Current Commentary
Helminth Infections A New Global Women’s Health Agenda Peter Hotez,
MD, PhD,
and Megan Whitham
Emerging evidence over the past decade has implicated helminth infections as important yet stealth causes of adverse pregnancy outcomes and impaired women’s reproductive health. The two most important helminth infections affecting women living in poverty in Africa and elsewhere in the developing world are hookworm infection and schistosomiasis. In Africa alone, almost 40 million women of childbearing age are infected with hookworms, including almost 7 million pregnant women who are at greater risk of severe anemia, higher mortality, and experiencing poor neonatal outcome (reduced birth weight and increased infant mortality). Possibly, tens of millions of women in Africa also suffer from female genital schistosomiasis associated with genital itching and pain, stress incontinence, dyspareunia, and infertility and experience social stigma and depression. Female genital schistosomiasis also is linked to horizontal transmission of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) and it may represent one of Africa’s major cofactors in its AIDS epidemic. There is urgency to expand mass drug administration efforts for hookworm and schistosomiasis to include women of reproductive age and to shape new policies and advocacy initiatives for women’s global health to include helminth control. In parallel is a require-
From the Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine at Baylor College of Medicine, and the Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, Houston, Texas; and Virginia Tech Carilion School of Medicine, Roanoke, Virginia. Peter Hotez received support to develop vaccines for helminth infections from the Bill & Melinda Gates Foundation, Dutch Ministry of Foreign Affairs, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Blavatnik Family Foundation, Dr. Gary Michelson, Mort and Chris Hyman, and Texas Children’s Hospital. Corresponding author: Peter Hotez, MD, PhD, Baylor College of Medicine, National School of Tropical Medicine, 1 Baylor Plaza, MS 113, Houston, TX 77030; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2013 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
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ment to better link global health programs for HIV and AIDS and malaria with helminth control and to simultaneously launch initiatives for research and development. (Obstet Gynecol 2014;123:155–60) DOI: 10.1097/AOG.0000000000000025
M
ost obstetricians and gynecologists do not routinely think about parasitic worm (helminth) infections nor see them as central or perhaps even relevant to their clinical practices. However, new information published within the last decade has revealed that helminth infections are responsible for a huge but mostly hidden or stealth burden of morbidity among young women living in Africa and other developing regions. The helminthiases represent some of the most common global health conditions of women living in developing countries (Table 1),1 and two helminth infections in particular—hookworm infection and schistosomiasis— stand out for their devastating effect on reproductive health.2 We summarize some of the current and recently published information on these links and new global approaches to control these neglected tropical diseases in resource-poor countries.
HOOKWORM INFECTION AND PREGNANCY Hookworm infection is one of the most common soiltransmitted helminth infections of humans, affecting up to hundreds of millions of people mostly in areas of ruraly poverty in sub-Saharan Africa, south and east Asia, Oceania, and Central and South America.3 Anemia is the major morbidity resulting from the presence of adult hookworms, which are nematode parasites—either Necator americanus or Ancylostoma duodenale—attached to the inner wall of the small intestine.4 Hookworms can live for years in the intestine where they remove host blood to cause iron and protein losses that ultimately lead to iron deficiency anemia (microcytic hypochromic anemia) and protein malnutrition, respectively.4 Hookworms are important public health threats among women of reproductive age. Whereas other
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Table 1. Helminth Infections Among Women in Africa Disease or Condition Hookworm infection
Schistosomiasis
Lymphatic filariasis
Onchocerciasis
No. of Cases
Major Pathologic Sequelae Relevant to Women’s Health
198 million cases in sub-Saharan Maternal and child Africa, approximately one half anemia among women (99 million cases) 37.7 million women of reproductive age 6.9 million pregnant women 192 million cases in sub-Saharan Female genital Africa, approximately one half schistosomiasis, among women (96 million cases) approximately 20– 150 million cases in sub-Saharan Africa
Alternative estimates indicate that 586–659 million people at any given time live with some form of schistosomiasis, 90% of whom live in sub-Saharan Africa 46–51 million cases in subBreast and vulvar Saharan Africa, approximately lymphoedema one half among women (23–25 million cases) 37 million cases in sub-Saharan Onchocerca skin Africa, approximately one half disease among women (18 million cases)
