Cumberland P, Shulman CE, Maple PA, Bulmer JN, Dorman EK, Kawuondo K, et al. Maternal HIV infection and placental malaria reduce transplacental antibody transfer and tetanus antibody levels in newborns in Kenya. J Infect Dis 2007 Aug 15;196(4):550-7.
To study the effects of maternal HIV infection and placental malaria on the placental transfer of antibodies to tetanus in newborns.
This study is a prospective cohort of eligible pregnant women delivering between January 1996 and July 1997.
The study was conducted in the maternity department of Kilifi District Hospital in the mainly rural coastal district of Kilifi in Kenya, where transmission of Plasmodium falciparum is perennial, with peaks during June-August and November-December.
All women delivering between January 1996 and July 1997 at Kilifi District Hospital were assessed for eligibility to participate. Exclusion criteria were failure to give consent, twin pregnancy, significant antepartum hemorrhage, and miscarriage. A total of 725 women were enrolled in the study, of whom 21 with missing data on history of tetanus toxoid (TT) vaccination were excluded. Of the 704 women included in the study, 87 (12%) were HIV-positive, 312 (44%) had placental malaria, and 48 (7%) had both. Women with active-chronic malarial infection were younger and of lower parity, and their newborns were more likely to be preterm or of low birth weight. HIV-positive women were slightly older than HIV-negative women (23.5 vs. 22.0 years), but otherwise similar in terms of parity, body mass index (BMI), and birth weight and term delivery of their newborns. All but 44 women (6%) reported having received one or more TT vaccinations during their current pregnancy. Reported TT vaccination was not associated with HIV infection or placental malaria (p=0.83 and p=0.99, respectively). It is unlikely that many women in the study received diptheria-TT-pertussis (DTP) vaccinations during childhood, as most were born before 1980, when Kenya did not have a school-based vaccination program and DTP vaccination coverage was less than five percent.
Maternal-cord paired serum samples were collected and used to determine HIV infection status and to measure tetanus antibody levels. Placental biopsy samples were taken to classify malarial infection status as either active-acute infection, active-chronic infection, past infection or negative. Study participants reported their TT vaccination history for the current pregnancy, and verification from their antenatal clinic books was done where possible. Tetanus antitoxin was measured by laboratory ELISA assay and were performed blinded to maternal HIV and malarial infection statuses. A cutoff level of 0.1 IU/L was used in the tetanus serology assay.
The primary outcomes were: 1) geometric mean antibody titers (GMTs), as calculated by using logarithms of maternal and cord tetanus antibody levels; 2) placental transfer, as measured by cord: maternal ratio (CMR)?the ratio of titer in cord serum to that in the respective maternal serum; 3) association between tetanus antibody levels and maternal HIV infection; 4) association between tetanus antibody levels and placental malaria.
The relationship between tetanus antibody status and other variables, including maternal age, parity, post-delivery BMI, gestational age, infant birth weight, ethnic group, and indicators of socioeconomic status, were also assessed.
Factors associated with tetanus seronegativity and anibody levels in maternal serum: Thiry-seven women (5.3%) were negative for tetanus antibodies; 70% of these women were primigravidae and were younger (IQR, 18-22 years) than the tetanus-seropositive women (IQR, 19-26 years; p=0.001). Twenty-three of the tetanus-seronegative women self-reported receiving one or more doses of vaccine during the current pregnancy. Those who did not receive the TT vaccine during their current pregnancy were 12.5 times more likely than vaccinated women to be seronegative. GMT of maternal tetanus antobodies was 2.78 IU/ml (95% CI, 2.3-3.1 IU/ml) overall, and 1.86 IU/ml (95% CI, 1.0-3.2 IU/ml) in women with both placental malaria and HIV infection. Tetanus antibody levels were significantly lower in women with active-chronic or past placental malaria and in HIV-infected women, with adjusted reductions being 36% (95% CI, 12%-53%), 41% (95% CI, 21%-57%) and 38% (95% CI, 11%-56%), respectively. Antibody levels increased with age and parity.
Factors associated with placental transfer of tetanus antibodies: The mean CMR was 0.90 (95% CI, 0.86-0.93) overall and was 30% (95% CI, 18%-40%) lower in unvaccinated than in vaccinated women. The CMR in women with both placental malaria and HIV infection was 0.74 (95% CI, 0.64-0.85). The ratio was significantly lower in women with active-chronic or past placental malaria and in HIV-infected women, with reductions being 17% (95% CI, 9%- 26%), 11% (95% CI, 1%-19%) and 22% (95% CI, 13%-31%), respectively. It was also 8% (95% CI, 0.1%-15%) lower in women with low BMI and 15% (95% CI, 4%-24%) lower in women with preterm delivery.
