Date Published: June 17, 2008
Publisher: Public Library of Science
Author(s): Nicholas J White, Rose M McGready, François H Nosten
Abstract: Nicholas White and colleagues discuss why it is so important to conduct clinical trials of malaria treatments in pregnancy.
Partial Text: There were an estimated 536,000 maternal deaths in the world in 2005, of which 533,000 (99%) occurred in developing countries . Maternal and perinatal conditions are a major contributor to the global burden of disease, yet the pipeline of new drugs specifically for maternal health is alarmingly small . Only 17 drugs are under active development for maternal health indications—less than 3% of the pipeline in cardiovascular health. Since the disaster of thalidomide 50 years ago, the medical profession has been rightfully very cautious about giving newly developed drugs to pregnant women, for fear that they might damage the unborn baby. Particular caution has been exercised in the first trimester to avoid teratogenicity during organogenesis.
The result has been that newly introduced medicines often carry a prescribing caveat that they should not be used in pregnancy. There may have been no worrying results from reproductive toxicology testing to warrant this caution—simply insufficient clinical information in pregnancy. But for a new drug, there is never sufficient clinical information in pregnancy. Pregnant women with potentially fatal illnesses may be treated with inferior drugs to avoid a hypothetical risk to the unborn child (and the consequent liability).
Malaria, the most important parasitic infection of humans, illustrates this problem well. Malaria infects about 5% of the world’s population at any time, and is a particular problem in pregnancy. There is a renewed international interest in the infection, and malaria in pregnancy is rightly considered a priority area. Malaria in pregnancy reduces birth weight (and thereby infant survival). In low-transmission areas there is an increased risk of severe falciparum malaria and consequent death of both mother and foetus . The health community has finally realised that even if the mother is asymptomatic, the presence of malaria parasites in the blood is always harmful to the foetus and must be treated promptly and effectively.
The safety of the artemisinin derivatives in early pregnancy remains uncertain, as these drugs are embryotoxic in animals [9,10]. They are not recommended for uncomplicated malaria in the first trimester, unless effective alternatives are unavailable.
What is needed now is evidence. Industry is usually reluctant to underwrite studies of new drugs in pregnant women , particularly in the tropics. Research centres need to be encouraged to study the treatment of infections in pregnancy. There is now active research on HIV, malaria, and helminth infections in pregnancy, but not for other tropical infections. For antimalarial, antitrypanosomal, and antileishmanial drugs, the pharmaceutical industry’s role in drug development will be increasingly assumed by public–private partnerships such as the Medicines for Malaria Venture and the Drugs for Neglected Diseases Initiative. International agencies and funders need to provide adequate support for quality studies in pregnancy and, in an increasingly litigious climate, to underwrite the liabilities. Pregnancy registries should be established to facilitate systematic recording of adverse effects on the newborn, and assessment of the neurological development of infants until at least one year of age, and preferably longer.
“Better safe than sorry” is the mantra of our risk-averse age, and there are few more challenging areas of drug development than establishing drug safety in pregnancy. Add to this the difficulties in conducting clinical trials and pharmacokinetic studies in pregnancy in most tropical countries, and it is not difficult to understand our current state of ignorance. We do not know how best to treat most tropical infectious diseases in pregnancy. It is a difficult problem, but one that should no longer be ignored.