FocusMalaria

Combating low birth weight due to malaria infection in pregnancy

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Science Translational Medicine  07 Mar 2018:
Vol. 10, Issue 431, eaat1506
DOI: 10.1126/scitranslmed.aat1506

Abstract

Decreased l-arginine and nitric oxide bioavailability in pregnant women with malaria contributes to low birth weight, suggesting that l-arginine supplementation could be a potential treatment (McDonald et al.).

Birth weight is a major determinant of mortality risk both in the neonatal period (under 1 month) and during infancy (under 1 year). Low birth weight is defined as a birth weight below 2500 g, regardless of gestational age. It results from fetal growth restriction or premature delivery (<37 weeks of gestation) or may reflect constitutionally small newborns. In 2013, low birth weight affected more than 20 million infants (1 in 6 deliveries) worldwide, and most of these occurred in low- to middle-income countries. Low birth weight is the biggest risk factor for neonatal death, associated with about 80% of deaths (1). In 2016, about 2.6 million neonates died, accounting for almost half of all deaths among children under 5 years (2). Significantly, a recent study of almost 1 million pregnancies in Scotland confirmed that the risk of increased mortality is not restricted to those with defined low birth weight but increases once birth weight drops below the 25th percentile (3). The impact of low birth weight on neonatal mortality is therefore likely to be underestimated. Low birth weight and being small for gestational age are also leading risk factors for early childhood stunting, or reduced growth and development, and can contribute to chronic poor health and impaired cognitive development (1). In recognition of these global health issues, UNICEF (United Nations Children’s Fund) has called for new interventions that start early in pregnancy, and the World Health Organization has reaffirmed that reducing the prevalence of low birth weight by 30% by 2025 is a global health priority.

Despite the enormous burden of poor maternal health and pregnancy outcomes globally and the clear need for new interventions, investment in and development of new therapeutics for maternal health are very limited (4). There is a striking paucity of drugs in development, or in clinical or preclinical trials, and only one class of drugs has been licensed in recent decades (4). New findings by McDonald et al. (5) published in this issue now provide insights into the mechanisms of low birth weight caused by malaria and poor nutrition and reveal potential new strategies for developing interventions to protect against low birth weight caused by malaria infection of the mother during pregnancy.

MECHANISMS AND CAUSES OF LOW BIRTH WEIGHT

Malaria infection during pregnancy and poor maternal nutrition are leading causes of low birth weight globally, yet they are preventable with the right interventions. Malaria infection during pregnancy causes an estimated 900,000 low birth weight deliveries worldwide and may contribute to 100,000 infant deaths annually (6). When assessed through maternal anthropometrics, poor maternal nutrition may account for half of the cases of low birth weight in many resource-poor countries (7) and contributes to ~800,000 neonatal deaths annually (6).

In low- to middle-income countries, fetal growth restriction is the main preventable cause of low birth weight, with malaria and other infections also being important preventable causes of premature delivery. Various maternal stressors can lead to fetal growth restriction through different mechanisms, depending on the time in pregnancy at which they occur. Typically, early-onset fetal growth restriction (that is, before 32 weeks of gestation) is caused by impaired formation of the placenta and placental development, including impaired vasculogenesis and angiogenesis. Examples of causes of early-onset fetal growth restriction include preeclampsia and cigarette smoking. In vitro evidence suggests that malaria infection early in pregnancy could impair placental development due to maternal hormonal and inflammatory disturbances, which may affect vasculogenesis and cause early-onset fetal growth restriction. Stressors occurring later in pregnancy, including malaria infection, cause fetal growth restriction principally by impairing placental function, especially nutrient transport, during a phase of rapid fetal growth.

Fetal nutrient supply, especially of amino acids, is the strongest determinant of fetal growth and largely depends on maternal supplies and the capacity of the placenta to transport nutrients to the fetus. Maternal undernutrition directly affects fetal growth through reduced nutrient supply. Poor placental formation or impaired placental development can reduce placental blood flow, thereby decreasing nutrient supply to the placenta. Placental amino acid transport is regulated by mTOR (mechanistic target of rapamycin) signaling. Recently, evidence that placental mTOR signaling is inhibited by the placental inflammatory response to malaria infection has emerged, decreasing placental amino acid transport and contributing to fetal growth restriction and reduced birth weight (Fig. 1) (8). Placental mTOR signaling is also regulated by maternal nutrition, and certain amino acids, such as leucine and arginine, can activate mTOR signaling. A range of other environmental, maternal, and fetal factors can affect fetal growth either directly or through placental dysfunction. These include chromosomal and metabolic anomalies, intrauterine and congenital infections, inflammation, increased cortisol due to various stressors, and other maternal factors and medical conditions.

