Influence of placental malaria infection and maternal hypergammaglobulinaemia on materno-foetal transfer of measles and tetanus antibodies in a rural west African population

Placental malaria infection jeopardizes pregnancy outcome, and its influence may also impair the transplacental transfer of some antibodies. Two hundred and thirteen Gambian mother-baby pairs were studied to determine the influence of placental malaria infection and maternal hypergammaglobulinaemia on transplacental transfer of measles and tetanus antibodies in Gambian population. Placental blood and tissue were collected for placental malaria diagnosis. Cord and maternal sera were tested for total IgG concentration by laser nephelometry and for IgG antibody to tetanus toxoid and measles by ELISA. The prevalence of placental malaria infection was 51.1%. Mothers whose placentae were parasitized had a significantly higher mean total serum IgG (22.0 g/L vs 11.3 g/L, p < 0.001) and measles antibody level (4.02 IU/mL vs 1.21 IU/mL, p < 0.01), but not tetanus antibody, than mothers with non-parasitized placentae. Results of multiple regression analysis showed that placental malaria infection and maternal hypergammaglobulinaemia were associated with the reduction of 72% (95% CI 67.84) and 86% (95% CI 76.91) in transplacental transfer of measles antibody respectively but did not influence the transfer of tetanus antibody. It is concluded that the combined influence of placental malaria infection and maternal hypergammaglobulinaemia is significantly associated with the transfer of impaired measles antibody in this population.     

Placental malaria and pregnancy outcome in a peri urban area in Senegal

BACKGROUND: In areas of seasonal malaria transmission in Senegal, two previous studies have found that maternal direct obstetrics deaths and preeclampsia were more frequent during the rainy/malaria season. These observations suggest a possible link between malaria and maternal or fetal morbidity and mortality. In this study, we explore this link in a peri urban maternity in Senegal. METHODS: We carried out an exhaustive survey at "Maternité Roi-Baudouin" in Guédiawaye, which is the main maternity of the suburb of Dakar, Senegal. From August 1998 to December 1999, we included all women attending the maternity for delivery. Placental malaria was diagnosed by the presence of parasites or malarial pigment in placental apposition. Delivery diagnosis was assessed by obstetricians or midwives. Sociodemographic data and information about chloroquine intake were recorded. Multivariate analysis was performed to compare prevalence of placental malaria between normal and poor deliveries outcomes. RESULTS: Eight thousand two hundred and seventy three women were included. There were 5597 (67.7%) normal deliveries, 1214 (14.6%) low birth weight babies (<2500 g) and 1462 (17.7%) deliveries with a maternal or fetal poor outcome. Placental malaria prevalence was 9.5% (785/8273). Placental malaria was associated with low birth weight (adjusted OR=2.06 (1.72-2.57)), preterm birth (adjusted OR=3.51 (1.84-6.68)) and perinatal mortality (adjusted OR=2.56 (1.65-3.97)). We did not find an association between placental malaria and occurrence of a maternal pathology (dystocia, preeclampsia, eclampsia, retroplacental haematoma). CONCLUSION: Although malaria at delivery is not associated with occurrence of a maternal obstetric pathology, it has detrimental effects for the fetus and newborns. Effective antimalarial strategies during the antenatal period are urgently needed.     

Maternal cigarette smoking and pregnancy outcome

Maternal smoking rates in pregnancy have declined, particularly in the non-manual social classes, and perinatal mortality rates have fallen over the last 20 years. We have therefore re-evaluated the relationship between maternal cigarette smoking and pregnancy outcome against this background. A total of 608 stillbirths and 634 infant deaths were identified using the All Wales Perinatal Survey. The cause of death was classified using the clinicopathological system. Maternal smoking rates and social class groupings were compared with those in a cohort of 16047 survivors born to women resident in South Glamorgan. The smoking rate was 37.8% in mothers of babies who died compared with 27.2% in mothers of survivors, an odds ratio (OR) of 1.63 [95% CI 1.44, 1.84]. The OR for unexplained stillbirth was 1.72 [95% CI 1.38, 2.13], placental abruption 2.07 [95% CI 1.29, 3.31], infection 3.70 [95% CI 2.23, 6.13] and sudden infant death syndrome 4.84 [95% CI 3.05, 7.69]. Maternal smoking was not associated with death due to prematurity or a congenital anomaly. Despite changes in smoking habits and the causes of perinatal death, smoking during pregnancy continues to be strongly associated with fetal and infant mortality. It is important that health promotion activities are effective in reducing smoking during pregnancy.     

