Tropical Health Matters

Intermittent preventive treatment (or therapy) in pregnancy (IPTp) with the drug sulfadoxine-pryimethamine (SP) is a key strategy for controlling morbidity and mortality associated with malaria in both pregnant women and newborns. IPTp when given at least twice, one month apart after quickening, reduces maternal anemia, placental malaria, and low birth weight. IPTp with SP has many characteristics of a good public health intervention in that is is relatively low cost, is easy to deliver, and is generally acceptable and available. The longer half-life of SP gives it comparative advantage over alternatives.

Recently questions have arisen about the value of SP as IPT when there are increasing reports of drug resistance when tested and used in children under five years of age. Of note is a lack of study of resistance in pregnant women themselves, which always poses an ethics problem for researchers. WHO African Region issued a statement in 2005 on the efficacy of SP even under conditions of drug resistance in children under 5 and recommended continued use of SP even where resistance levels in children were up to 50%.

To support this position ter Kuile et al. concluded in the June 20th 2007 issue of JAMA that, “In areas in which 1 of 4 treatments with sulfadoxine-pyrimethamine fail in children by day 14, the 2-dose IPT with sulfadoxine-pyrimethamine regimen continues to provide substantial benefit to HIV-negative semi-immune pregnant women. However, more frequent dosing is required in HIV-positive women not using cotrimoxazole prophylaxis for opportunistic infections.” O’Meara et al. further contend that IPTp is unlikely to significantly impact the spread of SP resistant parasites.

While alternative drugs are being considered, none so far are as cheap as SP. These also require more than one dose and thus make directly observed treatment within the context of antenatal care quite difficult. More research is needed to find appropriate substitutes. Basically it is important for countries to continue using SP for IPTp for the meantime, and of course ensure that all pregnant women obtain and sleep under ITNs.

The August issue of Tropical Medicine and International Health demonstrates the fact that malaria control interventions do not implement themselves. Providing commodities is only part of the picture. Ouma et al. representing a team from KEMRI, JHPIEGO, CDC and the University of Amsterdam have shown that coverage of Intermittent Preventive Treatment in Pregnancy is enhanced when health workers received training on focused antenatal care (FANC) and the national malaria guidelines.

“The 3-day training used a competency-based learning approach, emphasizing theory with one full day spent in a clinical setting for practical experience. The training materials included a training/orientation package of two-page laminated service provider job aids on malaria in pregnancy and FANC/MIP and community brochures.”

Ironically in Kenya there had been an IPTp policy since 1998, but without adequate staff capacity building the policy was not achieving results. The situation is similar in other countries.

An assessment for malaria in pregnancy in Akwa Ibom State in southeast Nigeria documented that two years after the national Malaria in Pregnancy Guidelines had been published (2005), front line antenatal clinic staff were not familiar with the term IPT. JHPIEGO has worked with the Federal Ministry of Health to develop the guidelines and an orientation package on FANC and MIP and is now planning to roll out MIP training for the health workers in Akwa Ibom State with support from the ExxonMobil Foundation. Hopefully this will produce similar results as the efforts in Kenya.

In conclusion, national malaria control programs and projects cannot succeed on commodities alone. Health workers need basic orientation and skills to roll back malaria

The Sixtieth Session of the World Health Assembly (WHA) endorsed the creation of Malaria Day to bring global awareness to what has been to date Africa Malaria Day Resolution (A60/12). This follows on the heels of creation of Malaria Awareness Day in the US to compliment Africa Malaria Day. In the process the WHA wound up officially excluded Intermittent Preventive Treatment for pregnant women (IPTp) from the list of key interventions to being simply an activity that is implemented in Africa. This follows elevation by the WHO’s Global Malaria Program of IRS to a key global strategy and demonstrating that pregnant women in Africa are no longer important to the global fight against malaria – just a regional anomaly.

One excuse for demoting IPTp is supposed sulfadoxine-pyrimethamine (SP) resistance. Interestingly it is the same WHO along with researchers who have found that SP for IPTp is effective even at rates of 50% resistance among non-immune children under five years of age. No less an authority than peer reviewed Lancet articles have recently made the case for continuing IPTp with SP. Maybe the WHA has been tricked by people who don’t realize that even in a ‘global’ malaria program, the greatest burden of malaria falls on children and pregnant women in Africa.

The American Journal of Tropical Medicine and Hygiene published a unique article in its May 2007 issue that documents how the timing and number of malaria infections during pregnancy influences child birth weight outcomes in Burkina Faso. Infection after 6 months of pregnancy was the strongest factor associated with low birth weight (LBW), but LBW was also associated with infection in early pregnancy. The challenge in determining the latter is that women in the study, as is the case in much of Africa, tended to register for antenatal care later in pregnancy. Fortunately in this study one-third of the women enrolled had first attended ANC in the first trimester and could be followed longer. This helped provide information for another important finding, that LBW is also more likely when women are infected with malaria multiple times during pregnancy.

