Prenatal malaria immune experience affects acquisition of Plasmodium falciparum merozoite surface protein-1 invasion inhibitory antibodies during infancy

African infants are often born of mothers infected with malaria during pregnancy. This can result in fetal exposure to malaria-infected erythrocytes or their soluble products with subsequent fetal immune priming or tolerance in utero. We performed a cohort study of 30 newborns from a malaria holoendemic area of Kenya to determine whether T cell sensitization to Plasmodium falciparum merozoite surface protein-1 (MSP-1) at birth correlates with infant development of anti-MSP-1 Abs acquired as a consequence of natural malaria infection. Abs to the 42- and 19-kDa C-terminal processed fragments of MSP-1 were determined by serology and by a functional assay that quantifies invasion inhibition Abs against the MSP-1(19) merozoite ligand (MSP-1(19) IIA). Infants had detectable IgG and IgM Abs to MSP-1(42) and MSP-1(19) at 6 mo of age with no significant change by age 24-30 mo. In contrast, MSP-1(19) IIA levels increased from 6 to 24-30 mo of age (16-29%, p < 0.01). Infants with evidence of prenatal exposure to malaria (defined by P. falciparum detection in maternal, placental, and/or cord blood compartments) and T cell sensitization at birth (defined by cord blood lymphocyte cytokine responses to MSP-1) showed the greatest age-related increase in MSP-1(19) IIA compared with infants with prenatal exposure to malaria but who lacked detectable T cell MSP-1 sensitization. These data suggest that fetal sensitization or tolerance to MSP-1, associated with maternal malaria infection during pregnancy, affects the development of functional Ab responses to MSP-1 during infancy.     

Acquired immune responses to Plasmodium falciparum merozoite surface protein-1 in the human fetus.

Infants born in areas of stable malaria transmission are relatively protected against severe morbidity and high density Plasmodium falciparum blood-stage infection. This protection may involve prenatal sensitization and immunologic reactivity to malaria surface ligands that participate in invasion of red cells. We examined cord blood T and B cell immunity to P. falciparum merozoite surface protein-1 (MSP-1) in infants born in an area of stable malaria transmission in Kenya. T cell cytokine responses to the C-terminal 19-kDa fragment of MSP-1 (MSP-1(19)) were detected in 24 of 92 (26%) newborns (4-192 IFN-gamma and 3-88 IL-4-secreting cells per 10(6)/cord blood lymphocytes). Peptide epitopes in the N-terminal block 3 region of MSP-1 also drove IFN-gamma and/or IL-13 production. There was no evidence of prenatal T cell sensitization to liver-stage Ag-1. A total of 5 of 86 (6%) newborns had cord blood anti-MSP-1(19) IgM Abs, an Ig isotype that does not cross the placenta and is therefore of fetal origin. The frequency of neonatal B cell sensitization was higher than that indicated by serology alone, as 5 of 27 (18%) cord blood samples contained B cells that produced IgG when stimulated with MSP-1(19) in vitro. Neonatal B cell IgG responses were restricted to the Q-KNG allele of MSP-1(19), the major variant in this endemic area, whereas T cells responded to all four MSP-1(19) alleles evaluated. In utero sensitization to MSP-1 correlated with the presence of malaria parasites in cord blood (chi(2) = 20, p < 0.0001). These data indicate that prenatal sensitization to blood-stage Ags occurs in infants born in malaria endemic areas.     

Helminth- and Bacillus Calmette-Guérin-induced immunity in children sensitized in utero to filariasis and schistosomiasis.