Risk factors for malaria in UK travellers

After observing an apparent increase in severe falciparum malaria among travellers returning from The Gambia to the United Kingdom (UK) in the last quarter of 2000, we conducted a case-control study to investigate risk factors for malaria. The study participants had visited The Gambia between 1 September and 31 December 2000, travelling with the largest UK tour operator serving this destination. The main outcome measures were risk factors associated with malaria. Forty-six cases and 557 controls were studied. Eighty-seven percent of all participants reported antimalarial use (41% chloroquine/proguanil, 31% mefloquine). On univariate analysis the strongest risk factors for disease were: early calendar period of visit, longer duration of stay, non-use of antimalarial prophylaxis, non-use of mefloquine, lack of room air-conditioning, less use of insect repellent, prior visit to another malarial area and accommodation in 'hotel X'. After adjustment in multivariate analysis, use of mefloquine remained strongly protective (odds ratios, OR 0.13 [95% confidence intervals, 95% CI 0.04-0.40]), and the strongest independent risk factors for malaria were early calendar period (OR 5.19 [2.35-11.45] for 1 September to 9 November 2000 versus 10 November to 31 December 2000), prior visit to another malarial area (OR 3.27 [1.41-7.56]), main accommodation in 'hotel X' (OR 3.24 [1.51-6.97]) and duration of stay (OR 2.05 per extra week [1.42-2.95]). Neither any use, nor > 90% adherence to chloroquine/proguanil were protective (adjusted OR for any use 0.57 [0.27-1.21], P = 0.14). We concluded mefloquine use was strongly protective against malaria (87% protective efficacy), whereas chloroquine/proguanil, which is no longer recommended but remains widely used, was less than half as effective (43% protective efficacy). Waning efficacy of chloroquine/proguanil may have contributed to the observed increase in malaria among travellers to The Gambia in 2000. Local factors may also influence the risk of malaria. Malaria could be prevented among travellers to West Africa if current national guidelines on antimalarial prophylaxis were better implemented.     

The effects of malaria chemoprophylaxis given by traditional birth attendants on the course and outcome of pregnancy

A trial of malaria chemoprophylaxis given by traditional birth attendants was undertaken in a rural area of The Gambia where access to antenatal clinics is difficult. Women received one or more doses of Maloprim or placebo from a traditional birth attendant during 1049 of 1208 pregnancies (87%) recorded in 16 villages over a 3-year period. Primigravidae who received Maloprim had a lower parasite rate and a significantly higher mean packed cell volume than primigravidae who received placebo, and their babies were significantly heavier (6% low birth weight vs 22%). In multigravidae chemoprophylaxis reduced malaria parasitaemia but it had no beneficial effect on haemoglobin level and much less effect on birth weight than was observed in primigravidae. However, the mean birth weight of babies born to grandemultigravidae who received chemoprophylaxis was significantly higher than that of babies born to grandemultigravidae who did not.     

Efficacy of chemoprophylaxis in preventing Plasmodium falciparum parasitaemia and placental infection in pregnant women in Malawi

73 pregnant women in Malawi were given weekly antimalarial chemoprophylaxis under observation and were monitored for Plasmodium falciparum parasitaemia and placental infection. 3 of 19 women (16%) who were parasitaemic at the time they began chemoprophylaxis were infected with chloroquine-resistant P. falciparum. After clearance of initial infections, 25% of the 73 women became parasitaemic while taking prophylaxis and 56% had evidence of active or past placental infection at the time of delivery. None of the women who were parasitaemic at the time of enrollment, and only 11% of those who had breakthrough parasitaemias while taking prophylaxis, had a history of fever and signs or symptoms that they recognized as malaria. Although the density of P. falciparum infection and rates of placental infection appeared to be lower among women taking regular chloroquine prophylaxis, this drug did not prevent P. falciparum infection among pregnant women.     

