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Quinine and Severe Falciparum-Malaria in Late Pregnancy
Abstract
Quinine dihydrochloride was given intravenously to 12 women with severe falciparum malaria in the third trimester of pregnancy. The initial dose consisted of 10 or 20 mg salt/kg over 4 h and was followed by 10 mg salt/kg every 8 h until patients were fit to swallow, when quinine sulphate tablets were given. Uterine activity showed little or no change despite rising quinine concentrations. Of 3 patients in labour, 2 proceeded normally while a third had a successful caesarean section for fetal distress. Late (type II) decelerations of the fetal heart rate were recorded in 6 patients before treatment but in most patients signs of fetal distress diminished as the maternal temperature fell. Hypoglycaemia and hyperinsulinaemia developed in 7 patients, in 2 before quinine was started. The important toxic effect of quinine in late pregnancy is not an oxytocic action but rather its capacity to release insulin.
... However, various studies show that in stable malaria endemic regions, pregnant women have frequent episodes of malaria from early to mid pregnancy [3][4][5]. It is recommended that pregnant women should be given antimalarial drugs at their first antenatal visit and perhaps earlier in pregnancy whether or not they show symptoms to prevent adverse effect of malaria on the mother and foetus [6]. In areas of stable malaria transmission of sub-Saharan Africa, intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) (IPTp-SP) is recommended for all pregnant women at each scheduled antenatal care visit (at least one month apart) up to the time of delivery [7]. ...
... In areas of stable malaria transmission of sub-Saharan Africa, intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) (IPTp-SP) is recommended for all pregnant women at each scheduled antenatal care visit (at least one month apart) up to the time of delivery [7]. Treatment of falciparum malaria involves administration of quinine plus clindamycin (if available) and if treatment fails, Artesunate combined therapy (ACT) is recommended [6,8]. ...
... Symptoms commonly associated with malaria parasitaemia include fever, headache and shivering [5]. It is possible that in malaria stable transmission areas, the burden of malaria is been underestimated, as most studies have been carried out in women reporting for scheduled visits or at delivery to investigate placental malaria [6,9,10]. ...
Background:
Pregnant women in malaria endemic areas are at high risk of P. falciparum infection and its complications. This study investigated the prevalence and risk factors for P. falciparum infection and malaria among pregnant women reporting for first antenatal care (ANC) clinic visit in the mount Cameroon area.
Methods:
Venous blood samples from consented pregnant women were screened for malaria parasitaemia by light microscopy. Haemoglobin levels, white blood cell (WBC) counts, lymphocyte counts and percentage were determined using an automated haematology analyser. Socio-demographic/economic data, environmental factors and use of malaria control measures were documented. Univariate and multivariate statistical analyses were used.
Results:
Sixty-eight (22.4 %; N = 303) of the women enrolled were positive for P. falciparum parasitaemia. Malaria parasitaemia was significantly (P < 0.001) associated with febrile illness. The overall prevalence of malaria and asymptomatic infection was 16.0 % (95 % CI = 11-20 %) and 10.5 % (95 % CI = 7.3-15 %) respectively. A greater proportion of the malaria cases (61 %) reported at the clinic during unscheduled days meanwhile women with asymptomatic parasitaemia mostly (92.8 %) seek for ANC during scheduled clinic days. Lower lymphocyte percentage was significantly associated with increase parasite density (r = - 0.34; P = 0.011) and febrile status (MU = 2.46; P = 0.014). While age and gravidity were significant factors associated with P. falciparum infection and/or malaria, the presence of bush and/or standing water around human residence was an independent risk factor of P. falciparum parasitaemia (OR = 3.3: 95 % CI = 1.6 - 7.0; P = 0.002) and malaria ( OR = 5.2: 95 % CI = 2.0 - 14; P = 0.001). Being unmarried was significantly associated with increase risk (OR = 2.6:95 % CI = 1.1 - 6.0; P = 0.032) of P. falciparum parasitaemia. Similarly, single women (938) had a significantly higher (t = 2.70; P = 0.009) geometric mean parasite density (GMPD) compared with married women (338).
Conclusion:
Marital status and human residence in areas with bushes and/or standing water modify risk of P. falciparum infection and malaria. Education on early ANC attendance and environmental sanitation are important public health targets for malaria control in pregnancy in this setting.
... Pregnant women with malaria are also at increased risk of hypoglycemia, acute respiratory distress syndrome (ARDS) [15], and hyperparasitemia [3] than non-pregnant women. In a review of severe malaria in pregnancy in the Asia Pacific region (227 women in eight studies) [14,[16][17][18][19][20][21][22], the median mortality rate was 39 % but ranged from 8 to 100 % [6]. This wide range is related to the broad WHO definition of severe malaria: the lowest mortality was reported in pregnant women whose only sign of severity was hypoglycemia. ...
... One study reported an increased risk of miscarriage and stillbirth associated with first-trimester exposure to quinine compared with AL [119]. Despite previous concerns, quinine at treatment doses does not induce abortion or labor [18]. ...
Severe malaria in pregnancy is a large contributor to maternal morbidity and mortality. Intravenous quinine has traditionally been the treatment drug of choice for severe malaria in pregnancy. However, recent randomized clinical trials (RCTs) indicate that intravenous artesunate is more efficacious for treating severe malaria, resulting in changes to the World Health Organization (WHO) treatment guidelines. Artemisinins, including artesunate, are embryo-lethal in animal studies and there is limited experience with their use in the first trimester. This review summarizes the current literature supporting 2010 WHO treatment guidelines for severe malaria in pregnancy and the efficacy, pharmacokinetics, and adverse event data for currently used antimalarials available for severe malaria in pregnancy. We identified ten studies on the treatment of severe malaria in pregnancy that reported clinical outcomes. In two studies comparing intravenous quinine with intravenous artesunate, intravenous artesunate was more efficacious and safe for use in pregnant women. No studies detected an increased risk of miscarriage, stillbirth, or congenital anomalies associated with first trimester exposure to artesunate. Although the WHO recommends using either quinine or artesunate for the treatment of severe malaria in first trimester pregnancies, our findings suggest that artesunate should be the preferred treatment option for severe malaria in all trimesters.
... Increased risks of foetal loss and SGA after severe malaria in pregnancy, particularly among those with organ dysfunction, were reported previously in a small case series [30]. The majority of foetal losses (84.0%) occurred within the first week of diagnosis; 44.7% of the SMRU severe malaria with organ dysfunction group had either maternal death, foetal loss or preterm birth within 1 week. ...
Background
Severe malaria in pregnancy causes maternal mortality, morbidity, and adverse foetal outcomes. The factors contributing to adverse maternal and foetal outcomes are not well defined. We aimed to identify the factors predicting higher maternal mortality and to describe the foetal mortality and morbidity associated with severe falciparum malaria in pregnancy.
Methods
A retrospective cohort study was conducted of severe falciparum malaria in pregnancy, as defined by the World Health Organization severe malaria criteria. The patients were managed prospectively by the Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border or were included in hospital-based clinical trials in six Southeast Asian countries. Fixed-effects multivariable penalised logistic regression was used for analysing maternal mortality.
Results
We included 213 (123 SMRU and 90 hospital-based) episodes of severe falciparum malaria in pregnancy managed between 1980 and 2020. The mean maternal age was 25.7 (SD 6.8) years, and the mean gestational age was 25.6 (SD 8.9) weeks. The overall maternal mortality was 12.2% (26/213). Coma (adjusted odds ratio [aOR], 7.18, 95% CI 2.01–25.57, p = 0.0002), hypotension (aOR 11.21, 95%CI 1.27–98.92, p = 0.03) and respiratory failure (aOR 4.98, 95%CI 1.13–22.01, p = 0.03) were associated with maternal mortality. Pregnant women with one or more of these three criteria had a mortality of 29.1% (25/86) (95%CI 19.5 to 38.7%) whereas there were no deaths in 88 pregnant women with hyperparasitaemia (> 10% parasitised erythrocytes) only or severe anaemia (haematocrit < 20%) only. In the SMRU prospective cohort, in which the pregnant women were followed up until delivery, the risks of foetal loss (23.3% by Kaplan–Meier estimator, 25/117) and small-for-gestational-age (38.3%, 23/60) after severe malaria were high. Maternal death, foetal loss and preterm birth occurred commonly within a week of diagnosis of severe malaria.