Infants and children are routinely vaccinated with bacillus Calmette-Guérin (BCG) in areas of the world where worm infections are common. Because maternal helminth infection during pregnancy can sensitize the developing fetus, we studied whether this prenatal immunity persists in childhood and modifies the immune response to BCG. Children and newborns living in rural Kenya, where BCG is administered at birth and filariasis and schistosomiasis are endemic, were examined. T cells from 2- to 10-year-old children of mothers without filariasis or schistosomiasis produced 10-fold more IFN-gamma in response to mycobacterial purified protein derivative than children of helminth-infected mothers (p < 0.01). This relationship was restricted to purified protein derivative because maternal infection status did not correlate with filarial Ag-driven IL-2, IFN-gamma, IL-4, or IL-5 responses by children. Prospective studies initiated at birth showed that helminth-specific T cell immunity acquired in utero is maintained until at least 10-14 mo of age in the absence of infection with either Wuchereria bancrofti or Schistosoma haematobium. Purified protein derivative-driven T cell IFN-gamma production evaluated 10-14 mo after BCG vaccination was 26-fold higher for infants who were not sensitized to filariae or schistosomes in utero relative to subjects who experienced prenatal sensitization (p < 0.01). These data indicate that helminth-specific immune responses acquired during gestation persist into childhood and that this prenatal sensitization biases T cell immunity induced by BCG vaccination away from type 1 IFN-gamma responses associated with protection against mycobacterial infection.     

Polio antibody outfit of newborns and infants born after 20 years of mass vaccination with live poliovaccine

Antibodies against type 1 and 2 poliovirus were tested in 250 infants and against type 3 poliovirus in 341 infants aged 0-13 months to compare the polio antibody outfit of newborns and infants born to three groups of mothers: (a) nonvaccinated, above 35 years of age; (b) vaccinated with attenuated poliovirus but having had chance of contact with wild poliovirus during childhood, age 22-35 years, and (c) vaccinated but not having had contact with wild poliovirus, below 22 years of age. Over 90% of newborns had specific neutralizing antibodies against all three poliovirus types. With increasing infant age the percentage of antibody-positive infants decreased: by age 9-11 months only 46%, 27% and 14% of infants displayed antibodies to polio-virus types 1, 2 and 3, respectively. Geometric mean titres decreased accordingly. Differences between infants born to mothers of the above three groups were nonsignificant: the results obtained suggest that future newborns will also possess satisfactory levels of antibodies acquired from mothers who have only had contact with attenuated vaccine poliovirus.     

Evidence for persistent, occult infection in neonatal macaques following perinatal transmission of simian-human immunodeficiency virus SF162P3

To model human immunodeficiency virus (HIV) perinatal transmission, we studied infection of simian-human immunodeficiency virus (SHIV) SF162P3 in 10 pregnant Macaca nemestrina females and their offspring. Four of nine infants born to and suckled by these dams had evidence of infection, a transmission rate of 44.4% (95% confidence interval, 13.7% to 78.8%). We quantified transplacentally acquired and de novo Env-specific immunoglobulin G (IgG), IgM, and neutralizing antibodies in newborns. Transmission of escape variants was confirmed. In utero infection (n = 1) resulted in high viremia, depletion of peripheral CD4+ T cells, and rapid evolution of env in blood and tissues. Peripartum or postpartum SHIV infection (n = 3) resulted in postacute viral control that was undetectable by very sensitive multiplex PCR, despite increasing antibodies. Seropositive infants with highly controlled viremia had homogeneous peripheral blood env sequences, and their tissues had <3 copies per million cells. A high incidence of seropositive virus-low or -negative SHIV infection in infant macaques has implications for HIV type 1 perinatal transmission and detection.     

Placental Malaria: Decreased Transfer of Maternal Antibodies Directed to Plasmodium falciparum and Impact on the Incidence of Febrile Infections in Infants

The efficacy of mother-to-child placental transfer of antibodies specific to malaria blood stage antigens was investigated in the context of placental malaria infection, taking into account IgG specificity and maternal hypergammaglobulinemia. The impact of the resulting maternal antibody transfer on infections in infants up to the age of 6 months was also explored. This study showed that i) placental malaria was associated with a reduced placental transfer of total and specific IgG, ii) antibody placental transfer varied according to IgG specificity and iii) cord blood malaria IgG levels were similar in infants born to mothers with or without placental malaria. The number of malaria infections was negatively associated with maternal age, whereas it was not associated with the transfer of any malaria-specific IgG from the mother to the fetus. These results suggest that i) malaria-specific IgG may serve as a marker of maternal exposure but not as a useful marker of infant protection from malaria and ii) increasing maternal age contributes to diminishing febrile infections diagnosed in infants, perhaps by means of the transmission of an effective antibody response.     