乙型肝炎病毒宫内传播机制的分子流行病学研究

为了解乙型肝炎病毒 ( HBV)宫内传播的危险因素与机制 ,笔者进行了病例对照研究与胎盘组织的免疫组化。收集陕西省妇幼保健院 2 4 2例 HBs Ag阳性的孕妇及其新生儿作为研究对象。结果显示 ,母亲 HBe Ag阳性 ( OR=32 .63)和先兆早产史 ( OR=2 2 .80 )是主要的危险因素。在 32例足月孕妇的免疫组化 HBs Ag阳性的胎盘组织中 ,HBs Ag阳性率在脱膜细胞层为 10 0 % ,滋养层细胞为 59.38% ,绒毛间质细胞为 65.50 % ,绒毛毛细血管内皮细胞为 39.38% ,表明 HBV感染从母面到胎儿血管呈逐渐下降趋势 ( P<0 .0 1)。而且绒毛毛细血管 HBs Ag阳性与婴儿宫内感染有关( OR=2 0 .86,P<0 .0 1)。根据上述结果 ,我们提出假设 :HBV宫内传播可能有两条途径 :经先兆早产等引起的胎盘血管渗漏的“血源传播”和 HBV经胎盘各层细胞“转移”至胎儿血循环的“细胞转移传播”。     

Placental malaria and foetoplacental function: low plasma oestradiols associated with malarial pigmentation of the placenta

Placental biopsies were taken immediately post partum from 65 Gambian mothers who had not received anti-malaria chemoprophylaxis during pregnancy whilst living in an area hyperendemic for Plasmodium falciparum malaria. The biopsies were examined without knowledge of the mothers' health or the outcome of pregnancies. Histologically, they were divided into two groups: those with macrophages containing malarial pigment in the inter-villous spaces, and those without such pathology. Babies with pigmented placentae had a mean (SD) weight for gestational age of 83.3 (10.6)%, which was significantly lower (p less than 0.01) than that of 91.2 (7.7)% in the non-pigmented group. The plasma oestradiol concentrations in the mothers who later delivered pigmented placentae were significantly lower from 32 weeks of gestation onwards, and did not continue to rise in the last trimester as they did in the non-pigmented group. The last trimester appears to be the critical time for protection of the foeto-placental unit against malaria. Anti-malaria chemoprophylaxis should be given to all pregnant women.     

In vivo effects of maternal immunosuppression during pregnancy on the immune function of newborn infants

When used in pregnancy, immunosuppressants can cross the placental barrier and enter foetal circulation, possibly affecting the immune system of the foetus. This study evaluated the immune function in eight children born by mothers with connective tissue diseases who received immunosuppressants (cyclosporine A or dexamethasone) during pregnancy and in six babies from mothers with similar diseases, but who did not receive any treatment. Judging by the cytokine production of interleukin-2 and interferon-gamma in peripheral blood mononuclear cells stimulated by phorbol-myristate-acetate (PMA) and ionomycin, immunosuppressive drugs given for rheumatic disorders during pregnancy do not induce significant immunosuppression in babies.     

Malaria chemoprophylaxis, birth weight and child survival.

Study of the effects of malaria chemoprophylaxis given during pregnancy on birthweight and investigation of the influence of birthweight on child survival suggest that, in a rural area of The Gambia, chemoprophylaxis given during pregnancy might reduce infant mortality by about one-fifth in the children of primigravidae but by less than 5% in the children of multigravidae. In malaria endemic areas, primigravidae should be protected against malaria not only for their own sake but also for that of their infants.     

Malaria in pregnancy as an indirect cause of infant mortality in sub-Saharan Africa

Although randomized controlled trials of interventions to reduce malaria in pregnancy have demonstrated an increase in the birthweight of the newborn in primigravidae, the subsequent impact on infant mortality in all-parities has not been assessed. The aim of this paper was to model the possible impact of placental malarial infection on infant mortality through reduced birthweight. An extensive literature search was undertaken to define a series of parameters describing the associations between placental infection, birthweight and premature mortality in sub-Saharan Africa. It was shown that a baby is twice as likely to be born of low birthweight if the mother has an infected placenta at the time of delivery (all-parities: 23% vs 11%, primigravidae only: 32% vs 16%), and that the probability of premature mortality of African newborns in the first year of life is 3 times higher in babies of low birthweight than in those of normal birthweight (16% vs 4.6%). Assuming 25% of pregnant women in malaria-endemic areas of Africa harbour placental malarial infection, it is suggested that 5.7% of infant deaths in malarious areas could be an indirect cause of malaria in pregnancy. This would imply that, in 1997, malaria in pregnancy could have been responsible for around 3700 infant deaths under the diverse epidemiological conditions in Kenya. Placental infection with Plasmodium falciparum appears to have a more significant role in infant survival in Africa than has been previously assumed. This may explain the high reduction in infant mortality rates from interventions aimed at reducing transmission, over and above that expected from a decline in direct malaria-specific mortality alone.     