Conclusions
Vital organ dysfunction in pregnant women with severe malaria was associated with a very high maternal and foetal mortality whereas severe anaemia or hyperparasitaemia alone were not associated with poor prognosis, which may explain the variation of reported mortality from severe malaria in pregnancy. Access to antenatal care must be promoted to reduce barriers to early diagnosis and treatment of both malaria and anaemia.
... For uncomplicated malaria, ACTs such as artemetherlumefantrine are associated with significantly better treatment outcomes than quinine in all trimesters, [27] and are therefore the recommended treatment in SA. [28] Severe malaria in pregnancy should be preferentially treated with IV artesunate, as pregnant women are at significantly increased risk of quinine-associated hypoglycaemia. [29] ...
As September marks the start of the malaria season in South Africa (SA), it is essential that healthcare professionals consider both COVID-19 and malaria when a patient who lives in or has recently travelled to a malaria area presents with acute febrile illness. Early diagnosis of malaria by either a rapid diagnostic test or microscopy enables prompt treatment with the effective antimalarial, artemether-lumefantrine, preventing progression to severe disease and death. Intravenous artesunate is the preferred treatment for severe malaria in both children and adults. Adding single low-dose primaquine to standard treatment is recommended in endemic areas to block onward transmission. Use of the highly effective artemisinin-based therapies should be limited to the treatment of confirmed malaria infections, as there is no clinical evidence that these antimalarials can prevent or treat COVID-19. Routine malaria case management services must be sustained, in spite of COVID-19, to treat malaria effectively and support SA's malaria elimination efforts.
... For uncomplicated malaria, ACTs such as artemetherlumefantrine are associated with significantly better treatment outcomes than quinine in all trimesters, [27] and are therefore the recommended treatment in SA. [28] Severe malaria in pregnancy should be preferentially treated with IV artesunate, as pregnant women are at significantly increased risk of quinine-associated hypoglycaemia. [29] ...
As September marks the start of the malaria season in South Africa (SA), it is essential that healthcare professionals consider both COVID- 19 and malaria when a patient who lives in or has recently travelled to a malaria area presents with acute febrile illness. Early diagnosis of malaria by either a rapid diagnostic test or microscopy enables prompt treatment with the effective antimalarial, artemether-lumefantrine, preventing progression to severe disease and death. Intravenous artesunate is the preferred treatment for severe malaria in both children and adults. Adding single low-dose primaquine to standard treatment is recommended in endemic areas to block onward transmission. Use of the highly effective artemisinin-based therapies should be limited to the treatment of confirmed malaria infections, as there is no clinical evidence that these antimalarials can prevent or treat COVID-19. Routine malaria case management services must be sustained, in spite of COVID-19, to treat malaria effectively and support SA's malaria elimination efforts.
... Over one-third of deaths occurred in primigravid adolescents, primarily associated with severe anemia. Autopsies on 161 women showed that 44 (27.3%) had evidence of splenic malarial infection (Looareesuwan et al, 1985). At the main referral hospital in Gambia estimated that, during malaria season, there was a 168% increase in maternal mortality rate and a three-fold increase in proportion of deaths due to anemia. ...
Human malaria is caused by five species of Plasmodia: P. falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi. Most infections are due to either P. falciparum or P. vivax, but mixed infections with more than one malarial species also occur. The majority of malaria-related deaths are due to P. falciparum. Generally, the pregnant women are a high risk group, as malaria can be a life threatening infection for both mother and fetus. Risk of stillbirth, spontaneous abortion, and other adverse pregnancy outcomes is increased in the setting of malaria, and pregnant travelers should be advised to defer travel until after delivery whenever feasible.
... Tinnitus and dizziness reported to be frequently associated with quinine have the potential to make it intolerable (Fungladda et al. 1998). Quinine can also induce hyperinsulinaemia which potentially can aggravate hypoglycaemia (White et al. 1983;Looareesuwan et al. 1985;) associated with malaria in pregnancy. These potential adverse events related to quinine are likely to discourage the use of quinine during pregnancy and thus a regime of quinine may be difficult to implement. ...
A thesis presented on a clinical trial of amodiaquine (AQ) and sulphadoxine-pyrimethamine (SP) used singly and in combination (AQ+SP) compared with chloroquine (CQ) for the treatment of 900 pregnant women who had falciparum malaria infection detected by a screening programme using OptiMAL antigen dipsticks during routine antenatal clinic sessions at the St. Theresa's hospital. Enrolment into the study began in March 2003 and ended in September 2004 but follow up of treated women continued to March 2005.
... Parenteral quinine is no longer commercially available in the U.S [113]. Both quinine and quinidine including hydroxychloroquine may cause or aggravate hypoglycemia by stimulating insulin secretion, but quinine's effect is more potent [113,114]. ...
... 10,11 Febrile malaria episodes which are more likely among women with low immunity, are thought to induce uterine contractions which are mediated by elevated levels of TNF-alpha leading to preterm birth. 12,13 Malaria is also associated with hypertensive disorders of pregnancy such as gestational hypertension and preeclampsia in young primigravid women [14][15][16] and these are risk factors for LBW. 17 Low birth weight children have an increased incidence of hypertension in later life. ...
Rationale:
Several studies have demonstrated links between infectious diseases and cardiovascular conditions. Malaria and hypertension are widespread in many low and middle-income countries but the possible link between them has not been considered.
Objective:
In this article we outline the basis for a possible link between malaria and hypertension, and discuss how the hypothesis could be confirmed or refuted.
Methods and results:
We reviewed published literature on factors associated with hypertension and checked whether any of these were also associated with malaria. We then considered various study designs that could be used to test the hypothesis. Malaria causes low birth weight, malnutrition and inflammation, all of which are associated with hypertension in high-income countries. The hypothetical link between malaria and hypertension can be tested through the use of ecological, cohort or Mendelian randomization studies, each of which poses specific challenges.
Conclusions:
Confirmation of the existence of a causative link with malaria would be a paradigm shift in efforts to prevent and control hypertension and would stimulate wider research on the links between infectious and non-communicable disease.
... Mild side effects include tinnitus and slight hearing impairment. The hearing loss is, however, short-term and in most cases reversible(Looareesuwan et al., 1985). Other side effects include: dizziness, vomiting, headaches andnausea, abdominal pain, diarrhoea, and loss of vision. ...
The objective of this study was to perform a synthesis and analysis of the most important information on quinine and its derivatives, which are still very important in the treatment of malaria. The analysis of stereoisomers of quinine and its derivatives was conducted using two techniques, i.e. high-performance liquid chromatography and capillary electrophoresis. Particularly noteworthy is the technique used for the determination of isotachophoresis, referred to as one of the so-called green chemistry techniques. A particular attention was paid to properties and the use of quinine and its derivatives in the treatment of malaria. The analytical part will supplement the knowledge about quinidine, quinine and cinchonidine, and will contribute to the growth of research on the so-much-needed drugs against malaria.
Background
Standard dosage regimens of quinine formulated for adult patients with uncomplicated and complicated malaria have been applied for clinical uses in children, pregnant women, and elderly. Since these populations have anatomical and physiological differences from adults, dosage regimens formulated for adults may not be appropriate. The study aimed to (i) review existing information on the pharmacokinetics of quinine in children, pregnant women, and elderly populations, (ii) identify factors that influence quinine pharmacokinetics, and (iii) analyse the relationship between the pharmacokinetics and treatment outcomes (therapeutic and safety) of various dosage regimens of quinine.