Factors associated with tetanus seronegativity and anibody levels in cord serum: A total of 55 newborns (7.8%) were seronegative for tetanus antibody. Of babies born to seronegative mothers, 35 of 37 were seronegative (the two seropositive babies had antibody levels of 0.11 and 0.12 IU/ml, and their mothers has antibody levels of 0.08 and 0.09 IU/ml, respectively). The remaining 20 tetanus-seronegative babies were born to tetanus-seropositive mothers who had a median titer of 0.14 (IQR, 0.12-0.18). Four (20%) of these mothers were HIV positive,16 (80%) had active-chronic or past placental malaria, and six reported not having received TT vaccinations in their current pregnancies. Of the 44 newborns whose mothers reported not receiving vaccination in the current pregnancy, 19 (43.2%) were seronegative, compared with 5.5% of babies born to vaccinated mothers. Other factors significantly associated with seronegativity in newborns included maternal HIV infection (OR, 2.48), active chronic malaria (OR, 2.74), and past malaria (OR, 3.16). Tetanus antibody levels were lower in newborns born to mothers who were not TT vaccinated (one-tenth of those born to vaccinated mothers). Antibody levels were also 52% (95% CI, 30%-67%) lower in newborns of HIV-infected mothers, 47% (95% CI, 26%-62%) lower in newborns whose mothers had active-chronic or past placental malaria, 26% (95% CI, 3%-44%) lower in newborns of mothers who were malnourished, and 30% (95% CI, 3%-52%) lower in preterm babies.
The study found that HIV-infected women had lower tetanus antibody levels, a reduced transplacental transfer of tetanus antibody, and approximately 50% lower antibody levels in cord serum. Reduced antibody levels were also found in women with active-chronic or past placental malaria. There was no evidence of modification of the effect of maternal HIV status on tetanus antibody levels by placental malarial status, or vice versa, and the authors conclude that the pathophysiologic basis for reduced tetanus antibody levels in HIV and malaria were likely to be different, and that their effects did not appear to be multiplicative. TT vaccination status appeared to be the most important determination of tetanus antibody levels in both maternal and cord serum. The study found that only 3.6% of women who were TT vaccinated were seronegative, suggesting that mass vaccination of women of childbearing age should be effective even in areas with prevalent HIV and malaria infections.
According to the Newcastle-Ottawa scale for assessing the quality of observational cohort studies, this study was of adequate quality. The study was limited by observing only mothers who were delivering at the hospital, where they were more likely to have received TT vaccination than were women who delivered at home. Lack of detailed TT vaccination information, such as timing and number of doses, could have affected the association found between vaccination and maternal and cord antibody levels. The vaccination data were also self-reported and may have been inaccurate. Additionally, 57% of primigravida women in the study were enrolled in a trial of malaria prophylaxis, potentially causing an underestimate of the effect of malaria at the population level. The extent of HIV disease was also not reported and may have an effect on transplacental antibody transfer.
The decrease in maternal tetanus antibody levels in HIV-infected women is consistent with data from Senegal(1) and Brazi.l(2) A small study in Malawi(3) found no relationship between the two; however, it did not adjust for TT vaccination status. A reduction in CMR among HIV-infected women in CMR and neonatal tetanus antibody levels has also been reported in Brazil.(4) The association between malarial infection and decreased tetanus antibody levels is also consistent with finding in Papua New Guinea, with studies in Malawi and Gambia(5) reporting no effect. The authors attribute difference in findings to small sample sizes, controlling for TT vaccination, different epidemiological settings, and/or different methods used.
Tetanus is a highly preventable infection, and the findings in this study suggest that mass vaccination for tetanus immunity should be effective even where Malaria and HIV are prevalent. Immunity rates should increase even further with expansion of HIV and malarial prevention and treatment programs. It is particularly important to protect women of childbearing age and to improve efforts in eliminating maternal and neonatal tetanus.
- Dieye TN, Sow PS, Simonart T, Gueye-Ndiaye A, Popper SJ, Delforge ML, et al. Immunologic and virologic response after tetanus toxoid booster among HIV-1- and HIV-2-infected Senegalese individuals. Vaccine 2001 Dec 12;20(5-6):905-13.
- Bonetti TC, Succi RC, Weckx LY, Tavares-Lopes L, de Moraes-Pinto MI. Tetanus and diphtheria antibodies and response to a booster dose in Brazilian HIV-1-infected women. Vaccine 2004 Sep 9;22(27-28):3707-12.
- de Moraes-Pinto MI, Verhoeff F, Chimsuku L, Milligan PJ, Wesumperuma L, Broadhead RL, et al. Placental antibody transfer: influence of maternal HIV infection and placental malaria. Arch Dis Child Fetal Neonatal Ed 1998 Nov;79(3):F202-5.
- de Moraes-Pinto MI, Almeida AC, Kenj G, Filgueiras TE, Tobias W, Santos AM, et al. Placental transfer and maternally acquired neonatal IgG immunity in human immunodeficiency virus infection. J Infect Dis 1996 May;173(5):1077-84.
- Okoko BJ, Ota MO, Yamuah LK, Idiong D, Mkpanam SN, Avieka A, et al. Influence of placental malaria infection on foetal outcome in the Gambia: twenty years after Ian McGrego. J Health Popul Nutr 2002 Mar;20(1):4-11.