These findings highlight the challenges of reaching pregnant women in a timely manner with malaria prevention measures including insecticide treated nets (ITNs) and intermittent preventive therapy during pregnancy (IPTp). The authors note the value of a full course of IPTp in preventing LBW, but lament that there are currently no safe drugs to use for IPTp in the first trimester. An additional challenge is that many women register for ANC too late or attend too infrequently to benefit from at least two doses after quickening at one month apart.

This points to the need to ensure that all ANC clinics have ITNs to give women on their very first visit. For those who attend and are not yet eligible for IPTp, ITNs too, prevent LBW and will provide the protection for the early infections that lead to LBW. Then if a woman gets a net early in pregnancy, she will be less likely to suffer multiple malaria infections, another risk factor for LBW.

The challenge if one of policy versus logistics. Although most malaria endemic countries point to guidelines that say a pregnant should sleep under an ITN, few have figured out the logistics of guaranteeing a regular and dedicated supply of ITNs for ANC clinics. At present ITN distribution favors campaigns as opposed to integration into routine Maternal and Child Health services. While this may favor achieving large targets among children under five years of age, it usually bypasses pregnant women.

Last week a colleague at JHPIEGO suggested that all women of reproductive age should be given an ITN. This would certainly help keep them safe from malaria whenever they get pregnant. Are donors willing to take up this challenge?

How does maternal mortality become a priority health issue? Shiffman provides case examples in the May 2007 issue of the American Journal of Public Health. He examined policy and program changes in 5 countries: Guatemala, Honduras, India, Indonesia, and Nigeria, and provides a valuable framework for identifying the domestic and international influences and barriers on policy change. The example of Nigeria helps us see how malaria in pregnancy funding and programming might help draw attention to reducing maternal mortality.

Nigeria has the highest maternal mortality rate of the 5 countries (704/100,000 live births), and Shiffman reports that Safe Motherhood is still not receiving the attention it needs in Nigeria. One hopes that the problem of maternal mortality will receives greater attention because of increased malaria program efforts. Participation by Nigeria in the Roll Back Malaria Partnership and its management of malaria grants from the Global Fund have put a spotlight on the contribution of malaria control to safer motherhood. The National Guidelines for Prevention and Control of Malaria During Pregnancy (2005) outline clearly the path from malaria to anemia to maternal mortality and estimate that malaria contributes to 11% of the nation’s maternal mortality rate. The guidelines therefore stress IPTp, ITNs for pregnant women and prompt case management when pregnant women experience an episode of malaria. Likewise the National Reproductive Health Strategic Framework lists malaria among the preventable causes of maternal morbidity and mortality.

Donors are supporting MIP prevention and control activities. IPTp and ITNs are a key component of Nigeria’s Global Fund grant. USAID and the World Bank Booster program are also operating in Nigeria, and both include MIP interventions, particularly nets and IPTp. This level of external support and attention demonstrates “Transnational influences” on policy through norm promotion and resource provision, as explained by Shiffman.

There remain domestic policy challenges to Safe Motherhood in Nigeria. While partners are pulling together to fight malaria, the same cannot be said for Safe Motherhood. A recent MIP strategy workshop in Abuja sponsored by USAID’s ACCESS project and involving both the malaria and reproductive health (RH) program units of the Federal and some State Ministries of Health specifically forged stronger working relationships between the two program areas such that greater attention to malaria may in fact benefit Safe Motherhood. Shiffman emphasized the importance of reaching out to state and local decision makers too, since in Nigeria they make major decisions about allocating resources for public health.

If international malaria partners continue to stress the importance of addressing malaria in pregnancy using all three key control measures as part of a comprehensive malaria strategy, as is done in Nigeria, their efforts will hopefully also have the benefit of making Motherhood Safer.

A current article by Ye et al. in Malaria Journal stresses that while malaria may be a national problem, there are important local variations in malaria risk in an area of northwestern Burkina Faso. Ecological and economic factors may likely play a role and include seasonal rice farming, cattle rearing, irrigation, and living in a semi-urban area. They conclude that, “malaria control strategies should be designed to fit location-specific contexts.” Just because a community has a different ecological setting or requires a different malaria control strategy does not mean it is not part of the global fight against malaria. One size does not fit all.