Methods
Web of Sciences, Cochrane Library, Scopus, and PubMed were the databases applied in this systematic search for relevant research articles published up to October 2020 using the predefined search terms. The retrieved articles were initially screened by titles and abstracts to exclude any irrelevant articles and were further evaluated based on full-texts, applying the predefined eligibility criteria. Excel spreadsheet (Microsoft, WA, USA) was used for data collection and management. Qualitative data are presented as numbers and percentages, and where appropriate, mean + SD or median (range) or range values.
Results
Twenty-eight articles fulfilled the eligibility criteria, 19 in children, 7 in pregnant women, and 2 in elderly (14 and 7 articles in complicated and uncomplicated malaria, respectively). Severity of infection, routes of administration, and nutritional status were shown to be the key factors impacting quinine pharmacokinetics in these vulnerable groups.
Conclusions
The recommended dosages for both uncomplicated and complicated malaria are, in general, adequate for elderly and children with uncomplicated malaria. Dose adjustment may be required in pregnant women with both uncomplicated and complicated malaria, and in children with complicated malaria. Pharmacokinetics studies relevant to clinical efficacy in these vulnerable groups of patients with large sample size and reassessment of MIC (minimum inhibitory concentration) should be considered.
Chloroquine is currently used as a monotherapy in regions with chloroquine-susceptible infections. In contrast, the drug is no longer recommended for the prophylaxis against P. falciparum.
Introduction:
Malaria in pregnancy and postpartum cause maternal mortality and adverse fetal outcomes. Efficacious and safe antimalarials are needed to treat and prevent such serious consequences. However, because of the lack of evidence on fetal safety, quinine, an old and less efficacious drug has long been recommended for pregnant women. Uncertainty about safety in relation to breastfeeding leads to withholding of efficacious treatments postpartum or cessation of breastfeeding. Areas covered: A search identified literature on humans in three databases (MEDLINE, Embase and Global health) using pregnancy or lactation, and the names of antimalarial drugs as search terms. Adverse reactions to the mother, fetus or breastfed infant were summarized together with efficacies. Expert opinion: Artemisinins are more efficacious and well-tolerated than quinine in pregnancy. Furthermore, the risks of miscarriage, stillbirth or congenital abnormality were not higher in pregnancies exposed to artemisinin derivatives for treatment of malaria than in pregnancies exposed to quinine or in the comparable background population unexposed to any antimalarials, and this was true for treatment in any trimester. Assessment of safety and efficacy of antimalarials including dose optimization for pregnant women is incomplete. Resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum and long unprotected intervals between intermittent treatment doses begs reconsideration of current preventative recommendations in pregnancy. Data remain limited on antimalarials during breastfeeding; while most first-line drugs appear safe, further research is needed.
Background
We aimed to quantify the glycemic effects of quinine in healthy individuals.
Methods
We evaluated the glycemic profile in response to 4 h infusion of 500 ml of 0.9% saline versus 5% glucose solution with and without quinine at therapeutic dose (500 mg) in ten healthy volunteers (8 men) aged 28 ± 9 years. The order of the fourth explorations was randomly assigned. During these explorations, we measured blood glucose every 15 min for 4 h and compared the mean and glycemic fluctuations for each test. A resting ECG was performed before and after quinine infusion in each participant.
Results
The mean glycemic level during the 4-h infusion was 83 ± 5 mg/dl without quinine versus 74 ± 5 mg/dl with quinine (p < 0.001) using saline solute versus 92 ± 7 mg/dl without quinine versus 82 ± 5 mg/dl with quinine (p < 0.001) when associated with the glucose solute. In isotonic dirty solute, quinine induces a cumulative glycemic decrease of 17.5% (p = 0.01) characterized by a nadir estimated at −26.5% at the 60th minute (65 ± 23 mg/dl), p <0.001 followed by a gradual increase until the 4th hour. There were no signs of hypoglycemia or significant prolongation of the QT interval at the ECG. Overall, quinine did not induce a significant change in blood glucose with glucose compared to saline.
Conclusion
The intravenous infusion of quinine at a therapeutic dose induces a light drop in blood glucose with a significant nadir at the 60th minute in the healthy subject without hypoglycemia. This suggests the need for close monitoring in patients at risk of hypoglycemia such as those with severe malaria especially during the first hour of quinine infusion.
Malaria is one of the most common infectious diseases, which has become a great public health problem all over the world. Ineffectiveness of available antimalarial treatment is the main reason behind its menace. The failure of current treatment strategies is due to emergence of drug resistance in Plasmodium falciparum and drug toxicity in human beings. Therefore, the development of novel and effective antimalarial drugs is the need of the hour. Considering the huge biomedical applications of nanotechnology, it can be potentially used for the malarial treatment. Silver nanoparticles (AgNPs) have demonstrated significant activity against malarial parasite (P. falciparum) and vector (female Anopheles mosquito). It is believed that AgNPs will be a solution for the control of malaria. This review emphasizes the pros- and cons of existing antimalarial treatments and in depth discussion on application of AgNPs for treatment of malaria. The role of nanoparticles for site specific drug delivery and toxicological issues have also been discussed.
Normal vaginal floraVaginal discharge in pregnancyBacterial vaginosisTrichomonas vaginalis. 504CandidiasisGonorrhoeaChlamydia1 infectionMycoplasmasSyphilisAcute chorioamnionitisPostpartum pyrexia and puerperal (postabortal) sepsisGroup 8 streptococcusUrinary tract infectionListeriosisToxoplasmosisMalaria
Herbert Gilles played an important role in the establishment of the Wellcome-Mahidol University, Oxford Tropical Medicine Research Programme in Thailand in 1979. The randomized, placebo-controlled trial of dexamethasone in cerebral malaria that was carried out in Chantaburi in 1980 yielded results which led to the abandonment of ancillary corticosteroid therapy in this disease and contributed to a rejection of the ‘permeability hypothesis’. The clinical manifestations of strictly defined cerebral malaria have now been described both in non-immune adults in Thailand and Vietnam and in African children. Clinical and histopathological studies in human patients, together with laboratory studies of cyto-adherence, malaria ‘toxin’ and cytokine production have provided some evidence for both the ‘mechanical’ and ‘toxin-cytokine’ hypotheses to explain the pathophysiology of this condition. Chemotherapy is challenged by the continuing evolution of antimalarial resistance. Recently, the most powerful studies ever carried out with antimalarial drugs have demonstrated that artemether and quinine achieve similar case fatalities, in the range 11%–21%, and that both drugs have some advantages and disadvantages. Further studies are needed to define the efficacy and safety of prophylactic anticonvulsants and exchange transfusion in cerebral malaria. Cerebral malaria remains a major cause of mortality and, in African children, morbidity.
Malarial fever and dengue fever are major global health problems with about half of the world population at risk. Malaria is caused by protozoal parasite of genus Plasmodium by bite of infected female Anopheles mosquito while dengue is caused by dengue virus by bite of infected female Aedes aegypti mosquito. Pregnant patients because of their lowered immunity are at increased risk of developing the severe disease. Complicated malaria and severe dengue lead to adverse maternal and perinatal outcome including mortality. Also there is increased risk of vertical transmission in both. Parenteral artemisinin-based chemotherapy should be started without delay in severe malaria. There is no specific antiviral drug for dengue fever and treatment is mainly supportive and symptomatic. Malaria when timely and adequately treated does not have a residual deficit and the patients recover fully. In dengue fever recovery from infection provides lifelong immunity to that serotype, but subsequent infections by other serotypes increase the risk of developing severe dengue.