common intestinal nematodes such as Ascaris lumbricoides or Trichuris trichiura exhibit their highest intensity in early childhood, so that young children tend to harbor the largest number of these worms in their gut, hookworms are exceptional in that adult populations frequently exhibit the highest intensities and worm burdens of hookworm in endemic areas.5 Therefore, hookworm-associated iron deficiency anemia is commonly found among adolescent girls and women of reproductive age.6 In a systematic review, Brooker et al6 found that during pregnancy, increasing hookworm infection intensity is associated with anemia, ie, lower hemoglobin levels. Indeed, in sub-Saharan Africa where almost 200 million cases of hookworm infection occur,3 it was estimated that 37.7 million women of reproductive age are infected with hookworms at any given time.6 Based on the number of live births that occur in sub-Saharan Africa, it was determined that 6.9 million pregnant women are infected with hookworms, ie, between one fourth and one third of pregnancies in sub-Saharan Africa.6 Thus, hookworm infection (and hookworm–malaria coinfections) may represent one of the most common obstetric complications on the African continent. Moreover,
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Additional Comments
Reference
Sub-Saharan Africa only
3,6,42
The differences in the total number of cases in sub-Saharan Africa are based on studies that for every egg-positive individual diagnosed there may be 1 or 2 individuals who are egg-negative at the time of diagnosis yet still infected21 Female genital schistosomiasis estimates are preliminary and nonpeer-reviewed
20,21,28,42
Sub-Saharan Africa only
42
Sub-Saharan Africa only
42,43
hookworm infection is not restricted to Africa, and high rates of hookworm infection in pregnancy have also been found in impoverished areas of South Asia7 and South America.8 An earlier estimate indicated that 44 million pregnant women globally are infected with hookworms.9 The World Health Organization (WHO) recommends annual deworming of children at risk for acquiring hookworm and other intestinal helminth infections.10 Deworming is typically conducted with a single 400-mg tablet of albendazole or a 500-mg tablet of mebendazole, although sometimes twiceyearly treatments are required.10 Mass treatments are given without first conducting individual diagnostic examinations and instead are provided based on the prevalence and intensity of the helminth infections in the community. Currently, the WHO estimates that almost 900 million children are at risk for acquiring intestinal helminth infections, of which approximately one third actually receive deworming medication globally, and only 23% in Africa.11 As a result, programs of advocacy and resource mobilization were launched to expand global deworming coverage.12
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Currently most global deworming activity does not extend to pregnant women or adult women of reproductive age despite its demonstrated benefit (together with iron–folic acid supplementation) in some settings in terms of reducing maternal morbidity and mortality and improving neonatal outcome (in terms of increased birth weight and reduced infant mortality).7,8,13,14 Indeed, there is an expanding evidence base to support use of antenatal anthelminthic treatment in the second or third trimester with either albendazole or mebendazole given that the risks of hookworm in pregnancy appear to outweigh potential toxicities noted in preclinical animal testing with these medications.15,16 However, in other settings, including a study of more than 2,000 pregnant women in Uganda with low-intensity helminth infections, there was no overall benefit of using of anthelminthics during pregnancy,17 and there was even an increased risk of infantile eczema among newborns.18 In the systematic review published in 2008, there were insufficient data to confirm the benefits of deworming on anemia in pregnancy,6 but gradually and cautiously the global health community is moving toward extending coverage of anthelminthic treatment to pregnant women, especially in areas where pharmacovigilance can be assured.19
FEMALE GENITAL SCHISTOSOMIASIS: AFRICA’S MOST COMMON CHRONIC GYNECOLOGIC DISEASE? Beyond hookworm and the other intestinal nematode infections, schistosomiasis appears to be the next most common helminth infection of humankind.1 The infection is acquired through contact with fresh water contaminated with Schistosome cercariae. The most recent published estimate was that 207 million people are infected worldwide, with greater than 90% of those infections in sub-Saharan Africa.20 However, revised estimates indicate that the actual number of infections may be several times higher21 so that schistosomiasis might emerge as the most common helminth infection in sub-Saharan Africa.22 There are several different species of schistosomes that cause human disease. In Africa, where most of the cases of schistosomiasis occur, approximately two thirds are caused by Schistosoma haematobium, the etiologic agent of urinary tract schistosomiasis.23 This form of schistosomiasis results from adult S haematobium worm pairs living in the small veins draining the bladder; the female worm releases terminal spine-shaped eggs that enter the tissues of the bladder.24 The resulting granulomas produce inflammation and bleeding that can result in hematuria.23,24 In addition, these gran-