Peripheral Blood Mononuclear Cell Traffic Plays a Crucial Role in Mother-to-Infant Transmission of Hepatitis B Virus

The role of peripheral blood mononuclear cells (PBMCs) in HBV intrauterine infection is not fully defined. Particularly the origin of PBMCs in HBV-infected neonates remains to be addressed. We carried out a population-based nested case-control study by enrolling 312 HBsAg-positive mothers and their babies. PBMC HBV DNA as well as serum HBsAg and HBV DNA was tested in cohort entry samples. Totally, 45.5% (142/312) of the newborns were found to be infected with HBV in perinatal transmission. 119 mother-infant pairs were identified to be different in the genetic profile of maternal and fetal PBMCs by AS-PCR and hemi-nested PCR. Among them, 57.1% (68/119) of the maternal PBMCs in index cases were positive for HBV DNA while 83.8% (57/68) of the HBV DNA positive maternal PBMCs passed the placental barrier and entered the fetus. Furthermore, maternal PBMC HBV infection was significantly associated with newborn infants HBV infection. PBMC traffic from mother to fetus resulted in a 9.5-fold increased risk of HBV infection in PBMC HBV DNA positive newborn infants. These data indicate that maternal PBMCs infected with HBV contribute to HBV intrauterine infection of newborn infants via PBMC traffic from mother to fetus.     

Sudden infant death syndrome and postneonatal mortality in immigrants in England and Wales.

To examine ethnic differences in postneonatal mortality and the incidence of sudden infant death in England and Wales during 1982-5 records were analysed, the mother''s country of birth being used to determine ethnic group. Postneonatal mortality was highest in infants of mothers born in Pakistan (6.4/1000 live births) followed by infants of mothers born in the Caribbean (4.5) and the United Kingdom and Republic of Ireland (4.1). Crude rates were lower in infants of mothers born in India (3.9/1000), east and west Africa (3.0), and Bangladesh (2.8) than in infants of mothers born in the United Kingdom despite less favourable birth weights. Mortality ratios standardised separately for maternal age, parity, and social class were significantly higher in infants of mothers born in Pakistan and lower in those of mothers born in Bangladesh. The ratio for infants of Caribbean mothers was significantly higher when adjusted for maternal age. Ratios for infants of Indian and east African mothers did not show significant differences after standardisation. An important finding was a low incidence of sudden infant death in infants of Asian origin. This was paralleled by lower mortality from respiratory causes. During 1975-85 postneonatal mortality in all immigrant groups except Pakistanis fell to a similar or lower rate than that in the United Kingdom group; Pakistanis showed a persistent excess. During 1984-5 several immigrant groups (from the Republic of Ireland, India, west Africa, and the Caribbean) recorded an increase in postneonatal mortality. Surveillance of postneonatal mortality among ethnic communities should be continued, and research is needed to identify the causes underlying the differences.     

Vertical transmission of Trypanosoma cruzi in the Province of Choapa, IV Region, Chile: Preliminary Report (2005-2008)