The arthropod-borne protozoan parasitoses caused by Plasmodium sp have produced incalculable human misery, morbidity, and mortality since antiquity; it is clear that Plasmodium sp is related to the coccidia (Chap. 4) (Bruce-Chwatt 1988a), and that the primate-vector cycle was established around 30 million years ago. It seems certain that early man, in the cradle of civilization of Africa (Stringer 1988; Stringer and Andrews 1988), must have been subjected to this group of infections. ‘Malaria’, which replaced the older term ague during the eighteenth century and is derived from the Italian description mal aria (poisonous air), is not a single disease. Human infection by four separate protozoan parasites belonging to the genus Plasmodium (which probably evolved from intestinal coccidia millions of years ago), presents as four diverse and characteristic clinical entities (Spencer and Strickland 1984; Bruce-Chwatt 1985; Haworth 1987; Cook 1989a). That produced by P falciparum causes an acute and potentially lethal illness (‘malignant tertian’ malaria, in the older terminology) while at the opposite end of the spectrum, P malariae produces a very chronic infection that may continue, often without serious morbidity, for 50 years or more (Table 1.1.). Diseases with intermediate clinical presentations result from infection with P vivax and P ovale; though neither is characteristically associated with acute mortality or great chronicity, both result in considerable subacute morbidity.
This chapter discusses diagnosis, clinical features, management, prognosis, and antimalarial chemotherapy of cerebral malaria. In cerebral malaria, mild hyponatremia and hypocholeremia are common. The blood urea is often elevated because of dehydration, but some degree of renal impairment is common. Abnormal liver function tests are also common, but difficult to interpret because of the coexisting hemolysis and release of muscle enzymes. The alanine aminotransferase value is usually proportionately lower than the corresponding aspartate aminotransferase or lactate dehydrogenase values, and the alkaline. The essentials of management are prompt administration of effective schizonticidal antimalarial drugs, intensive care of the unconscious patient and early detection or, where possible, avoidance of life-threatening complications, such as acute pulmonary edema, metabolic acidosis, renal failure, bacterial septicemia and aspiration pneumonia. If the clinical presentation and background are suggestive of cerebral malaria, then after a brief clinical examination, intravenous antimalarial should be given in case of pending results of the routine baseline hematological and biochemical tests. A finger prick stick test is useful in the diagnosis and monitoring of hypoglycemia. It should be remembered that false low readings may be obtained with old or damp strips.
Fever and host immune response in pregnancyGenital infections in pregnancyNongenital infections in pregnancyPuerperal infectionsObstetric anesthesia concerns related to thermoregulation and infection in pregnancyReferences
This article reviews the parasitology of malaria, epidemiology in pregnancy, pathogenesis of increased susceptibility to infection in pregnancy, the effect of pregnancy on the clinical manifestations of malaria, the effect of malaria on perinatal outcomes, the safety of antimalarial agents during pregnancy, the role of chemoprophylaxis for inhabitants and travelers to endemic areas, and treatment of clinical malarial infections during pregnancy.
Malaria is the preeminent infectious threat to tropical travelers, striking 15 per 1000 per month and killing 2% to 4% of those infected. Though no effective vaccine is yet available, malaria can be prevented by avoiding anopheline mosquito bites and by conscientiously taking prophylactic antimalarial drugs. Should prevention fail, clinical malaria is curable unless diagnosis and treatment are delayed. No symptom or sign is pathognomic of malaria; tertian fevers and exotic paroxysms rarely occur. The diagnosis of 'viral syndrome' in a febrile tropical traveler is an euphemism for malaria. In the nonimmune traveler, pregnant woman, or young child, malaria may begin as a fever or flu-like illness, but fulminantly progress to life- threatening anemia, jaundice, hypoglycemia, acidosis, kidney failure, pulmonary edema, convulsions, coma, and death over 6 to 24 hours. No matter how fleeting the malarial exposure or how careful the prophylaxis, it must be assumed that every tropical traveler with fever or unexplained systemic illness has malaria, and thick and thin Giemsa-stained blood smears must be emergently examined to confirm the diagnosis. All patients with P. falciparum malaria should be admitted to the hospital and, if severely ill, treated with parenteral quinidine, quinine, or artemisinin combined with tetracycline or clindamycin. Exchange transfusion, though not yet proven to enhance survival, should be considered when P. falciparum parasitemias exceed 10% or when life- threatening complications supervene. Multidrug-resistant parasites and insecticide-resistant mosquitoes are spreading worldwide faster than new medicines and pesticides can be discovered. Just 40 years ago, malaria was endemic in 140 countries over two thirds of the Earth, an area now inhabited by 4 billion people. The emergence of untreatable malaria over the next decade would be cataclysmic, decimating a generation of tropical children and threatening to re-establish lethal malaria in vast subtropical and temperate regions where it has long been forgotten. A new global sense of urgency and sustained commitment are needed to contain the threat of this ancient and emerging pathogen.
The resurgence of malaria in the past two decades has stimulated a considerable amount of scientific and medical research. Understanding of pathophysiological mechanisms in malaria has advanced considerably in areas, such as the pathogenesis of metabolic dysfunction, the molecular processes involved in cytoadherence, and the causes of anaemia. However, in other areas progress has been slow. Much of the recent research has been conducted either with animal models or with cultured P. fakiparum parasites. The relevance of the observations, and the hypotheses they generate, to disease in man still needs to be established in many cases. The roles of cytoadherence, rosetting, and cytokine release have come to the fore, whereas the parts played by immune damage, intravascular coagulation, and increased vascular permeability have receded. Clinical investigation has taken some of the mystery out of malaria, but still relatively little is known for certain. The next challenge is to translate these advances in understanding of pathophysiology into improved treatments.
Lung involvement in malaria has been recognized for more than 200 hundred years, yet our knowledge of its pathogenesis and management is limited. Pulmonary edema is the most severe form of lung involvement. Increased alveolar capillary permeability leading to intravascular fluid loss into the lungs is the main pathophysiologic mechanism. This defines malaria as another cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).
Pulmonary edema has been described most often in non-immune individuals with Plasmodium falciparum infections as part of a severe systemic illness or as the main feature of acute malaria. P. vivax and P. ovale have also rarely caused pulmonary edema.
Clinically, patients usually present with acute breathlessness that can rapidly progress to respiratory failure either at disease presentation or, interestingly, after treatment when clinical improvement is taking place and the parasitemia is falling. Pregnant women are particularly prone to developing pulmonary edema. Optimal management of malaria-induced ALI/ARDS includes early recognition and diagnosis. Malaria must always be suspected in a returning traveler or a visitor from a malaria-endemic country with an acute febrile illness. Slide microscopy and/or the use of rapid antigen tests are standard diagnostic tools. Malaria must be treated with effective drugs, but current choices are few: e.g. parenteral artemisinins, intravenous quinine or quinidine (in the US only). A recent trial in adults has shown that intravenous artesunate reduces severe malaria mortality by a third compared with adults treated with intravenous quinine. Respiratory compromise should be managed on its merits and may require mechanical ventilation.
Patients should be managed in an intensive care unit and particular attention should be paid to the energetic management of other severe malaria complications, notably coma and acute renal failure. ALI/ARDS may also be related to a coincidental bacterial sepsis that may not be clinically obvious. Clinicians should employ a low threshold for starting broad spectrum antibacterials in such patients, after taking pertinent microbiologic specimens. Despite optimal management, the prognosis of severe malaria with ARDS is poor.
ALI/ARDS in pediatric malaria appears to be rare. However, falciparum malaria with severe metabolic acidosis or acute pulmonary edema may present with a clinical picture of pneumonia, i.e. with tachypnea, intercostal recession, wheeze or inspiratory crepitations. This results in diagnostic confusion and suboptimal treatment. Whilst this is increasingly being recognized in malaria-endemic countries, clinicians in temperate zones should be aware that malaria may be a possible cause of ‘pneumonia’ in a visiting or returning child.