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ulomas can coalesce to obstruct the ureteral entrance to the bladder, resulting in higher urinary tract disease and even kidney failure.23,24 Studies of S haematobium infection in Africa reveal that adolescents and young adults on average harbor the highest intensity schistosome infections25 and therefore experience the greatest morbidity from many adult parasites depositing eggs in the urinary tract. Newer evidence indicates that between one third and three fourths of girls and women with S haematobium infection also suffer from parasite egg deposition in the uterus, cervix, vagina, and vulva, a condition known as female genital schistosomiasis or female urogenital schistosomiasis.26 The “classical” lesions of female genital schistosomiasis are so-called “sandy patches” in the female genital tract, which are comprised of eggs and surrounding granulomas associated with increased vascularity and host inflammation.26 Sandy patches often bleed on contact and also cause genital itching and pain, stress incontinence, dyspareunia, and possibly infertility.26,27 Female genital schistosomiasis has also been linked to social stigma and depression.26,27 Based on the number of estimated cases of S haematobium in Africa, one of us (P.H.) has suggested (in a non-peer-reviewed editorial) that female genital schistosomiasis could affect between 20 and 150 million girls and women there.28 If confirmed, female genital schistosomiasis could emerge as one of the most common gynecologic conditions in sub-Saharan Africa.12 Additional evidence from two epidemiologic studies conducted in Zimbabwe and Tanzania indicates that female genital schistosomiasis is linked to a 2.9-fold and fourfold increase in risk of acquiring human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), respectively.27,29,30 It is believed that highly vascular and CD4+ cell-enriched sandy patches in the cervix or elsewhere in the female genital tract may provide host entry routes for sexually transmitted HIV, although other mechanisms are plausible.26 There is an urgent need for expanded studies, but, if these findings are confirmed, female genital schistosomiasis from S haematobium infection also could emerge as one of the most important cofactors of Africa’s AIDS epidemic.28 Such findings are critical for designing potential intervention strategies. The major approach to controlling schistosomiasis in Africa relies on annual anthelminthic treatment with praziquantel, which has been shown to effectively treat human schistosome infections, although it does not effectively prevent posttreatment reinfection.22 Programs of mass drug administration with praziquantel are currently being conducted in
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more than a dozen African countries with efforts being led by Ministries of Health in Africa together with the WHO and its regional office for Africa and several nongovernmental organizations for technical assistance.31 However, there is a need for further studies to determine whether praziquantel administered annually or regularly to young girls in mass treatment programs would actually prevent the onset of female genital schistosomiasis. Although praziquantel destroys the egg-laying adult schistosomes, once genital lesions develop, antihelminthic therapy may not affect the presence of adult sandy patches or contact bleeding.26 Thus, although praziquantel has a beneficial effect in terms of curing schistosomiasis and even resolves schistosomerelated infertility,26 it may not reverse the lesions of female genital schistosomiasis. Therefore, if praziquantel were to be used as a female genital schistosomiasis prevention strategy, it is likely that young girls would need access to the drug early in life to prevent the lesions from developing in the first place. Further epidemiologic studies and prospective clinical trials may be required to confirm such assumptions. It has been further suggested that potentially, mass treatment of girls and young women with praziquantel by preventing female genital schistosomiasis could serve as a surrogate AIDS prevention strategy.32 Indeed, at least one modeling study based on data from Zimbabwe indicates that mass treatment with praziquantel would be highly cost-effective and even costsaving as a means to prevent HIV and AIDS in Africa.33 Possibly this strategy is even more cost-effective than other current approaches such as male circumcision.33 Therefore, there is an urgent need to conduct prospective clinical studies to confirm the ability of praziquantel mass drug administration to prevent female genital schistosomiasis and HIV and AIDS. In the meantime, we advocate for better links between programs of parasite control that use praziquantel and global HIV and AIDS programs such as the President’s Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS, Tuberculosis, and Malaria.34 Beyond female genital schistosomiasis, there is emerging evidence that S haematobium infection is common in pregnancy in Africa35 and, as with hookworm infection, schistosomiasis may exert adverse effects on pregnancy outcome.36 In vitro schistosome egg antigens can activate proinflammatory responses in trophoblasts.37 Accordingly, the WHO now recommends praziquantel to women with schistosomiasis who are pregnant and lactating,26 whereas a WHO informal consultation has further recommended that “women of childbearing age should not be excluded from population-based chemotherapy programmes for schistosomiasis.”38