Estimation of effectiveness of interventions for malaria control in pregnancy using the screening method

BACKGROUND: The evaluation of the effectiveness of antimalarial drugs and bed net use in pregnant women is an important aspect of monitoring and surveillance of malaria control in pregnancy. In principle the screening method for assessing vaccine efficacy can be applied in non-vaccine settings for assessing interventions for malaria control in pregnancy. METHODS: In this analysis field data on the proportion of placental malaria cases treated with two doses of sulphadoxine-pyrimethamine (SP) and the uptake of two doses of SP in the antenatal clinic was used in a case-coverage method to assess the protective effectiveness (PE) of intermittent preventive treatment with SP for malaria control in pregnancy. PE was assessed using placental malaria, low birthweight and maternal anaemia at delivery as outcome variables. The method was also applied to an evaluation of the protective effectiveness of self-reported use of impregnated bed nets (ITNs). RESULTS: Effectiveness was highest for reduction of low birthweight in multigravidae (87.2%, 95% CI, 83.2-91.3%). PE was lower for placental malaria (61.6% primigravidae, 28.5% multigravidae), and maternal anaemia (Hb < 8.0 g/dl, 37.8% primigravidae, 29.6% multigravidae). Estimates for PE of self-reported use of ITNs gave values for all three outcome parameters that were much lower than for SP use. For women of all parties effectiveness estimates for reduction of low birthweight were 22% (95% CI, 17.7-26.4), prevention of placental malaria (all types) 7.1% (95% CI, 4.4-9.8), prevention of active placental infection 38.9% (95% CI, 27.4-50.4), and for maternal anaemia 8.8% (95% CI, 0-20.0). CONCLUSIONS: The case-coverage method could provide a useful and practical approach to routine monitoring and evaluation of drug interventions to control malaria in pregnancy and has potentially wide applications. Effectiveness estimates related to reported ITN use in pregnancy may be less reliable. The method should be further evaluated using currently available data sets.     

Malaria infection of the placenta in The Gambia, West Africa; its incidence and relationship to stillbirth, birthweight and placental weight

The incidence of placental malaria at parturition and its effects on the conceptus have been investigated in The Gambia, West Africa. Malarious placentae occurred in 1300 (20.2%) of 6427 singleton births, in 32 (18.6%) of 172 sets of twins and in none of six sets of triplets. Plasmodium falciparum infections predominated; P. malariae or P. ovale infections were found in only nine instances. In the large group of single births placental malaria occurred less frequently (12.0%) in residents of urban than of other, more rural, communities (27.1%). In the former group incidence showed no clear change with season; in the latter group it was highest in the trimester following the end of the rains and lowest in the second half of the dry season. In both residential groups it was more frequent in primiparae (urban 16.1%; other 46.9%) than in multiparae (urban 8.9%; other 20.3%). The sex of the child did not influence malaria incidence. Dense placental infections were more frequent in primiparae. Stillbirth rates of singleton infants were significantly higher for males than for females, but no clear and consistent relationship between stillbirth and placental malaria was detected. Mean singleton birthweights were depressed by about 170 g in the presence of malaria; the deficits were statistically significant only among first born infants and tended to diminish progressively with increasing maternal parity. No distinct gradient linking birthweight with ascending density of placental parasitaemia was observed. Singleton birthweights of 2.5 kg or less occurred more frequently in association with malarious than non-malarious placentae and the association was more marked among first born than later birth rank infants. Differences between the weights of malarious and non-malarious placentae were small and not significant. The findings of the study are discussed in relation to the widely prevalent view that pregnancy exacerbates maternal malaria by attenuating acquired immunity.     