In the developing world, hypoglycemia is a frequent complication among admitted children, particularly in malaria-endemic areas, and a defining feature of severe malaria and associated with high case fatality rates (CFR). This complication could be much more common than currently considered, particularly because it frequently occurs without a direct immediate clinical translation. Its etiology has not yet been fully understood and is likely to be multifactorial. Routine screening and treatment of hypoglycemia, as recommended by international guidelines, may be challenging to perform indeveloping countries on account of the limited resources available. In this review, we discuss the published literature in relation with the incidence, risk factors, and consequences of hypoglycemia among malaria patients, aiming to improve our current understanding of this common and life-threatening complication of malaria.
By adulthood repeated exposure to Plasmodium falciparum, the causative agent of the most severe form of malaria in humans, can induce semi-immunity to clinical infection. During pregnancy, however, there is a striking recurrence of severe disease, a syndrome described as pregnancy-associated malaria (PAM). This is caused by P. falciparum-infected erythrocytes binding to receptors on the placental endothelium that are expressed uniquely during pregnancy. This subset of parasites binds by virtue of expressing a cell surface antigen that is the ligand for the corresponding endothelial receptor, thereby providing a selective pressure for its clonal expansion. The antigen also triggers a protective antibody-mediated immune response. With subsequent pregnancies and further exposure to these variant parasites, antibodies develop earlier and women may experience milder infections. Women with PAM exhibit more severe malaria infections than do non-gravid women, with 2,500-10,000 deaths each year due to haemolytic anaemia. PAM also has a detrimental effect on the foetus, increasing the risk of low birth weight, which causes 60,000-200,000 infant deaths annually in sub-Saharan Africa. Current research aims to produce a vaccine to stimulate development of antibodies which would be protective against infection with wild-type parasites. This is hampered by significant diversity in variant surface antigens and available vaccine candidates may only protect women living in malaria-endemic areas. While placental-parasite interactions are not sufficiently understood, incremental progress is being made towards producing an effective vaccine. This review focuses on the molecular structures involved in binding to consider the prospects for a vaccine mimicking naturally-acquired immunity to PAM.
Three classes of antimalarial drugs are useful for cerebral malaria: the 4-aminoquinolines (chloroquine), the cinchona alkaloids (quinine, quinidine) and the artemisinin compounds (artesunate, artemether). Chloroquine is the drug of choice in the few areas of the world where the falciparum parasite remains sensitive. In most malarious regions, however, the cinchona alkaloids and the artemisinin compounds are the only remaining options. In some areas of Southeast Asia, resistance to quinine is established, further limiting treatment options and raising concerns for the future. Artemisinin compounds, an exciting new class of antimalarial drugs developed in China, are the most rapidly acting of all the antimalarial drugs, with little known toxicity. Despite new insight into the pathogenesis of cerebral malaria and powerful antiparasitic therapies, the mortality rates in patients with this disease have remained stable over many years and are unacceptably high, ranging from 10 to 50%. Thus, malaria remains a tremendous public health problem that requires continued efforts to better understand pathophysiology and develop more effective therapies.
Malaria, caused mostly by Plasmodium falciparum and P. vivax, remains one of the most important infectious diseases in the world. Antimalarial drug toxicity is one side of the risk-benefit equation and is viewed differently depending upon whether the clinical indication for drug administration is malaria treatment or prophylaxis. Drug toxicity must be acceptable to patients and cause less harm than the disease itself. Research that leads to drug registration tends to omit two important groups who are particularly vulnerable to malaria — very young children and pregnant women. Prescribing in pregnancy is a particular problem for clinicians because the risk-benefit ratio is often very unclear.
The number of antimalarial drugs in use is very small. Despite its decreasing efficacy against P. falciparum, chloroquine continues to be used widely because of its low cost and good tolerability. It remains the drug of first choice for treating P. vivax malaria. Pruritus is a common adverse effect in African patients. As prophylaxis, chloroquine is usually combined with proguanil. This combination has good overall tolerability but mouth ulcers and gastrointestinal upset are more common than with other prophylactic regimens. Sulfadoxine/pyrimethamine is well tolerated as treatment and when used as intermittent preventive treatment in pregnant African women. Sulfadoxine/pyrimethamine is no longer used as prophylaxis because it may cause toxic epidermal necrolysis and Stevens Johnson syndrome. Mefloquine remains a valuable drug for prophylaxis and treatment. Tolerability is acceptable to most patients and travellers despite the impression given by the lay press. Dose-related serious neuropsychiatric toxicity can occur; mefloquine is contraindicated in individuals with a history of epilepsy or psychiatric disease. Quinine is the mainstay for treating severe malaria in many countries. Cardiovascular or CNS toxicity is rare, but hypoglycaemia may be problematic and blood glucose levels should be monitored. Halofantrine is unsuitable for widespread use because of its potential for cardiotoxicity.
There is renewed interest in two old drugs, primaquine and amodiaquine. Primaquine is being developed as prophylaxis, and amodiaquine, which was withdrawn from prophylactic use because of neutropenia and hepatitis, is a potentially good partner drug for artesunate against falciparum malaria. Atovaquone/proguanil is a new antimalarial combination with good efficacy and tolerability as prophylaxis and treatment. The most important class of drugs that could have a major impact on malaria control is the artemisinin derivatives. They have remarkable efficacy and an excellent safety record. They have no identifiable dose-related adverse effects in humans and only very rarely produce allergic reactions. Combining an artemisinin derivative with another efficacious antimalarial drug is increasingly being viewed as the optimal therapeutic strategy for malaria.
Glucose homeostasis is maintained by a balance between the release and action of insulin, and the counterregulatory responses mediated principally by glucagon, catecholamines, growth hormone and cortisol. Hence, the effects of a drug on glucose metabolism may be mediated by any of these agents singly or in combination. Host factors, such as inherent glucoregulatory mechanisms, concurrent diseases, organ function and concomitant medications also increase the risk of drug-induced disturbances of glucose homeostasis in susceptible individuals. By far the most important agents causing hypoglycaemia are insulin and the sulphonylureas. Alcohol (ethanol), over-zealous glycaemic control, hypoglycaemic unawareness, defective counterregulation especially in insulin-dependent diabetes mellitus (IDDM), and renal and liver impairment are all important predisposing factors. Although antihyperglycaemic agents such as metformin and α-glucosidase inhibitors do not cause hypoglycaemia alone, they may enhance the hypoglycaemic effects of potent hypoglycaemic agents such as insulin and sulphonylureas. On the other hand, the potential hypoglycaemic effects of ACE inhibitors, α-blockers, lipid-lowering agents and recombinant human insulin-like growth factor demonstrated in experimental settings, are of potential therapeutic interest.
Iatrogenic hypoglycaemia and intensive insulin treatment are associated with hypoglycaemic unawareness which may be obviated by meticulous avoidance of hypoglycaemia. Effective patient education remains an important preventive measure. Oral glucose is used to treat mild hypoglycaemic episodes while more severe episodes are treated by intravenous glucose or glucagon. Nasal glucagon and theophylline are other experimental measures to improve recovery from hypoglycaemia. In refractory hypoglycaemia due to hyperinsulinaemia such as during sulphonylurea overdosage or quinine treatment, the long-acting somatostatin, octreotide, may suppress insulin release and restore euglycaemia.
Diuretics, β-blockers, sympathomimetics, corticosteroids and sex hormones are commonly prescribed drugs which may have adverse effects on carbohydrate metabolism especially in patients with diabetes mellitus or those who are at risk of developing glucose intolerance. Pentamidine was frequently associated with dysglycaemia due to its pancreatic β-cell cytotoxic effects but is now used less often to treat Pneumocystis carinii pneumonia in immunosuppressed patients.