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OTHER HELMINTH INFECTIONS Other helminth infections can also cause direct and indirect effects. For example, lymphatic filariasis, a tissue helminth infection associated with lymphedema and elephantiasis and transmitted by mosquitoes, can affect the breasts and cause genital deformities of the vulva.2,39,40 Most of the cases of lymphatic filariasis are caused by Wuchereria bancrofti. As with female genital schistosomiasis, lymphatic filariasis is also highly stigmatizing.41 In sub-Saharan Africa it has been estimated that there are approximately 46–51 million cases of lymphatic filariasis.42 Still another important helminth infection of women (transmitted by blackflies) is onchocerciasis.43 In addition, onchocerciasisassociated skin disease has also been demonstrated to be highly stigmatizing for women.2,43
A WOMEN’S HEALTH AGENDA Beginning in 2005 and 2006, global efforts at controlling the morbidity of the helminth infections were integrated through mass drug administration of a “rapid impact package” of medicines that simultaneously targeted hookworm and other intestinal helminth infections as well as lymphatic filariasis and onchocerciasis in addition to blinding trachoma (caused by the bacterial pathogen Chlamydia trachomitis).44,45 Today, under the auspices of the WHO (and their regional offices) and through generous drug donations by multinational pharmaceutical corporations, financial support of the governments of the United States and United Kingdom, and private organizations and foundations such as the Gates Foundation, the Ending Neglected Diseases Fund, and the Global Network for Neglected Tropical Diseases, more than 700 million people receive access annually to essential medicines for these neglected tropical diseases.46 Still unclear is the actual number of pregnant women and women at risk of female genital schistosomiasis who are receiving treatments. Recently the gender dimensions of treatment programs for helminth infections in Uganda were evaluated,47 but there is urgency to expand such studies globally. Helminth infections have been mostly ignored as part of UN Women and other global efforts to ensure gender equality and women’s empowerment2 (Hotez PJ. NTDs V.2.0: ‘Blue marble health’—neglected tropical disease control and elimination in a shifting health policy landscape; unpublished manuscript). The observation that hookworm, schistosomiasis, and other helminth infections have not yet been embraced by the President’s Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS, tuberculosis, and malaria34 is consistent with the lack of acceptance of these diseases as important women’s health threats. Beyond the
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global health policies and advocacy required to better integrate helminth control with other women’s health initiatives is an important research and development agenda, which includes programs of operational research and exploring new diagnostics, drugs, and vaccines for the major helminthiases outlined.48 New vaccines for hookworm and schistosomiasis are under development,49,50 which might one day join vaccines for human papillomavirus and tetanus as important new interventions to improve the health of girls and women who live in poverty. As we march toward 2015 and look beyond the UN Millennium Goals, it will be essential to fully explore the important yet often stealth role helminth infections have on such vulnerable populations. Helminth infections and other neglected tropical diseases may ultimately emerge as a major priority in women’s health alongside HIV and AIDS and other sexually transmitted diseases, nutrition, lack of access to contraception, violence, and poverty.
13. Casey GJ, Sartori D, Horton SE, Phuc TQ, Phu LB, Thach DT, et al. Weekly iron-folic acid supplementation with regular deworming is cost-effective in preventing anaemia in women of reproductive age in Vietnam. PLoS One 2010;6:e23723.
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1. Hotez PJ, Brindley P, Bethony J, King CH, Pearce E, Jacobson J. Helminth infections: the great neglected tropical diseases. J Clin Invest 2008;118:1311–21. 2. Hotez PJ. Empowering women and improving female reproductive health through control of neglected tropical diseases. PLoS Negl Trop Dis 2009;3:e559. 3. De Silva N, Brooker S, Hotez P, Montresor A, Engels D, Savioli L. Soil transmitted helminth infections: updating the global picture. Trends Parasitol 2003;19:547–51. 4. Hotez PJ, Brooker S, Bethony JM, Bottazzi ME, Loukas A, Xiao S. Hookworm infection. N Engl J Med 2004;351:799–807.
