Bill & Melinda Gates in Pailin, Cambodia (Photo/video still: Gates Foundation)

Large-scale drug administration campaigns are putting early pregnancies at risk in Southeast Asia where efforts are under way to eliminate malaria. World Health Organization (WHO) treatment guidelines state that frontline antimalarial drugs based on artemisinin should not be given to women in the first trimester of pregnancy. Animal studies have found artemisinin caused early termination of pregnancies and birth defects.

But few programs test for pregnancy, according to the US Centers for Disease Control (CDC). Even a malaria treatment project funded and visited by Bill & Melinda Gates in Pailin, Cambodia seems not to be screening for pregnancy and departing from WHO guidelines.

Eliminating drug resistance & gearing up for global eradication

In Southeast Asia, the countries surrounding the Mekong River are seeking to completely eliminate malaria. The driving force comes from concern that drug-resistant malaria might spread from Asia to Africa, which has happened twice in the past at enormous human cost. Now artemisinin is under threat. In addition, elimination efforts in the Mekong region can provide valuable experience for the much greater ambition of global malaria eradication. As Bill Gates put it, “We’re trying to figure out, can we do local eradications?”

Malaria elimination leans heavily on large-scale administration of the frontline antimalarial drugs, artemisinin combination therapy (ACTs). Some campaigns test for infection, the “screen & treat” approach. Other campaigns simply treat everyone regardless of infection status in mass drug administrations (MDAs).

“It’s not possible to generalize,” how drug campaigns handle pregnancy, according to Patrick Kachur, malaria branch chief at the CDC. There are many campaigns and multiple institutions behind them, sometimes in partnerships. According to Kachur:

"In some of the MDA trials or pilot programs currently pregnant women were excluded by design.  In others they were not (or that detail has not been reported).  In most of the test and treat approaches pregnant women were usually included (occasionally receiving a different treatment regimen than children and non-pregnant adults if they tested positive)."

As a result, women who are or might be in the first trimester of pregnancy are being given artemisinin in some campaigns. Some pregnant women treated for malaria might not even be infected with the disease. WHO guidelines call for quinine and clindamycin in the first trimester of pregnancy--when the mother actually has malaria.

Artemisinin appears to be safe for mothers in all stages of pregnancy. However, in animals, artemisinin is embryotoxic and causes birth defects. (See review here.) The animal exposures to artemisinin were not extreme but adjusted to be near the equivalent, WHO-recommended therapeutic dose for humans. Even so, animal models can be misleading. The shorter development period in rats might be far more sensitive to artemisinin exposure than the more prolonged development process in humans and that “could have a protective effect for human fetuses,” as one researcher noted. Artemisinin might be safe—or not.

Assessing risk: prioritize obstetrics or malaria control?

In 2007, researchers wrote that larger, “methodologically rigorous” studies of artemisinin and pregnancy were “urgently required.” The authors worried that “early pregnancy loss will be difficult to detect, especially in communities where artemisinins are likely to be used most frequently.”

But more recently, concerns have partly subsided, perhaps more among malaria specialists than obstetricians. “My concern has gone down on this issue,” said Brian Greenwood, of the London School for Hygiene and Tropical Medicine and co-author of the 2007 paper calling for examination of artemisinin safety. More recently, Greenwood said: “There is now extensive clinical experience that ACTs are safe in the second and third trimesters but, not surprisingly, less data on exposure in the first trimester.” 

There has been no larger, methodologically rigorous safety study; it might not be possible to perform ethically. Instead, “the numbers of documented cases of exposures in the first trimester is still fairly limited,” said Greenwood, “in the hundreds, so a rare event could not be excluded and it would be difficult, or probably impossible, to detect fetal resorption.” Fetal resorption is defined as “The disintegration and assimilation of the dead fetus in the uterus at any stage after the completion of organogenesis which, in humans, is after the 9th week of gestation.” 

The Gates Foundation, asked whether artemisinin posed a health risk in early pregnancy, demurred. Foundation spokesperson Bryan Callahan instead suggested seeking comment from WHO “on whether they are planning to revise their normative guidance.” Callahan expected that WHO “would take available scientific research into account in reviewing their guidance, including a growing body of observational research on pregnant women.” Meetings in coming months could see the WHO guidelines revised.