Despite the large number of anecdotal reports of drug-induced disturbances of glucose metabolism, many of the so-called adverse drug reactions were either idiosyncratic or coincidental. Nevertheless, they emphasise the complex nature of glucose homeostasis and its potential interactions with drugs, host factors and disease states. An understanding of these relationships may allow more critical interpretation of these clinical observations, better prediction of drug-induced adverse effects on carbohydrate metabolism and the implementation of more rational therapy. Hence, the hypoglycaemic effects of a drug may be turned to a therapeutic advantage in patients with glucose intolerance. Similarly, the hyperglycaemic effect of a drug may help to treat refractory hypoglycaemia.
This review article describes the epidemiology, pathological and clinical features offalciparum malaria infection in pregnancy. The effects of malaria in pregnancy on both mother and fetus vary greatly according to the immune status of the woman, which in turn is determined by her exposure to infection. Non-immune pregnant women are at a much greater risk of severe disease than non-pregnant women and are at three-fold greater risk of death if they do develop severe disease. Any woman with symptomatic malaria should be treated with great urgency, using the most effective anti-malarial drug available. Specific features of severe disease in pregnancy include: hypoglycaemia, severe anaemia, pulmonary oedema, hyperpyrexia and cerebral malaria. Any patient with signs of severe disease should be managed in an intensive care or high dependency setting.The effects of malaria on the fetus are discussed and current recommendations for treatment are outlined for clinicians in a developed country setting. Recommendations for advice to travelers are made and brief mention is made of treatment for non-falciparum malaria infections in pregnancy.
1. The placental blood film examination is worthy of routine application wherever aestivo-autumnal malaria is endemic. This type of malaria when associated with labor and the early days of the puerperium can be more easily and certainly diagnosed by the use of this film and a polychrome stain than by employing the usual films made from the mother's peripheral blood at the time of labor. The placental film in such an infection offers an abundance of adult parasites and far more evidence of the presence of pigment, while the peripheral blood film frequently offers but a scant number of the small ring or discoid forms of a parasite. The examination of the present series revealed positive placental films in nineteen cases, while but eight of these same cases were positive in the peripheral blood film examination. On the other hand, no peripheral blood films were found positive in which the associated placental films did not reveal a far more abundant evidence of the infection. 2. The early days of the puerperium can by this method be protected many times from a malarial outburst, and, as a rule, puerperal sepsis can be differentiated. 3. The intricate vascular architecture of the mature placenta rivals that of the spleen, liver, and bone marrow as a harbor for adult malarial parasites of this type and as a storage for pigment. 4. The localization of parasites in the placenta is unique. Here is the one vascular system which particularly favors the development of the parasites but which at the same time is so situated that it may be spontaneously discarded by the body at the climax of the attack. By this simple act late in pregnancy the prognosis for both mother and child may be improved. 5. The pregnant state encourages attacks of malaria by lowering bodily resistance and by furnishing an additional harbor for the development of parasites. A tenable theory in regard to most attacks of this nature, occurring in cases under professional care, would appear to be the development of latent malaria (malarial carriers) into acute attacks toward the close of the pregnant state. The women who expose themselves (as the negroes in this series) offer favorable conditions to the introduction of a primary infection. Malaria frequently interrupts the late stages of pregnancy and sometimes causes the death of the mother and the fetus, more often the latter. The records at Ancon indicate that it more frequently exerts a harmful influence than other types of infectious diseases in this locality. 6. Most of the children in this series that were delivered while malaria was present in the mother, were of a race that seems to possess a relative immunity to the ravages of malaria. This may account for the fact that the negro fetus more nearly approximates the full term of development when associated with this disease and is comparatively subjected to a less number of the accidents of pregnancy. Many of them revealed evidence of prematurity and were jaundiced, but, as a rule, they developed rapidly. The commonest mishap is miscarriage late in pregnancy. Occasional still-births occur and sometimes there is a fatal issue to both the mother and child. 7. Cases diagnosed as congenital malaria probably indicate that some accident occurred to the placenta, because it practically never happens that fetal blood is positive at the time of birth, regardless of the degree of infection in the mother. Many of the cases now reported in the literature as congenital malaria suggest immediate postnatal infection as their history, as our pathological and clinical records testify. 8. The size of the intervillous spaces of the placenta and their adaptability in the localization of parasites seem to disprove to a certain extent the old idea that the localization depends on the smallness of the capillary caliber. If this were the case the brain should be more often the seat of an extensive localization than the spleen, bone marrow, and placenta, yet our anatomical records will not support that theory. A sluggish blood sinus with a large endothelial surface, a higher internal body temperature, and red blood cells burdened with parasites of a certain age beyond the ring form seem to be important factors in the localization and development of the aestivo-autumnal parasite. 9. The racial disparity of malarial infections shown in this series is believed to be due to local conditions and a wrong impression is apt to be given by our statistics in regard to the relative immunity of the negro race. The white women on the Canal Zone avail themselves of all the opportunities the sanitary system affords; they live well and place the entire course of their pregnant state under competent professional care, while the negro woman is indifferent to her pregnant state, works as a domestic servant, and lives in the cheapest unprotected quarters that can be rented in the suburban divisions of Panama City where the malarial rate is highest and the sanitary control is difficult. It should be noted that these negro women can carry an infection with little manifestation of its presence that would produce serious results in the white women brought from the temperate zone regions of Europe and the United States.
Hypoglycaemia is a biochemical sign of many different diseases and is not a diagnosis in its own right: merely a pointer to one. It owes its importance to the fact that it produces symptoms referrable to the nervous system which are often the reason for the patient seeking medical help. Apart from emergency treatment which is always to raise the blood glucose concentration to the upper range of normoglycaemia and maintain it there until the patient recovers the correct treatment of hypoglycaemia is that of the primary disease causing it. Appropriate use of laboratory and radiological procedures makes this possible in almost every case. The protocol of investigation used in the author's laboratory is described.
It is widely accepted that metabolites of glucose rather than glucose itself trigger insulin release from β-cells. If so, level changes of such metabolites ought to occur in β-cells within seconds of a glucose pulse. To examine this hypothesis, glucose, glucose-6-P, fructose-diP plus triose-P, 6-P-gluconate, ATP, and P-creatine were measured in individual rat islets after intravenous infusion for 1 to 60 min of glucose, mannoheptulose, and xylitol, or combinations of these compounds. Insulin levels in serum were determined concomitantly. Some of the animals were fasted for 5 or 6 days prior to glucose infusion.
Individual islets were dissected from freeze-dried sections sampled with quick freezing methods. The sensitivity and specificity needed for analysis of metabolites and cofactors were gained by using enzymatic fluorometric procedures combined with an oil well method and enzymatic cycling of pyridine nucleotides. Serum insulin was determined immunochemically.
Insulin levels in peripheral blood rose within 1 min of injection of glucose. Mannoheptulose as well as fasting blocked this glucose effect. Penetration of glucose, although very rapid, was carrier mediated, since under special conditions mannoheptulose and also xylitol caused exit countertransport of glucose from the β-cells. This shows that mannoheptulose has effects on glucose metabolism of islets that are independent of its ability to inhibit phosphorylation. Most of the metabolites and cofactors measured were unchanged during the first 5 min of glucose infusion. Fructose-diP plus triose-P rose within 1 min in fed animals, but also increased when insulin release was blocked in various ways.
After 1 hour of hyperglycemia there was a marked rise in all metabolites and cofactors save ATP. The metabolic changes induced by glucose infusion in severely fasted animals, indicate that islet cell metabolism was stimulated, although insulin release was blocked.
These results and reports by other investigators suggest that glucose itself rather than its metabolites triggers insulin secretion.
Intrapartum fetal heart rate monitoring was developed in the mid 1960s after patterns of heart rate change in relation to uterine contractions had been described by Hon, Caldero-Barcia and Hammacher. When the method was first developed, there were numerous non-randomized studies comparing electronically monitored patients to either historical controls or low-risk patients who were monitored by auscultation which was not rigorous. It was clear early on that the intrapartum fetal death rate was significantly less in electronically monitored patients than in the non-randomized controls, even if the controls were low risk and the electronically monitored patients were high risk. Many reports have indicated that fetal inflammatory response to maternal infection may result in the elaboration of proinflammatory cytokines that may be responsible for damage in the periventricular areas of the premature fetal brain resulting in spastic diplegia.