14. Passerini L, Casey GJ, Biggs BA, Cong DT, Phu LB, Phuc TQ, et al. Increased birth weight associated with regular pre-pregnancy deworming and weekly iron-folic acid supplementation for Vietnamese women. PLoS Negl Trop Dis 2012;6:e1608. 15. Gyorkos TW, Larocque R, Casapia M, Gotuzzo E. Lack of risk of adverse birth outcomes after deworming in pregnant women. Pediatr Infect Dis J 2006;25:791–4. 16. Larocque R, Gyorkos TW. Should deworming be included in antenatal packages in hookworm-endemic areas of developing countries? Can J Public Health 2006;97:222–4. 17. Ndibazza J, Muhangi L, Akisule D, Kiggundu M, Ameke C, Oweka J, et al. Effect of deworming during pregnancy on maternal and perinatal outcomes in Entebbe, Uganda: a randomized controlled trial. Clin Infect Dis 2010;50:531–40. 18. Mpairwe H, Webb EL, Muhangi L, Ndibazza J, Akishule D, Nampijja M, et al. Anthelminthic treatment during pregnancy is associated with increased risk of infantile eczema: randomizedcontrolled trial results. Pediatr Allergy Immunol 2011;22:305–12. 19. Deworming for Health and Development. Available at: http://whqlibdoc.who.int/hq/2005/who_cds_cpe_pvc_2005.14. pdf. Retrieved August 10, 2013.
21. King CH Parasites and poverty: the case of schistosomiasis. Acta Trop 2010;113:95–104. 22. Hotez PJ, Fenwick A. Schistosomiasis in Africa: an emerging tragedy in our new global health decade. PLoS Negl Trop Dis 2009;3;e485. 23. Van der Werf MJ, de Vlas SJ, Brooker S, Looman CW, Nagelkerke NJ, Habbema JD, et al. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop 2003;86:125–39.
5. Bundy DAP. Is the hookworm just another Geohelminth? In: Schad GA, Warren KS, editors. Hookworm disease current status and new directions. London (UK): Taylor and Francis; 1990. p. 147–64.
24. Brindley PJ, Hotez PJ. Break out: urogenital schistosomiasis and Schistosoma haematobium. infection in the post-genomic era. PLoS Negl Trop Dis 2013;7:e1961.
6. Brooker S, Hotez PJ, Bundy DAP. Hookworm-related anaemia among pregnant women: a systematic review. PLoS Negl Trop Dis 2008;2:e291.
25. Woolhouse MEJ, Taylor P, Matanhire D, Chandiwana SK. Acquired immunity and epidemiology of Schistosoma haematobium. Nature 1991;351:757–9.
7. Christian P, Khatry SK, West KP Jr. Antenatal anthelminthic treatment, birthweight, and infant survival in rural Nepal. Lancet 2004;364:981–3.
26. Kjetland EF, Leutscher PD, Ndhloovu PD. A review of female genital schistosomiasis. Trends Parasitol 2012;28:58–65.
8. Larocque R, Casapia M, Gotuzzo E, MacLean JD, Soto JC, Rahme E, et al. A double-blind randomized controlled trial of antenatal mebendazole to reduce low birthweight in a hookworm-endemic area of Peru. Trop Med Int Health 2006;11:1485–95. 9. Bundy DAP, Chan MS, Savioli L. Hookworm infection in pregnancy. Trans R Soc Trop Med Hyg 1995;89:521–2. 10. Hotez PJ. Mass drug administration and the integrated control of the world’s high prevalence neglected tropical diseases. Clin Pharmacol Ther 2009;85:659–64. 11. Soil-transmitted helminthiases: number of children treated in 2011. Wkly Epidemiol Rec 2013;88:145–52. 12. Barry MA, Simon G, Mistry N, Hotez PJ. Global trends in neglected tropical disease control and elimination: impact on child health. Arch Dis Child 2013;98:635–41.