Congenital Chagas disease acquired special importance in Chile after the certification of the control of Triatoma infestans and transmission by blood donors affected with Trypanosoma cruzi. In order to establish adequate protocols for intervention and control in infected mother-neonate pairs in endemic zones of Chagas disease, we present partial results (2005-2008) of a pilot project which is being carried out in the Province of Choapa, IV Region, Chile, whose objectives are: determine the current prevalence of the disease in pregnant women, estimate the incidence of vertical transmission of T. cruzi to newborns, determine the lineages of the parasite present in mothers who do and do not transmit the disease, determine the prevalence of Chagas disease in maternal grandmothers of neonates and study placental histopathology. Preliminary results indicated that in this study period, 3.7% of the women who gave birth in the Province have Chagas disease and 2.5% of their newborns were infected. The most frequent T. cruzi genotypes found in mothers studied during pregnancy were TCI and TCIId, either alone or in mixed infections. A high percentage (74.3%) of the grandmothers studied was infected with the parasite. In 29 placentas from mothers with Chagas disease we observed edema, necrosis, fibrinoid deposits and slight lymphoplasmocyte infiltration. In three placentas we found erythroblastosis and in one of them amastigote forms of T. cruzi; this was one of the cases of congenital infection. The evaluation of the diagnostic and control protocols generated will allow us to determine if it has been possible to modify the natural history of vertical transmission of T. cruzi in Chile.     

Maternal Social Disadvantage and Newborn Telomere Length in Archived Dried Blood Spots from the Michigan Neonatal Biobank

Telomeres are the protective caps at the ends of eukaryotic chromosomes. Short telomere length is associated with morbidity and mortality among adults and may mark the biological impact of social experiences. Using archived dried blood spots from the Michigan Neonatal Biobank, this study examined markers of maternal social disadvantage (educational attainment, receipt of public assistance, marital status, and race/ethnicity) from linked birth certificates as predictors of telomere length at birth in a sample of 192 singleton neonates born to non-Hispanic black, non-Hispanic white, and Latina mothers aged 20–35 years. Consistent with two recent studies in newborns, but counter to the idea that maternal social disadvantage is associated with shorter offspring telomere length, we found that infants born to black mothers had longer telomeres than those born to white mothers (b = 0.12, SE = 0.06, p = .05). However, black/white differences in newborn telomere length varied by receipt of public assistance. Among newborns whose mothers received WIC and/or Medicaid, there were no significant black/white differences in telomere length (b = 0.09, SE = 0.08, p = .25). In contrast, among those whose mothers did not receive public assistance—just 6 out of 69 infants born to black mothers versus 41 out of 69 infants born to white mothers—we found that babies born to black mothers had longer telomere length than babies born to white mothers (b = 0.37, SE = 0.16, p = .03). The interaction between black race/ethnicity and receipt of public assistance did not reach the conventional threshold for statistical significance (b = ?0.22, SE = 0.15, p = .13), suggesting that this finding may be due to chance. No other markers of maternal social disadvantage were related to infant telomere length. Although replication of these results in a larger sample with more infants born to black mothers with relatively high socioeconomic status is needed, this study offers preliminary support for the hypothesis that race/ethnic differences in newborn telomere length depend on social context.     

Maternal diabetes: an independent risk factor for major cardiovascular malformations with increased mortality of affected infants.

BACKGROUND: Intensive medical care of women with diabetes has reduced their risks of bearing infants with congenital anomalies. To assess the preventive potential of preconceptional care, the data of a population-based study of cardiovascular malformations (CVM) were analyzed to determine the morphogenetic specificity of maternal diabetes risks, the morbidity and mortality of the infants, and maternal characteristics that might affect these risks. METHODS: The Baltimore-Washington Infant Study was a case-control study (1981-1989) that included all live born infants with confirmed CVM; control infants were a representative sample of the birth cohort. A questionnaire administered in home visits recorded parental information on social, medical, occupational, and environmental factors. For these analyses of preconceptional diabetes risks, the case group excluded chromosomal and mendelian disorders and was divided into 3 developmental categories and 12 diagnostic groups. RESULTS: Preconceptional maternal diabetes was strongly associated with CVM of early embryonic origin (odds ratio [OR] = 4.7, 95% confidence interval [CI] 2.8-7.9) and with cardiomyopathy (OR = 15.1, 95% CI 5.5-41.3), but not with obstructive and shunting defects (OR = 1.4, 95% CI 0.7-3.0). There was heterogeneity within these developmental categories: among laterality defects, diabetes was associated only with cardiovisceral and atrioventricular discordance (OR = 10.0, 95% CI 3.7-27.0); among outflow tract anomalies, the risk was strongly associated with normally related great arteries (OR = 6.6, 95% CI 3.2-13.3) but not with simple transpositions; and among atrioventricular septal defects, diabetes was associated with the complete but not with the partial forms (OR = 22.8, 95% CI 7.4-70.5). The association in early CVM was strongest among infants with multisystem, predominantly VACTERL, anomalies. All-cause mortality of infants with CVM was 39% among those with diabetic mothers and 17.8% in those with nondiabetic mothers. Deceased infants of diabetic mothers were also more likely to have extracardiac anomalies (P = 0.041), to be born prematurely (P = 0.007), and to have low birth weight (P = 0.011). Multivariate analyses of maternal factors revealed no significant confounders of the diabetes associations. CONCLUSIONS: The evidence of diabetes-induced major cardiac defects is of urgent clinical significance. The effectiveness of early preconceptional care in the prevention of congenital anomalies has been demonstrated repeatedly.     