Fig. 1 Key mechanisms underlying low birth weight associated with malaria infection and undernutrition.

Optimal fetal growth requires adequate vascular development and function of the placenta and appropriate placental nutrient transport. Sufficient bioavailable l-arginine and NO are required for placental vascular development and function. Adequate nutrient transport requires active mTOR signaling and appropriate placental vasculature. Malaria infection during pregnancy negatively affects fetal growth in two ways: first, by increasing asymmetric dimethylarginine (ADMA), thereby reducing NO bioavailability, leading to reduced placental vascular development and function; and second, by causing inflammation in the placenta that inhibits mTOR signaling and placental nutrient transport. Inflammation of the placenta induced by malaria infection can also lead to premature delivery. Undernutrition can result in a decrease in bioavailable l-arginine, impairing mTOR signaling and NO pathway activity, contributing to poor fetal growth. Red lines indicate negative or inhibitory effects on fetal growth. Blue arrows indicate positive effects on fetal growth.

CREDIT: ADAPTED BY A. KITTERMAN/SCIENCE TRANSLATIONAL MEDICINE FROM P. BOEUF/BURNET INSTITUTE

INSIGHTS INTO LOW BIRTH WEIGHT ASSOCIATED WITH MALARIA INFECTION

New findings reported by McDonald et al. (5) suggest that malaria infection in pregnancy negatively affects the biosynthesis of nitric oxide (NO) from l-arginine, thereby leading to reduced birth weight (Fig. 1). l-Arginine is a precursor for the synthesis of NO, which is crucial for endothelial tissue growth and function. Reduced NO and l-arginine have been described in malaria infection among nonpregnant individuals, and a decrease in bioavailable NO appears to play a role during severe malaria infection. NO generation and bioavailability can be affected by asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). These metabolites found in blood plasma are generated through protein methylation and are structurally related to l-arginine. In particular, ADMA is a competitive inhibitor of NO synthase, which generates NO from l-arginine. Pregnancy also contributes to lower l-arginine, and diets may be poor in l-arginine in settings where malaria is endemic.

In a longitudinal study of pregnant women in Africa who experienced high rates of malaria infection and low birth weight babies, McDonald and colleagues found that malaria infection, caused by the protozoan parasite Plasmodium falciparum, was associated with raised ADMA and SDMA during pregnancy, suggesting that malaria infection may affect placental development and function through reduced bioavailability of NO. Notably, raised ADMA was associated with a substantially increased risk of delivering newborns small-for-gestational-age, presumably due to fetal growth restriction, and an increased risk of low birth weight. The authors further investigated potential causative mechanisms and therapeutic strategies in a mouse model of malaria infection in pregnancy using the rodent malaria parasite species Plasmodium berghei. Significantly, dietary l-arginine supplementation improved birth weight and offspring survival in the malaria-infected pregnant mice. l-Arginine supplementation also improved placental development in these mice and altered regulators of vascular development and inflammation. These findings support the notion that malaria infection during pregnancy negatively affects the l-arginine/NO pathway, leading to reduced birth weight, and highlight the potential benefit of l-arginine supplementation to improve pregnancy outcomes. Further studies by McDonald et al. (5) showed that l-arginine supplementation improved birth weight among mice fed an l-arginine–deficient diet. l-Arginine is also a known activator of mTOR signaling, and dietary l-arginine supplementation increases mTOR signaling in animal models. This raises the prospect that l-arginine supplementation might have dual benefits of enhancing NO bioavailability and placental development and activating mTOR to increase nutrient transport.