The safety of the combination artesunate and pyrimethamine-sulfadoxine given during pregnancy

Malaria during pregnancy is associated with an increased risk of severe anaemia and low-birthweight babies. Effective intermittent therapy with pyrimethamine-sulfadoxine (PSD) decreases parasitaemia and severe anaemia and improves birthweight in areas where Plasmodium falciparum is sensitive to this drug. Increasing resistance to PSD is a concern and alternative antimalarial regimens during pregnancy are needed. Artesunate with PSD is a promising antimalarial combination but few data are available on the safety of artemisinins when taken during pregnancy. Outcome of pregnancy was evaluated for 287 women in The Gambia who were exposed in June 1999 to a single dose of the combination artesunate and PSD during a mass drug administration and 172 women who were not exposed. Women who received placebo (40) and those who did not participate in the mass drug administration (132) comprised the non-exposed group. There was no difference in the proportion of abortions, stillbirths, or infant deaths among those exposed or not exposed to the drugs. The mean weight of 18 infants born to mothers who had received artesunate and PSD during the third trimester was 3.10 kg compared to a mean weight of 2.62 kg of the 10 infants of untreated mothers (adjusted P value = 0.05). We found no evidence of a teratogenic or otherwise harmful effect of gestational exposure to artesunate and PSD. Treatment of a self-selected group of pregnant women with PSD and artesunate during pregnancy was associated with a greater birthweight, which may have resulted from clearance of malaria parasites. However, the influence of confounding factors cannot be excluded.     

Importance and prevention of malaria in pregnancy

Malaria in pregnancy is one of the most important preventable causes of low birthweight deliveries worldwide. It is also a major cause of severe maternal anaemia contributing to maternal mortality. It is estimated that 40% of the world's pregnant women are exposed to malaria infection during pregnancy. The clinical features of Plasmodium falciparum malaria in pregnancy depend to a large extent on the immune status of the woman, which in turn is determined by her previous exposure to malaria. In pregnant women with little or no pre-existing immunity, such as women from non-endemic areas or travellers to malarious areas, infection is associated with high risks of severe disease with maternal and perinatal mortality. Women are at particular risk of cerebral malaria, hypoglycaemia, pulmonary oedema and severe haemolytic anaemia. Fetal and perinatal loss has been documented to be as high as 60-70% in non-immune women with malaria. Adults who are long-term residents of areas of moderate or high malaria transmission, including large parts of sub-Saharan Africa, usually have a high level of immunity to malaria. Infection is frequently asymptomatic and severe disease is uncommon. During pregnancy this immunity to malaria is altered. Infection is still frequently asymptomatic, so may go unsuspected and undetected, but is associated with placental parasitization. Malaria in pregnancy is a common cause of severe maternal anaemia and low birthweight babies, these complications being more common in primigravidae than multigravidae. Preventative strategies include regular chemoprophylaxis, intermittent preventative treatment with antimalarials and insecticide-treated bednets.     

Acquisition of antibodies to variant antigens on the surface of Plasmodium falciparum-infected erythrocytes during pregnancy

Pregnancy-associated malaria is characterized by Plasmodium falciparum adherence to chondroitin sulfate A (CSA) in placenta, through a particular variant surface antigen (VSA). VSA(CSA)-specific IgG are involved in protection against placental malaria. In order to assess the relationship between VSA(CSA)-specific antibody responses and parity as well as protection against placental malaria, the occurrence of P. falciparum infection was assessed in 306 pregnant women from a low malaria transmission area of Senegal. Anti-VSA(CSA) antibodies against three placental parasite isolates were measured by flow cytometry, at enrollment and delivery. Placental infection prevalence rates were highest in primigravidae, but no clear decreasing trend was observed from the second pregnancy onwards. Anti-VSA(CSA) antibody prevalence rates increased with parity. Both anti-VSA(CSA) antibody prevalence rates and levels increased during pregnancy only in women infected with P. falciparum. Although a single or a very limited number of P. falciparum infections were able to induce an anti-VSA(CSA) antibody response, the level or the quality of this response did not appear to confer protection against placental malaria infection.     