Risk of Early-Onset Neonatal Infection with Maternal Infection or Colonization: A Global Systematic Review and Meta-Analysis

Background

Neonatal infections cause a significant proportion of deaths in the first week of life, yet little is known about risk factors and pathways of transmission for early-onset neonatal sepsis globally. We aimed to estimate the risk of neonatal infection (excluding sexually transmitted diseases [STDs] or congenital infections) in the first seven days of life among newborns of mothers with bacterial infection or colonization during the intrapartum period.

Methods and Findings

We searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, and the World Health Organization Regional Databases for studies of maternal infection, vertical transmission, and neonatal infection published from January 1, 1960 to March 30, 2013. Studies were included that reported effect measures on the risk of neonatal infection among newborns exposed to maternal infection. Random effects meta-analyses were used to pool data and calculate the odds ratio estimates of risk of infection. Eighty-three studies met the inclusion criteria. Seven studies (8.4%) were from high neonatal mortality settings. Considerable heterogeneity existed between studies given the various definitions of laboratory-confirmed and clinical signs of infection, as well as for colonization and risk factors. The odds ratio for neonatal lab-confirmed infection among newborns of mothers with lab-confirmed infection was 6.6 (95% CI 3.9–11.2). Newborns of mothers with colonization had a 9.4 (95% CI 3.1–28.5) times higher odds of lab-confirmed infection than newborns of non-colonized mothers. Newborns of mothers with risk factors for infection (defined as prelabour rupture of membranes [PROM], preterm <37 weeks PROM, and prolonged ROM) had a 2.3 (95% CI 1.0–5.4) times higher odds of infection than newborns of mothers without risk factors.

Conclusions

Neonatal infection in the first week of life is associated with maternal infection and colonization. High-quality studies, particularly from settings with high neonatal mortality, are needed to determine whether targeting treatment of maternal infections or colonization, and/or prophylactic antibiotic treatment of newborns of high risk mothers, may prevent a significant proportion of early-onset neonatal sepsis. Please see later in the article for the Editors'' Summary     

HPRT gene alterations in umbilical cord blood T-lymphocytes in newborns of mothers exposed to tobacco smoke during pregnancy

Prenatal exposure to tobacco smoke has been associated with an increased risk of pediatric malignancies, yet the transplacental induction of genetic alterations by tobacco smoke carcinogens and their implication to childhood diseases remain poorly understood. We characterized mutations in the HPRT gene in umbilical cord blood T-lymphocytes of self-reported 103 never-smoking mothers and 104 smoking mothers (54 mothers smoked throughout and 50 mothers quit smoking during pregnancy). The results showed the illegitimate V(D)J recombinase-mediated deletion of HPRT exons 2-3 was the most prominent alteration occurring in 48.2% (26/54) of mutants from neonates of the smoking mothers who smoked during pregnancy, compared with 28.0% (14/50) from those of smoking mothers who quit smoking during pregnancy (p=0.035, Fisher's exact test), 34.9% (36/103) from never-smoking mothers (p=0.08), or 32.7% (50/153) of those of neonates born from the latter two groups of mothers combined (p=0.043). There was no significant difference in the frequency of this deletion between neonates of the never-smoking mothers and the smoking mothers who quit smoking during pregnancy (34.9% versus 28.0%, respectively, p=0.39). The results show an increase in illegitimate V(D)J recombinase-mediated deletion of HPRT exons 2-3 in cord blood T-lymphocytes of newborns of mothers who smoked during pregnancy, compared with the group of mothers who did not smoke during pregnancy, implying an increase in illegitimate V(D)J recombinase-mediated alteration, a genetic recombination event associated with childhood malignancies, may be induced in utero during pregnancy by maternal exposure to tobacco smoke-derived genotoxicants.     