Obesity complicating pregnancy continues to be a major clinical problem for the obstetrician and the obstetric anaesthetist. Studies suggest that the physiological changes of pregnancy, designed to increase maternal energetic efficiency and liberate fetal substrates, may contribute to a worsening of obesity in susceptible subjects. Adverse outcomes of pregnancy that are significantly more common in the obese include maternal death, thromboembolism, preeclampsia, gestational diabetes, emergency caesarean section, neonatal death and fetal overgrowth. Outside pregnancy, obesity in the mother and the newborn contribute to later disease patterns that can shorten life expectancy.
1. Membrane potentials and input resistance were measured in beta-cells from mouse pancreatic islets of Langerhans in a study designed to assess the role of a K permeability specifically blocked by quinine or quinidine and activated by intracellular calcium ion concentration ([Ca2+])i-activated PK). 2. Addition of 100 microM-quinine to the perifusion medium resulted in a 10--30 mV depolarization of the membrane and an increase in the input resistance of ca. 4.10(7) omega. 3. In the absence of glucose, 100 microM-quinine induced electrical activity. 4. In the presence of glucose, 100 microM-quinine abolished the burst pattern of electrical activity and very much reduced the graded response of spike frequency normally seen with different concentrations of glucose. 5. Addition of mitochondrial inhibitors, KCN, NaN3, DNP, CCCP, FCCP, to the perifusion medium containing glucose rapidly hyperpolarized the beta-cell membrane, inducing a concomitant decrease in input resistance. 6. In the presence of glucose, these mitochondrial inhibitors reversibly blocked electrical activity; upon removal of the inhibitor, recovery of electrical activity followed a biphasic pattern. 7. The effects of mitochondrial inhibitors were partially reversed by 100 microM-quinine. 8. It is proposed that the membrane potential of the beta-cell in the absence of glucose is predominantly controlled by the [Ca2+]i-activated PK. It is further suggested that this permeability to K controls the level for glucose stimulation and leads to the generation of the burst pattern.
Electronic fetal heart rate (FHR) monitoring has become one of the most widespread techniques of antepartum surveillance in high-risk pregnancy. Currently two tests in this format are being used, either alone or in combination, the nonstress test (NST) and the contraction stress test (CST). There is considerable debate about which of these two tests is the more useful and which the more reliable. The purpose of this report is to compare the role of each test in antepartum fetal evaluation in an attempt to reconcile the different approaches and statistics published in the literature. These schemes and concepts are still developing, and the ultimate benefits of NST-CST testing remain to be determined. What seems conclusive is that some form of fetal testing must be incorporated into the evaluation of all pregnancies. As pointed out above, the value of testing cannot be divorced from the program of care of which monitoring is only a part. It can be argued that the greater impact on outcome is the benefit of being in an organized program of perinatal care. However, the availability of sensitive tests of fetal well-being is necessary if we are to maximize those statistics.
The birth weights and gestational ages of normal infants born to 1,000 consecutive healthy middle class Thai mothers who fitted the given criteria were studied. The mean gestational period of uncomplicated pregnancies was 280 ± 7 days. 3.3% of pregnancies were prolonged. The mean birth weight of males and females was 3,249 ± 311 g and 3,176 ± 321 g respectively. Males were thus 73 ± 39 g heavier than females. The birth weights of first male and female babies were 92 ± 52 g and 144 ± 56 g respectively, lower than those of subsequent babies. No significant differences in the birth weights of second and subsequent babies were observed. There were no differences in birth weights of infants in which the gestational period ranged from 266 to 298 days.
After dinner at 6 P.M. food was withheld from non-pregnant women and women in the third trimester of pregnancy: there were lean and obese women in each group, and all had normal carbohydrate metabolism. Levels of circulating fuels and glucoregulatory hormones were monitored between 6 A.M. (12 h fast) and noon (18 h fast) the following day. In non-pregnant women plasma levels of glucose, alanine, free fatty acids (FFA) beta-hydroxybutyrate, insulin, and glucagon remained constant between 6 A.M. and noon except for slight fall in plasma alanine in the obese women and slight increases in beta-hydroxybutyrate in the lean. By contrast, in pregnant women the concentrations of all substances measured changed profoundly after extension of the overnight fast. Levels of plasma glucose, which were significantly lower than those in non-pregnant women at 6 A.M., fell further during the subsequent 6 h; plasma alanine levels declined significantly during the same interval, and there were coincident rises in plasma FFA and beta-hydroxybutyrate and reductions in plasma insulin. The changes in lean and obese women were of similar magnitude; habitus did not therefore seem to have effects additional to those of pregnancy on the response to skipping breakfast. In all the pregnant women final levels of FFA and beta-hydroxybutyrate were strongly correlated and inversely related to final levels of plasma glucose. The studies indicate that "accelerated starvation" can be unmasked during pregnancy even with the minor dietary deprivation common in conventional clinical circumstances. Thus, insofar as it may be desirable to avoid ketonaemia during pregnancy, the common practice of skipping breakfast whether by personal preference or for doctor-initiated laboratory testing should be avoided in pregnant women.
We studied the occurrence, clinical manifestations, and mechanism of hypoglycemia in patients with falciparum malaria in eastern Thailand. Hypoglycemia, which was often severe and recurrent, occurred in 17 patients, including 12 in a series of 151 patients with cerebral malaria. Thirty episodes were investigated. Plasma concentrations of insulin and C peptide were inappropriately high, and lactate and alanine concentrations were significantly higher than in patients with falciparum malaria who were normoglycemic (P less than 0.05). Sixteen patients had received quinine; plasma quinine and insulin concentrations were correlated at the time of hypoglycemia (P = 0.007). In seven healthy fasting volunteers intravenous quinine increased the mean plasma insulin concentration (+/- S.D.) from 8.9 +/- 3.1 to 17.1 +/- 8.4 mU per liter (P = 0.02) and reduced the mean plasma glucose concentration from 88 +/- 20 to 68 +/- 23 mg per deciliter (P = 0.002). Our observations indicate that in falciparum malaria quinine-induced insulin secretion may precipitate hypoglycemia, but other factors, including the large glucose requirements of the malaria parasites may also contribute. This important complication, associated with pregnancy and severe disease, must be excluded in all patients with falciparum malaria who have impaired or deteriorating consciousness.
This paper describes the results of testing the susceptibility of 60 isolates of the human malaria parasite Plasmodium falciparum from Thailand, and single isolates from five other countries, to five drugs: chloroquine, pyrimethamine, quinine, mefloquine and amodiaquine. The Thai isolates were obtained from patients in three different regions of the country (Chantaburi, Songkhla and Mae Sod), and were first grown in culture by the Trager-Jensen candle-jar technique. Samples were then exposed to a range of concentrations of the five drugs, in Falcon microtest culture wells, for 72 hours, with daily changes of medium (with or without added drug solutions). Presence or absence of parasites was then determined by microscope observations on thin-film Giemsa-stained preparations.
Most Thai isolates showed a minimum inhibitory concentration (MIC) for chloroquine of 10⁻⁶M or higher, and were classified as highly resistant, though one cloned isolate was as sensitive to this drug as a chloroquine-sensitive isolate from West Africa. Similarly most Thai isolates showed a very high resistance to pyrimethamine (MIC 10⁻⁴M to 10−bM), but a few clones were sensitive (MIC 10⁻⁹) to it. Susceptibility to quinine showed some variation (MIC varied between 10⁻⁶M and 10⁻⁸M), and some isolates were thought to be incapable of responding to a therapeutically permissible dose of this drug. Little variation was found in the reaction of any of the isolates to mefloquine or amodiaquine, and by the in vitro technique used in this study, it was found that chloroquine-resistant and chloroquine-sensitive isolates were equally susceptible to amodiaquine.