This brings to mind discussions over the past year whether intermittent preventive treatment for pregnant women (IPTp) is considered a major strategy by WHO’s Global Malaria Control Program (GMP). As of this date (20 April 2007) right in the center of the GMP web page one finds the following statement: “IRS is now one of three main interventions promoted by WHO to control malaria.” This refers to a 2006 document on Indoor Residual Spraying (IRS), which on page 1 recommends the following three ‘primary’ interventions for the control of malaria:

• diagnosis of malaria cases and treatment with effective medicines;
• distribution of insecticide-treated nets (ITNs) to achieve full coverage of populations at risk of malaria; and
• indoor residual spraying (IRS) as a major means of malaria vector control to reduce and eliminate malaria transmission including, where indicated, the use of DDT.

People have taken this to mean that IPTp is no longer considered to be a primary intervention. Recent discussions with colleagues revealed that there is a school of thought that says since IPTp is a key tool for the African Region, it is not a ‘global’ strategy. They explained that pregnant women are a focus when it comes to ITNs. They note further that there are links to a fact sheet on malaria in pregnancy at the Roll Back Malaria Website that lists IPTp as part of a three-pronged approach to malaria control, as well as a link to WHO’s Regional Office for Africa and its Strategic Framework for Prevention and Control of Malaria During Pregnancy, which also lists IPTp as a major strategy.

While these links to other organizations are helpful, they do not dispel the uncomfortable feeling that pregnant women in Africa do not rate the status of being part of the ‘global’ malaria control effort. One also wonders about their sisters in Papua New Guinea or Brazil where falciparum malaria also is of concern.

If one wants to be particular, one can even question whether the GMP is actually global. What are its strategies for controlling malaria in Norway or New Zealand, for example? Obviously what makes the fight against malaria global is the fact that people and agencies in both endemic and non-endemic countries are joining together to do whatever it takes to control the disease.

Excluding IPTp from the ‘global’ arsenal presents a false distinction and reinforces the perceptions of neglect, which Africa and women’s health have suffered on many fronts for too long. As Ye et al. have found, there is no single global malaria context, and while we have a variety of tools to fight malaria, there is no one magic global bullet to eliminate malaria in every situation. Let’s form a global alliance that recognizes a wide arsenal of malaria tools but adapts them to the local ecology and local needs.

The present WHO malaria treatment guidelines state that, “The antimalarials considered safe in the first trimester of pregnancy are quinine, chloroquine, proguanil, pyrimethamine and sulfadoxine–pyrimethamine. Of these, quinine remains the most effective and can be used in all trimesters of pregnancy including the first trimester.”  The guidelines go on to say that, “There is increasing experience with artemisinin derivatives in the second and third trimesters (over 1000 documented pregnancies). There have been no adverse effects on the mother or fetus.”  Where problems arise is choosing a safe partner drug for ACTs, as WHO has come out against monotherapy artemisinin treatment. The unfortunate balance is between known safe drugs, for which resistance has grown, or drugs that have not been sufficiently tested.  WHO concludes that, “Despite these many uncertainties, effective treatment must not be delayed in pregnant women.”

The thorny issue of treating malaria in pregnancy has been addressed in recent journal articles.  In The Lancet Nosten et al. Emphasize the importance of prompt and appropriate treatment because of the severe impact malaria has on the mother, the fetus and eventually the newborn. Dellicour et al. in Malaria Journal conclude that with the ‘limited data available’ artemisinins are unlikely to cause fetal loss or abnormality when used late in pregnancy.

Ward et al. in The Lancet believe that adequate ‘information is not available’ on toxicological liabilities of artemisinins on the mother and fetus.  At the same time Valley et al. in Malaria Journal provide a whole table of potential drugs that can be used in pregnancy for IPTp and discuss the safety of these.

All authors agree that there are inadequate studies of large enough size to come to definitive solutions, and all are concerned about the ethnics of testing drugs during pregnancy.  Is the answer to this dilemma treatment with pharmacovigilance, which would be challenging in resource poor endemic areas? Is the solution clinical trials?  Pharmacovigilance faces another challenge. When health workers are told on one hand not to give artemisinins to pregnant women and on the other to report any adverse reactions to artemisinins the result is no data due to fear of repercussions if supervisors found that artemisinins were given to a pregnant woman

Can infected women wait? The reality is that in most endemic countries national malaria case management policy simply states that health workers should prescribe the currently accepted national malaria treatment for pregnant women, though they do address the need for such drugs as quinine during the first trimester.

Health workers in the field need answers and guidance, and international bodies like WHO need to step forward quickly with a more definitive course of action to find those answers.

Advocacy for strengthening malaria in pregnancy control programs is founded on the assumption that malaria is an important cause of both maternal morbidity and mortality as well as child/birth outcomes. UNICEF has recently undertaken work in India to pinpoint more accurately the various causes of maternal deaths. According to The Hindu Newspaper, “The Maternal and Perinatal Death Inquiry (MAPEDI) or the social audit — also known as verbal autopsy.” The survey in West Bengal found that, “Of the 106 maternal mortalities reported … Fifty one per cent deaths were due to direct obstetric causes like bleeding, infection, eclampsia, and obstructed labour, 27 per cent due to indirect causes like anaemia, malaria, hepatitis, tuberculosis and cardiac, while 22 per cent died due to other causes.”