Vertically transmitted HIV infection in the British Isles.

OBJECTIVE--To describe the epidemiology of vertically acquired HIV infection in the British Isles, the level of underreporting, the vertical transmission rate, and clinical spectrum of paediatric AIDS. DESIGN--Confidential, linked registers based on reporting from obstetricians and paediatricians; anonymous unlinked neonatal HIV serosurveys. SETTING--British Isles. SUBJECTS--Children born to mothers with HIV infection. MAIN OUTCOME MEASURES--Trends in HIV infection and vertical transmission rate. RESULTS--In Scotland and the Irish Republic, where most maternal HIV infection is related to drug misuse, the annual number of reports of children born to infected mothers has fallen since 1989. In England and Wales nearly half of maternal infections have been acquired overseas, and the number of children born to these women, and to women who became infected in Britain, is increasing. In south east England the proportion of live births to women whose infection was identified before delivery was only 17% (50/287), compared with 68% (26/38) in Scotland. The vertical transmission rate was 13.7% (23/168), and 23% of infected children developed AIDS in the first year of life. 41% (38/92) of children born to infected mothers who were ascertained after delivery were breast fed, compared with 5% (12/236) of those ascertained before delivery. CONCLUSIONS--The incidence of vertically transmitted HIV infection is increasing in England and Wales. More extensive antenatal testing would enable infected women to be counselled against breast feeding, which could prevent a substantial proportion of vertical transmission in some areas, and would increase opportunities for early diagnosis and treatment of infected children.     

Cell-mediated immune responses to Chlamydia trachomatis in mothers and infants

Cell-mediated immunity to Chlamydia trachomatis was studied in pregnant women with chlamydial infection of the cervix, in infants born vaginally to these women, and in infants presenting with chlamydial conjunctivitis. Uninfected pregnant women and their infants were studied as controls. McCoy cell cultures were used to isolate C. trachomatis from clinical specimens. Cell-mediated immunity was measured by lymphocyte proliferative responses in vitro to stimulation by chlamydial antigens. Chlamydial IgG antibody in serum specimens was detected by a microenzyme-linked immunosorbent assay technique. The mean lymphocyte proliferative responses to chlamydial antigens were greater in infected women than in uninfected women both during pregnancy and in the postpartum period. Lymphocyte responsiveness in infected pregnant women, however, was less than in postpartum women. Despite failure to detect chlamydial infection in exposed infants, lymphocyte proliferative responses were greater in umbilical cord blood and later in peripheral blood samples from neonates born to infected mothers than in infants born to uninfected mothers. These responses were also greater in infants with chlamydial conjunctivitis than in infants of uninfected mothers. These data suggest that cellular immune responses to chlamydial antigens are increased in infected mothers and infants and that infants may acquire chlamydial cell-mediated immunity transplacentally.     