In general the survey showed the existence of a marked correlation between development of drug resistance of Plasmodium falciparum and the extent to which a given drug had been used in Thailand.
Acute pharmacokinetics of intravenously infused quinine were studied in 25 patients with cerebral malaria and 13 with uncomplicated falciparum malaria. In patients with cerebral malaria receiving the standard dose of 10 mg/kg every eight hours, plasma quinine concentrations consistently exceeded 10 mg/liter, reaching a peak 60 +/- 25 hours (mean +/- 1 S.D.) after treatment was begun and then declining. Quinine total clearances (Cl) and total apparent volumes of distribution (Vd) were significantly lower than in uncomplicated malaria (Cl, 0.92 +/- 0.42 compared with 1.35 +/- 0.6 ml/min/kg, p = 0.03; Vd, 1.18 +/- 0.37 compared with 1.67 +/- 0.34 liter/kg, p = 0.0013). There was no significant difference between the two groups in elimination half-times (t/2) or renal clearances (Cu) (t/2, 18.2 +/- 9.7 compared with 16 +/- 7.0 hours; Cu, 0.21 +/- 0.16 compared with 0.21 +/- 0.08 ml/min/kg). In nine patients studied following recovery, Cl (3.09 +/- 1.18 ml/min), Vd (2.74 +/- 0.47 liter/kg), and Cu (0.53 +/- 0.22 ml/min/kg) were significantly greater (p less than or equal to 0.0004), and t/2 was significantly shorter (11.1 +/- 4.1 hours, p = 0.006) than during the acute illness. Cu accounted for approximately 20 percent of Cl in all groups. Renal failure did not alter the disposition kinetics in cerebral malaria. There was no clinical or electrocardiographic evidence of cardiotoxicity and no permanent neurotoxicity. Quinine toxicity in cerebral malaria has probably been overemphasized. The benefits of high plasma concentrations in the acute phase of this life-threatening disease appear to outweigh the risks, particularly in view of the increasing resistance of Plasmodium falciparum to quinine in Southeast Asia.
Placenta malarial changes (PMCs) related to maternal plasmodium infection were present in 33% (247 cases) of a series of 741 placentas collected from an unselected population living in an area of high malarial endemicity (Haut-Ogooué, Gabon, Africa). Plasmodia were found on material thick blood films taken at the time of delivery in 42% of the women with and 24% of women without associated PMCs. Plasmodium falciparum was the most frequent infecting organism. PMCs were more frequent and, in general, more marked in primiparas. The primiparas were significantly (P less than 0.001) more numerous in the group with PMCs than in the control group without such changes. The mean weight of term placentas with malarial changes was significantly (46 g; P less than 0.001) less than that of placentas without such changes. The morphologic changes were a combination of the following features: 1) presence of parasites in the intervillous spaces; 2) macrophage concentration in the intervillous spaces; 3) malarial pigment deposits; 4) excess of perivillous fibrinoid deposits; 5) syncytiotrophoblastic damage; and 6) trophoblastic basal lamina thickening. Plasmodia were found in placental intervillous spaces in 42% (105/247). Local parasitemia varied in magnitude; in a few cases, 30% or more of the maternal erythrocytes were infected. Macrophage concentration in the intervillous spaces was present in 29% (72/247) and was always associated with local parasitemia. Macrophages phagocytized red blood cells and malarial pigment, and their number varied inversely with that of the local parasites. It seems, therefore, that macrophages play an important role in local parasite clearance. Malarial brown pigment was observed in all cases from the series. It had characteristic ultrastructural features and occurred in perivillous deposits of fibrinoid, in macrophages, or free in intervillous spaces. Excessive perivillous fibrinoid deposits were a constant histologic finding and were usually associated with syncytiotrophoblastic necrosis or ultrastructural damage such as partial microvilli loss, filamentous material accumulation in intracytoplasmic vacuoles, and "podocytelike" cytoplasmic projections on the basal surface. At these sites the trophoblastic basal lamina was usually thickened. Previously reported morphologic data and our own findings suggest that the peculiar placental changes in malaria, restricted to intervillous spaces and to villous surfaces, may be related to an immunopathologic process.
This chapter discusses the problem of intra-uterine infections from the wider context of the fetal–maternal interaction as a whole. Maternal infections can be harmful to the fetus without the actual transmission of the pathogenic organisms. Clinical disease in the fetus resulting from intra-uterine infection is easily recognizable, but there may be less obvious manifestations. Early contact with parasitic antigens could modulate the fetus' future immune response, leading either to sensitization or to the development of a state of tolerance at the next encounter with similar parasites. This could alter the pathological spectrum of future infections, thus changing the whole pattern of parasitic diseases among indigenous populations of endemic areas. Fetal and maternal blood, are not in direct communication with each other but totally separated. This was the structural basis for the concept of the placental barrier. During pregnancy, there is a depression of maternal immune response. This lowered reactivity is directed toward fetal allo-antigenic determinants, and this process is concerned with maternal nonrejection of her immunologically alien conceptus. The parasites that can be transmitted from mother to fetus in utero are Toxoplasma, Plasmodium, Trypanosoma, Leishmania, and Helminths. Maternal parasitic infections can affect the fetus in two ways: by direct invasion of the fetus by the parasites and indirectly, by lowering maternal health to such a level as to interfere with fetal well-being. The fetus in utero, therefore, does not remain passive when confronted with parasitic organisms or their antigens but will be expected to mount an active immune response. In order for the placenta to fulfil the protective role, it should function as a barrier against the transmission of infective organisms from the mother.
Peritoneal exudate macrophages induced in male Holtzman rats with sodium caseinate produced a mediator with insulin-like activity as assessed by the conventional bioassay of increased glucose oxidation in epididymal fat pads. Salmonella enteritidis endotoxin increased secretion of macrophage insulin-like activity (MILA) either (a) when the endotoxin was added directly to acute cultures of macrophages co-incubated with epididymal fat pads in Krebs-Ringer bicarbonate buffer containing 5.55 mM D-glucose and 0.5 μCi/ml of U-D-14C-glucose or (b) when it was incubated with macrophage cultures in Dulbecco's modified Eagle's medium and subsequent bioassays of the conditioned media. It is postulated that MILA may play a role in the characteristic hypoglycemia of endotoxin shock.
DESPITE a voluminous amount of research directed at elucidating the mechanisms of human carbohydrate metabolism many unexplored areas remain, especially in the pregnant state. Many studies have made reference to the altered carbohydrate metabolism in pregnancy based upon changes in the oral glucose tolerance tests. Studies using intravenous glucose tolerance tests have shown normal curves during pregnancy and in fact suggest that more insulin may be released by the pancreas during the pregnant state.1 This is supported by pathological study of the pancreases of pregnant women that shows an increase in the size and number of the islands of Langerhans. . . .
ACUTE RENAL FAILURE during pregnancy or immediately postpartum accounts for 20% to 40% of all cases of acute renal failure.1,2 In the majority of these cases, renal failure results from ischemic tubular necrosis following shock precipitated by uterine hemorrhage or massive intravascular hemolysis1,3 following incompatible blood transfusions. Occasionally, bilateral renal cortical necrosis is responsible for the acute renal failure of these patients.1,4
Although rarely reported, quinine sulfate used as an abortifacient, or for some other purpose in the first trimester of pregnancy, may cause massive intravascular hemolysis followed by ischemic tubular necrosis and acute renal failure.5-9 A patient exhibiting acute renal failure following the ingestion of quinine sulfate during the eighth week of pregnancy has been studied. In this patient, uremia was controlled and complete recovery followed intensive medical management which included peritoneal dialysis.
Report of a Case
A 28-year-old Negro female entered the hospital on
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Outcome of pregnancy related to malaria P falciparum treated with quinine. 27th Siriraj Annual Symposium
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