Adverse birth outcomes in a malarious area

To determine factors associated with fetal growth, preterm delivery and stillbirth in an area of high malaria transmission in Southern Malawi, a cross-sectional study of pregnant women attending and delivering at two study hospitals was undertaken. A total of 243 (17.3%) babies were preterm and 54 (3.7%) stillborn. Intra-uterine growth retardation (IUGR) occurred in 285 (20.3%), of whom 109 (38.2%) were low birthweight and 26 (9.1%) preterm. Factors associated with IUGR were maternal short stature [adjusted odds ratio (AOR) 1.6, 95% confidence interval (CI) 1.0-2.5]; primigravidae (AOR 1.9, 95% CI 1.4-2.7); placental or peripheral malaria at delivery (AOR 1.4, 95% CI 1.0-1.9) and maternal anaemia at recruitment (Hb<8 g/dl) (AOR 1.9, 95% CI 1.3-2.7). Increasing parasite density in the placenta was associated with both IUGR (P=0.008) and prematurity (P=0.02). Factors associated with disproportionate fetal growth were maternal malnutrition [mid-upper arm circumference (MUAC)<23 cm, AOR 1.9, 95% CI 1.0-3.7] and primigravidae (AOR 1.8, 95% CI 1.0-3.1). Preterm delivery and stillbirth were associated with <5 antenatal care visits (AOR 2.2, 95% CI 1.3-3.7 and AOR 3.1, 95% CI 1.4-7.0 respectively) and stillbirth with a positive Venereal Disease Research Laboratory (VDRL) test (AOR 4.7, 95% CI 1.5-14.8). Interventions to reduce poor pregnancy outcomes must reduce the burden of malaria in pregnancy, improve antenatal care and maternal malnutrition.     

Prenatal and intrapartum events and sudden infant death syndrome

The purpose of this study was to evaluate specific pregnancy and labour and delivery events that may increase the risk of sudden infant death syndrome (SIDS). A matched case-control study was conducted in five counties in southern California, using California death certificate records. The sample consisted of 239 Caucasian, African-American, Hispanic and Asian mothers of SIDS infants and 239 mothers of control infants matched on sex, race, birth hospital and date of birth. Mothers participated in a detailed telephone interview and provided access to obstetric and paediatric records. More case than control mothers reported a family history of anaemia (OR=2.12, P < 0.001). Placental abruptions were strongly associated with SIDS (unadjusted OR=7.94, [95% CI 1.34,47.12]). There was an increased risk of SIDS death associated with maternal anaemia during pregnancy (OR=2.51, [95% CI 1.25,5.03]), while simultaneously adjusting for maternal smoking during pregnancy, maternal years of education and age, parity, infant birthweight, gestational age, medical conditions at birth, infant sleep position and post-natal smoking. Interactions of anaemia and prenatal smoking as well as anaemia and post-natal smoking were not statistically significant. There were no other statistically significant differences between case and control mothers for pregnancy conditions, labour and delivery events (e.g. caesarean sections, anaesthesia, forceps) or newborn complications (e.g. nuchal cord, meconium aspiration). Anaemia and placental abruptions were significantly associated with an increased risk of SIDS; both are circumstances in which a fetus may become hypoxic, thereby compromising the subsequent growth, development and ultimate survival of the infant.     

Protective Antibodies against Placental Malaria and Poor Outcomes during Pregnancy,Benin

Placental malaria is caused by Plasmodium falciparum–infected erythrocytes that bind to placental tissue. Binding is mediated by VAR2CSA, a parasite antigen coded by the var gene, which interacts with chondroitin sulfate A (CSA). Consequences include maternal anemia and fetal growth retardation. Antibody-mediated immunity to placental malaria is acquired during successive pregnancies, but the target of VAR2CSA-specific protective antibodies is unclear. We assessed VAR2CSA-specific antibodies in pregnant women and analyzed their relationships with protection against placental infection, preterm birth, and low birthweight. Antibody responses to the N-terminal region of VAR2CSA during early pregnancy were associated with reduced risks for infections and low birthweight. Among women infected during pregnancy, an increase in CSA binding inhibition was associated with reduced risks for placental infection, preterm birth, and low birthweight. These data suggest that antibodies against VAR2CSA N-terminal region mediate immunity to placental malaria and associated outcomes. Our results validate current vaccine development efforts with VAR2CSA N-terminal constructs.