However, the safety of artemisinin in early pregnancy is not established by evidence that would lead to regulatory approval in the developed world. Physicians in the United States would not administer artemisinin to a pregnant woman in the first trimester, particularly in the absence of a malaria infection, as is happening in countries like Cambodia and other nations in the Mekong River region.

Wealthy countries don’t have malaria and so can prioritize pregnancy. Still, a public health policy that increases pregnancy risks to mothers living with less money and more disease makes for a problematic ethical situation at best.

'Programs should screen for pregnancy'

“I think programs that use MDA should provide pregnancy testing like we do in Wellcome Trust units,” said Rose McGready from the Shoklo Malaria Research Unit in Mae Sot, Thailand. According to McGready, proving safety in first trimester drugs or vaccines “is extremely difficult and more so in countries where health systems are not working well.”

Even regarding currently approved drugs, McGready asked: “how much data do we have for them? Many are assumed to be safe [like] quinine; but only proper comparative studies will provide a definitive answer.”

Melinda Gates has been campaigning for “Putting women and girls at the center of development,” as she wrote last year in Science. According to Gates, the foundation focused in its earliest days on research. Its second phase included an emphasis on delivery. For the foundation's third incarnation, “what I’m making sure we add on now is the women and girls lens,” she recently said.

But that lens seems to have been absent when Melinda and Bill Gates visited a screen and treat program in Pailin, Cambodia earlier this year.

Blogged Bill Gates:

“we walked to a local school where the screening is taking place. That morning, about 120 people had come to get their blood drawn and tested for the malaria parasite. They also answered a few questions designed to find out whether they might have been exposed to the parasite (e.g., ‘Do you work in the forest?’).” 

Gates did not mention questions about pregnancy or pregnancy tests.

Dance of the blameless

Asked whether the Pailin program included pregnancy screening, foundation spokesperson Bryan Callahan replied: “We recommend that you direct any detailed questions to MORU,” Mahidol Oxford Tropical Medicine Research Unit. MORU was the foundation partner responsible for the project and orchestrated the Gates’ visit to Pailin. According to Callahan, “Like all foundation grantees, MORU was required to secure country-level IRB approval for its malaria treatment protocols, and these protocols include a pregnancy screening component.”

Callahan would not confirm that other Gates grantees were screening for pregnancy, although he acknowledged that he had "received the feedback that I had requested from partners" as part of what he termed "due diligence" in answering the "chemotherapy for pregnant women question."

Callahan would not provide a list of the Gates Foundation partners. “We list all of our Malaria program grantees on our website, and you are free to contact them,” said Callahan. A search for “malaria” on the foundation’s grant website returns 1,000 matches. 

Asked whether MORU specifically was testing for pregnancy rather than just required to, Callahan answered: “The partner is MORU, so you have an answer to your question.” The answer, however, was not “yes.” Pressed further, Callahan said: “As I have stated several times, foundation grantees are required to use protocols approved by local IRBs. You need to consult directly with MORU on your question.”

Asked for the most appropriate contact at MORU, Callahan supplied a link to the MORU contact page.

Buck passed

According to MORU’s Lorenz Von Seidlein, “We are coordinating several studies which include mass drug administrations and are funded by the BMGF,” the Bill & Melinda Gates Foundation. Regarding the scope of the effort, Von Seidlin wrote: “drugs have been administered in Vietnam and… in [the] Thai-Myanmar border areas [while] drug administrations are planned in Pailin/Battambang Cambodia in the coming weeks and in Laos at the beginning of next year.”

To describe the project, Von Seidlin pointed to a paper entitled “Fighting fire with fire.” It likened targeted malaria elimination to the tactic of “back burning” in battling forest fires. According to the paper, “all community members whether infected or not are offered antimalarial treatment.” The three-day treatment is given a minimum of three times, one month apart, creating multiple possible exposures of first trimester pregnancies. (It’s not clear that such a regimen has been tested in animal models. Some animal studies found pregnancy harms from artemisinin increased with dose size.)