Measurement of exact cause of death in rural and poor communities can be difficult. Sometimes the association between maternal mortality and malaria is circumstantial. Romagosa et al. found in Mozambique that maternal mortality followed the same seasonal pattern as malaria illness. They reported that malaria accounted for 23% of maternal deaths.

A new study published by Fortrell et al., has shown the challenges of obtaining reliable and valid data on maternal deaths that might be malaria. These challenges included among others 1) a general underestimation of malaria in pregnancy, 2) difficulty in distinguishing clinically among febrile illnesses, and 3) HIV and malaria co-infection. Different models and approaches, including verbal autopsy, to analyzing death data in Burkina Faso yielded widely varying estimates of the cause specific mortality fraction for malaria from 10% to nearly 25%.

These efforts show that malaria is certainly a factor in maternal mortality. Continued research support is needed, as explained in the UNICEF study for, ” providing an understanding of the contributing factors that can be used by decision-makers and stakeholders to address obstacles to quality obstetric care and to identify ways to prevent avoidable deaths.”

The Lancet Infectious Diseases had a recent special issue on malaria in pregnancy (MIP).  Of special interest is an article by Greenwood et al. (2007) that outlines some of our knowledge gaps in MIP and hence the need for future research.

One important research question is “The importance of malaria as a cause of maternal mortality in areas of medium or high malaria endemicity.”  These data would go a long way in advocacy efforts to increase support for funding MIP programs.

Another challenge is, “Finding new drugs for the treatment of malaria in pregnancy.” The authors point to the demise of chloroquine and SP. While come countries are including ACTS as accepted treatment in the second and third trimesters, studies are not available to confirm safety.  Designing drug research with pregnant women will remain a serious ethical problem, but one that cannot not be shied away from. Another crucial drug issue is “New drugs for IPTp.”   Drug efficacy studies have been done mostly with children, but the rapidly declining effectiveness of SP in treating childhood malaria naturally raises concern about SP for IPTp.

A basic assumption in MIP control programs is that intervention must be integrated within quality antenatal care.  The authors raise the need for, “Identification of optimum delivery strategies for scaling up the use of insecticide-treated nets and IPT,” that consider viable alternatives (see for example, item on community directed interventions in previous blog).  They note the low level of ANC utilization in many countries. This is coupled with the fact that the dropout rate between IPTp1 and IPTp2 is often substantial.  One therefore questions whether effective MIP control should be in the business of strengthening the quality of ANC services or find ways to deliver MIP control services in the most direct and safe way to pregnant women.

Of particular concern is the fact that women register for ANC late, and even if ITNs/LLINs are available at ANC, they could not protect most women in their first trimester as seen in the attached graph of ANC registration from Oyo State, Nigeria. The cultural elements of this problem include beliefs that one should protect a pregnancy by not letting others know until it shows and perceptions that since pregnancy is ‘normal’, one should not disrupt regular work routines to attend ANC.  Further social and operational research is definitely needed to find a MIP control package delivery mechanism that really reaches women.

The challenge of these and other suggestions for future research rest on funding sources.  In addition to the usual expected sources such as foundations and international development agencies, one would hope that those applying for Global Fund malaria grants would build operations research into their monitoring and evaluation systems so that countries can learn from real life experiences.

Adolescent health is often a neglected issue. To illustrate this, BBC recently featured the story a young Nigerian woman who married at the age of 12: “No-one has asked me whether I liked the man or not. When it was time for the marriage, I just heard that I had been married to him.” With early marriage comes early birth. The 2003 Nigeria Demographic and Health Survey reported that half of first births occur during adolescence. The Lancet Infectious Diseases in December 2006 reported that “in pregnant adolescents, the consequences of malaria are of great concern.”

The Lancet article was concerned that the problem of malaria in adolescence is overshadowed by that of young children, and yet the consequences of malaria on adolescents are not trivial. One quarter of young adolescents may develop severe anemia as a result of malaria. Somewhere between 1-10% of school days are missed because of malaria. Unfortunately adolescents often do not seek treatment, often for financial reasons, especially with the more expensive ACTs.

A RBM publication on gender and malaria reports that, “In many sub-Saharan African settings, adolescents are often parasitaemic and anaemic at the time that they first become pregnant,” but the Nigerian DHS found that only 50% of pregnant adolescents attend any antenatal care where they might benefit from malaria prevention.

Generally adolescents are not targeted for free ITNs and treatment by the common donor-supported malaria programs, and government health services are not making up the difference. This may lead to a dangerous ‘malaria’ generation gap.