Science commentary: Behaviour of hepatitis C virus

Objective: To determine the risk factors for and timing of vertical transmission of hepatitis C virus in women who are not infected with HIV-1. Design: Follow up for a median of 28 (range 24-38) months of babies born to women with antibodies to hepatitis C virus but not HIV-1. Subjects: 442 mothers and babies, of whom 403 completed the study. Main outcome measures: Presence of antibodies to hepatitis C virus and viral RNA and alanine aminotransferase activity in babies. Presence of viral RNA, method of infection with hepatitis C, method of delivery, and type of infant feeding in mothers.Results: 13 of the 403 children had acquired hepatitis C virus infection at the end of follow up. All these children were born to women positive for hepatitis C virus RNA; none of the 128 RNA negative mothers passed on the infection (difference 5%, 95% confidence interval 2% to 7%). 6 children had viral RNA immediately after birth. 111 women had used intravenous drugs and 20 had received blood transfusions. 11 of the infected children were born to these women compared with 2 to the 144 with no known risk factor (difference 7%, 2% to 12%).Conclusions: This study suggests that in women not infected with HIV only those with hepatitis C virus RNA are at risk of infecting their babies. Transmission does seem to occur in utero, and the rate of transmission is higher in women who have had blood transfusions or used intravenous drugs than in women with no known risk factor for infection.

Key messages

• Little information exists on vertical transmission of hepatitis C virus in women not infected with HIV
• This study in a large unselected population of infants born to HIV-1 negative mothers suggests that intravenous drug use itself is an important risk factor for transmission of hepatitis C virus
• Maternal post-transfusional hepatitis is also an important risk factor for infection of infants
• Viral genotype, maternal viraemia, type of delivery (vaginal delivery or caesarean section) and breast feeding do not seem to be risk factors
• In utero transmission of hepatitis C virus has been suggested by RNA positivity on day of birth in some infected children

     

IFN-gamma and IL-10 mediate parasite-specific immune responses of cord blood cells induced by pregnancy-associated Plasmodium falciparum malaria

Available evidence suggests that immune cells from neonates born to mothers with placental Plasmodium falciparum (Pf) infection are sensitized to parasite Ag in utero but have reduced ability to generate protective Th1 responses. In this study, we detected Pf Ag-specific IFN-gamma(+) T cells in cord blood from human neonates whose mothers had received treatment for malaria or who had active placental Pf infection at delivery, with responses being significantly reduced in the latter group. Active placental malaria at delivery was also associated with reduced expression of monocyte MHC class I and II in vivo and following short term in vitro coculture with Pf Ag compared with levels seen in neonates whose mothers had received treatment during pregnancy. Given that APC activation and Th1 responses are driven in part by IFN-gamma and down-regulated by IL-10, we examined the role of these cytokines in modulating the Pf Ag-specific immune responses in cord blood samples. Exogenous recombinant human IFN-gamma and neutralizing anti-human IL-10 enhanced T cell IFN-gamma production, whereas recombinant human IFN-gamma also restored MHC class I and II expression on monocytes from cord blood mononuclear cells cocultured with Pf Ag. Accordingly, active placental malaria at delivery was associated with increased frequencies of Pf Ag-specific IL-10(+)CD4(+) T cells in cord blood mononuclear cell cultures from these neonates. Generation and maintenance of IL-10(+) T cells in utero may thus contribute to suppression of APC function and Pf Ag-induced Th1 responses in newborns born to mothers with placental malaria at delivery, which may increase susceptibility to infection later in life.     

Maternal geohelminth infections are associated with an increased susceptibility to geohelminth infection in children: a case-control study

Background

Children of mothers infected with soil-transmitted helminths (STH) may have an increased susceptibility to STH infection.

Methods and Findings

We did a case-control study nested in a birth cohort in Ecuador. Data from 1,004 children aged 7 months to 3 years were analyzed. Cases were defined as children with Ascaris lumbricoides and/or Trichuris trichiura, controls without. Exposure was defined as maternal infection with A. lumbricoides and/or T. trichiura, detected during the third trimester of pregnancy. The analysis was restricted to households with a documented infection to control for infection risk. Children of mothers with STH infections had a greater risk of infection compared to children of uninfected mothers (adjusted OR 2.61, 95% CI: 1.88–3.63, p<0.001). This effect was particularly strong in children of mothers with both STH infections (adjusted OR: 5.91, 95% CI: 3.55–9.81, p<0.001). Newborns of infected mothers had greater levels of plasma IL-10 than those of uninfected mothers (p = 0.033), and there was evidence that cord blood IL-10 was increased among newborns who became infected later in childhood (p = 0.060).