The paper does not mention pregnancy screening. Asked in email, “Are the mass drug administrations screening for early pregnancy?” as the Gates Foundations says is required of its partners, Von Seidlen did not reply.

Echo?

The nonprofit FHI360 is administering a malaria grant from the Global Fund, also focused on Pailin. Asked if pregnancy screening was part of the program's protocol, an FHI360 spokesperson "reached out to our experts" but never replied to the question. FHI360 touts its namesake "360° perspective" and lists "gender" as a practice area.

WHO's Walter Kazadi coordinates the Emergency Response to Artemisinin Resistance (ERAR) in the Greater Mekong Subregion. Kazadi did not reply to email asking about anti-malarial administration and pregnancy screening.

Eradication: an experiment

Whether the drug-based strategy will eliminate malaria is not known. According to Von Seidlen’s paper, “It is not clear what coverage is required to interrupt transmission, a question mathematical modelers may be able to answer.” However, Gates-funded modelers have already said mass drug administration alone will not eliminate malaria in Southeast Asia.

Bednets and insecticide spraying will be hard pressed to close the gap as substantial numbers of people at risk for malaria live largely outdoors. Many do not wish to be offered malaria treatment or even to be found by government or non-government organizations. To gain cooperation in relatively docile Pailin, Bill Gates said those participating “were paid a day’s wages, the equivalent of about $2.50, and got a free lunch.”

About 1,700 people were processed, but the program would need to be scaled up to reach 4 million people in Cambodia, according to Gates. “We have to clear the parasites of all the humans in an area,” Gates said, making no exclusion for pregnancy. “Eradication is an ambitious goal,” concluded Gates. “It is a goal to which we remain 100% committed.”

'Radical cure' and pregnancy

Pregnancy might pose some difficulties for eradication. The Gates Foundation’s strategy calls for a “complete cure,” a new drug able to clear malaria infections in one dose, unlike today’s three-day regimen. However, the more radical the cure, the greater the potential impact on pregnancies.

Fortunately, one leading candidate, OZ439, looks far better than artemisinin: “OZ439 is 100 times safer,” according to Tim Wells, Chief Scientific Officer at the Medicines for Malaria Venture (MMV). Wells did not point to a paper or adduce evidence for his statement.

Another highly promising drug, KAE609, presents more of a mystery—even to Wells. Although KAE609 originated from a partnership of MMV and Novartis, the drug company re-possessed its intellectual property after discovering the considerable promise and commercial prospects of KAE609. The rest of the world and even Wells are now on the outside looking in. Novartis apparently has safety data but “has not talked about them externally,” according to Wells.

In early studies, KAE609 was given in multiple smaller doses: three times, 30 milligrams per dose, “which gives a certain plasma exposure,” said Wells. More recently, aiming for radical cure, a single dose of 75 milligrams has been tested. “If they have to go with the higher number," 2.5 times higher, "the safety margin is of course a little bit lower,” observed Wells.

Two other drug candidates are in development, providing a quite remarkable and impressive range of options. “The key will be that we can’t design molecules safe for pregnancy," said Wells, "but we can at least pick the most likely candidates, now that we have a little bit of choice.” 

The choice will be important. More mass drug administrations are likely. According to Bernard Nahlen, "the countries which have eliminated up to this point have not done so without MDA." Nahlen is the Deputy Coordinator of the President's Malaria Initiative. Also, malaria diagnostics aren’t sensitive enough to find low level infections. To clear every infection, including those that are undetectable, eradication would mean “treating” even the uninfected and the possibly pregnant. According to Wells, “for MDA where the subjects don’t have the disease, we need to be looking at vaccine levels of safety – say one serious adverse event in 20,000 cases.” 

However, given current practices which elide or ignore pregnancy concerns in Southeast Asia, global malaria eradication might expose much of a generation in Sub-Saharan Africa to antimalarials, whether artemisinin or new drugs in the pipeline, whose effects on pregnancy and development are not fully understood.

Article history:

[7/22/2015 2:46 PM] Quotation from Bernard Nahlen added