recommendations:

1. Mobile Health (mHealth) Solutions: Utilize mobile technology to provide maternal health information, reminders for prenatal care appointments, and access to telemedicine consultations.

2. Community Health Workers: Train and deploy community health workers to provide education, support, and basic maternal health services in remote or underserved areas.

3. Telemedicine: Implement telemedicine platforms to connect pregnant women in rural areas with healthcare providers for prenatal check-ups and consultations.

4. Maternal Health Vouchers: Introduce voucher programs that provide financial assistance for maternal health services, including prenatal care, delivery, and postnatal care.

5. Transportation Support: Develop transportation initiatives to ensure pregnant women can easily access healthcare facilities, especially in remote areas.

To simulate the impact of these recommendations on improving access to maternal health, a methodology could include the following steps:

1. Define the target population: Identify the specific demographic and geographic characteristics of the population that would benefit from the recommendations.

2. Collect baseline data: Gather data on the current access to maternal health services, including the number of pregnant women receiving prenatal care, the distance to healthcare facilities, and any existing barriers to access.

3. Develop a simulation model: Create a mathematical or computational model that simulates the impact of the recommendations on improving access to maternal health. This model should consider factors such as population size, geographical distribution, healthcare infrastructure, and resource availability.

4. Input data and parameters: Input the baseline data and parameters into the simulation model, including the number of pregnant women, the locations of healthcare facilities, and the expected impact of each recommendation.

5. Run simulations: Run multiple simulations using different scenarios and assumptions to assess the potential impact of the recommendations on improving access to maternal health. This could include varying factors such as the number of community health workers deployed, the coverage of mobile health services, or the availability of transportation support.

6. Analyze results: Analyze the simulation results to determine the potential impact of the recommendations on improving access to maternal health. This could include measuring changes in the number of pregnant women receiving prenatal care, reductions in travel time to healthcare facilities, or improvements in maternal health outcomes.

7. Refine and validate the model: Continuously refine and validate the simulation model based on real-world data and feedback from stakeholders. This will ensure the accuracy and reliability of the model’s predictions.

By following this methodology, policymakers and healthcare providers can assess the potential effectiveness of different innovations and make informed decisions on how to improve access to maternal health.

Author

Dima Health

Statistics:

Citations: 3

Identifiers:

DOI: 10.1080/21645515.2020.1763084

ISSN: 21645515

Research Areas:

Health System and Policy, Infectious Diseases, Maternal Access, Maternal and Child Health, Quality of Care

Study Design:

Cohort Study, Cross Sectional Study

Study Approach:

Quantitative

Participants Gender:

Male & Female