TOWARD NEW INTERVENTIONS FOR LOW BIRTH WEIGHT

In pregnancies exposed to malaria in low- to middle-income countries, intervention strategies to improve birth weight are currently largely limited to malaria control and maternal dietary supplementation of specific micronutrients. Malaria prevention strategies focus on deployment of long-lasting insecticide-treated bed nets and intermittent preventive treatment in pregnancy (IPTp), which is the administration of curative doses of antimalarial drugs to pregnant women attending antenatal clinics regardless of malaria infection status. Whereas both approaches have significant clinical and public health benefits, their limited efficacy is further compounded by poor population coverage. In sub-Saharan Africa, which has the highest burden of malaria, coverage is only about 24% for IPTp and 35% for long-lasting insecticide-treated bed nets (9). Furthermore, resistance to antimalarial drugs and insecticides used to control the mosquito vector is on the rise. Maternal dietary supplementation is typically provided as multiple micronutrients or as iron and folate only. Meta-analyses of randomized controlled trials conducted in malaria-exposed populations suggest that these interventions only have a modest benefit in improving birth weight (10). To effectively improve fetal growth and, therefore, birth weight, new interventions are needed to specifically target the mechanisms causing fetal growth restriction during malaria infection in pregnancy.

The McDonald et al. study and other recent findings reporting how malaria affects placental development and nutrient transport open new avenues for potential interventions to improve pregnancy outcomes for those at risk of malaria and undernutrition. The findings by McDonald and co-workers of improved outcomes in a mouse model achieved through l-arginine supplementation are exciting because of the potential simplicity, affordability, and practicality of the intervention. The use of l-arginine to improve NO bioavailability and placental function may be a suitable approach to complement current preventive interventions. l-Arginine supplementation could potentially be integrated into a nutritional supplement formulated to specifically promote placental development and function, and mTOR activation for amino acid transport, to have the greatest impact on fetal growth. To significantly alleviate the burden of malaria on fetal growth, interventions will need to cover both the early pregnancy period (and possibly the pregestational period) and the last weeks of pregnancy when fetal growth rate and fetal nutrient demand are at their highest. To work toward this potential outcome, additional studies in pregnant women exposed to malaria are needed to assess the generalizability of the findings regarding the impact of malaria on l-arginine biosynthesis and to quantify the contribution of these mechanisms to low birth weight. Additional studies in mice could further inform dosing regimens and evaluate toxicity; preclinical studies would need to be extended to other animal models and Plasmodium species. Although the murine model is informative for evaluating the benefit of l-arginine supplementation on pregnancy outcomes, it does have limitations and differences from human malaria infection and pregnancy. Therefore, careful consideration of how interventions will be evaluated in the future in this model and complemented by other approaches is needed. Looking beyond the prevention and treatment of malaria in pregnancy and nutritional factors, a number of other conditions prevalent in many low- to middle-income countries affect birth weight. Commonly occurring reproductive tract infections, such as chlamydia, gonorrhoea, trichomonas vaginalis, and bacterial vaginosis, can increase the risk of preterm birth and low birth weight babies and overlap with the burden of malaria infection and undernutrition. Addressing these infections, in addition to malaria and nutrition, may be essential for making major gains in reducing low birth weight.

CHALLENGES IN PROGRESSING NEW INTERVENTIONS FOR PREGNANCY

The global drought in therapeutics available or in development for maternal health is a major concern, given the enormous burden of disease. Recent analyses of this problem highlighted weaknesses in current R&D models for drug development and lack of adequate investment from industry, government, and other sources (4). Understandable barriers exist for the development of therapeutics in pregnancy, including a risk-averse culture, concerns over reproductive toxicity, and the potentially higher cost and regulatory hurdles for developing drugs to treat pregnant women. However, these barriers can be effectively addressed and, together with greater investment in research and translation from all sectors, the development of new therapies and interventions can lead to lifesaving improvements in maternal, newborn, and child health. Furthermore, the limited inclusion of pregnant women in clinical trials and the poverty of R&D on maternal health therapies also raise ethical issues. It is important for pregnant women to be appropriately included and represented in clinical trials and therapeutic development, given the compelling health and social needs. Recently, public-private partnerships have had some successes in progressing R&D for neglected diseases, malaria, and tuberculosis and may be effective models for specifically advancing therapeutics for maternal health.

Although progress on understanding the mechanisms of low birth weight and how to counteract the impact of malaria in pregnancy has been challenging, new insights reveal how malaria, and its interaction with nutrition, contributes to low birth weight. Advancing these insights into future therapeutics and interventions is a high priority and offers hope of greater improvements in maternal, newborn, and child health worldwide.

REFERENCES AND NOTES

Acknowledgments: Authors were supported by the National Health and Medical Research Council of Australia. The Burnet Institute was supported by an Operational Infrastructure Support grant from the Victorian state government.
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