Conclusion

Our data suggest that maternal STH infections increase susceptibility to infection during early childhood, an effect that was associated with elevated IL-10 in cord plasma.     

Maternal-fetal transmission of human immunodeficiency virus

The World Health Organization estimates that by year 2000, 10 million children will be infected with human immunodeficiency virus type 1 (HIV-1) at birth and will subsequently develop AIDS. Perinatally acquired infections account for the majority of all HIV-1 cases in children, with an estimated mother-to-infant transmission rate of more than 30%. It is not clear why more than half of the children born to HIV-1-infected mothers are uninfected. Maternal transmission of HIV-1 occurs at three levels: prepartum, intrapartum, and postpartum. Several maternal parameters including advanced clinical stages of the mother, low CD4+ lymphocyte counts, maternal immune response to HIV-1, recent infection, high level of circulating HIV-1, and maternal disease progression have been implicated in an increased risk of mother-to-infant transmission of HIV-1. Viral factors influencing mother-to-infant transmission are not known. Furthermore, several other factors such as acute infection during pregnancy, presence of other sexually transmitted diseases (STD) or other chronic infections, vaginal bleeding, disruption of placental integrity, premature rupture of membrane (PROM), and preterm PROM have been associated with mother-to-infant transmission of HIV-1. In addition, tobacco and cigarette smoking during pregnancy have been shown to triple the rate of maternal transmission of HIV-1. The AIDS Clinical Trial Group (ACTG) suggested that zidovudine (ZDV) can reduce the rate of mother-to-infant transmission of HIV-1 if administered to HIV-1-infected pregnant women with CD4 counts greater than 200. Moreover, this study failed to take into consideration several factors that may influence maternal transmission of HIV-1. However, the molecular mechanisms involved in mother-to-infant transmission of HIV-1 are not understood, which makes it more difficult to define strategies for effective treatment and prevention of HIV-1 infection in children. Several groups are engaged in the understanding of the molecular and biological properties of HIV-1 influencing mother-to-infant transmission. Results from my and several other laboratories suggest that the minor genotypes, subtypes, or variants of HIV-1 found in a genetically heterogeneous virus population of infected mothers are transmitted to their infants. The minor HIV-1 genotype predominates initially as a homogeneous population in the infant and then becomes diverse as the infant matures. Furthermore, transmission of a major or multiple HIV-1 genotypes from mother to infant has been reported. Taken together, these results strongly suggest that there are differences among the molecular and biological properties of the maternal variants that are transmitted to the infants and the maternal variants that are not transmitted to the infants. The understanding of the molecular and biological properties of the transmitted viruses will enable researchers to target a particular subtype in the mothers that is transmitted to the infants.     

Epstein-Barr virus infection in the neonatal period and in childhood

In an attempt to detect and characterize congenital, neonatal and early childhood EBV infections, a prospective sero-epidemiological study was undertaken in 112 newborn infants and their mothers, 25 additional newborns undergoing exchange transfusion, 114 randomly selected hospitalized infants aged 0 to 3 years, and 109 siblings and parents of these infants. Leukocyte culture was attempted in all the newborns and in 25 pre- and post-transfusion.The findings of EBV seroconversion in six patients without clearly apparent illness, infectious mononucleosis in only one case with significant EBV antibody rise, seroreversion in three cases in early childhood, higher newborn than maternal EBV antibody titres in three cases and the establishment of two permanent lymphoblastoid cell lines from newborns following exchange transfusion raise the possibility of abortive primary EBV infection in early life. Congenital or neonatal infections following exchange transfusions, however, could not be substantiated with certainty since the EBV antibodies did not persist at follow-up except possibly in two cases. Parenteral transmission of the EB virus by exchange transfusion at birth is probably prevented by the presence of EBV antibodies in either donor or recipient.