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27. Downs JA, Mguta C, Kaatano GM, Mitchell KB, Bang H, Simplice H, et al. Urogenital schistosomiasis in women of reproductive age in Tanzania’s Lake Victoria region. Am J Trop Med Hyg 2011;84:364–9. 28. Hotez P. Africa’s lowest cost AIDS prevention strategy? PLoS Med. Available at: http://blogs.plos.org/speakingofmedicine/2013/08/ 01/africas-lowest-cost-aids-prevention-strategy/. Retrieved August 10, 2013. 29. Kjetland EF, Ndhlovu PD, Gomo E, Mduluza T, Midzi N, Gwanzura L, et al. Association between genital schistosomiasis and HIV in rural Zimbabwean women. AIDS 2006;20: 593–600. 30. Mbabazi PS, Andan O, Fitzgerald DW, Chitsulo L, Engels D, Downs JA. Examining the relationship between urogenital schistosomiasis and HIV infection. PLoS Negl Trop Dis 2011; 5:e1396.
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31. Schistosomiasis Control Initiative. Available at: http://www3. imperial.ac.uk/schisto/wherewework. Retrieved August 10, 2013. 32. Hotez PJ, Fenwick A, Kjetland EF. Africa’s 32 cents solution for HIV/AIDS. PLoS Negl Trop Dis 2009;3:e430. 33. Ndeffo Mbah ML, Poolman EM, Atkins KE, Orenstein EW, Ancel Meyers L, Townsend JP, et al. Potential cost-effectiveness of schistosomiasis treatment for reducing HIV transmission in Africa—the case of Zimbabwean women. PLoS Negl Trop Dis 2013;7:e2346. 34. Hotez PJ, Mistry N, Rubinstein J, Sachs JD. Integrating neglected tropical diseases into AIDS, tuberculosis, and malaria control. N Engl J Med 2011;364:2086–9. 35. Salawu OT, Odaibo AB. Schistosomiasis among pregnant women in rural communities in Nigeria. Int J Gynaecol Obstet 2013;122:1–4. 36. Friedman JF, Mital P, Kanzaria HK, Olds GR, Kurtis JD. Schistosomiasis and pregnancy. Trends Parasitol 2007;23: 159–64. 37. McDonald EA, Kurtis JD, Acosta L, Gundogan F, Sharma S, Pond-Tor S, et al. Schistosome egg antigens elicit a proinflammatory response by trophoblast cells of the human placenta. Infect Immun 2013;81:704–12. 38. World Health Organization. Report of the WHO informal consultation on the use of praziquantel during pregnancy/ lactation and albendazole/mebendazole in children under 24 months. 2002. p. 1–34. Available at: http://whqlibdoc.who. int/hq/2003/WHO_CDS_CPE_PVC_2002.4.pdf. Retrieved September 14, 2013. 39. Adesiyun AG, Samaila MO. Huge filarial elephantiasis vulvae in a Nigerian woman with subfertility. Arch Gynecol Obstet 2008;278:597–600. 40. Christiana O, Olajumoke M, Oyetunde S. Lymphatic filariasis and associated morbidities in rural communities of Ogun State, Southwestern Nigeria. Travel Med Infect Dis 2013 Mar 18. pii: S1477-8939(13)00017-3. doi: 10.1016/j.tmaid.2013.02.006. [Epub ahead of print].
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41. Person B, Bartholomew LK, Gyapong M, Adiss DG, van den Borne B. Health-related stigma among women with lymphatic filariasis from the Dominican Republic and Ghana. Soc Sci Med 2009;68:30–8. 42. Hotez PJ, Kamath A. Neglected tropical diseases in Sub-Saharan Africa: review of their prevalence, distribution, and disease burden. PLoS Negl Trop Dis 2009;3:e412. 43. Amazigo U, Noma M, Bump J, Benton B, Liese B, Yaméogo L, et al. Onchocerciasis. In: Jamison DT, Feachem RG, Makgoba MW, Bos Er, Bingana FK, Hoffman KJ, et al, editors. Disease and mortality in sub-Saharan Africa. Washington (DC): World Bank; 2006. p. 215–22. Available at: http://www.ncbi. nlm.nih.gov/books/NBK2287/. Retrieved September 14, 2013. 44. Molyneux DH, Hotez PJ, Fenwick A. ‘Rapid-impact interventions’: how a policy of integrated control for Africa’s neglected tropical diseases could benefit the poor. PLoS Med 2005;2:e336. 45. Hotez PJ, Molyneux DH, Fenwick A, Ottesen E, Ehrlich Sachs S, Sachs JD. Incorporating a rapid-impact package for neglected tropical diseases with programs for HIV/AIDS, tuberculosis, and malaria. PLoS Med 2006;3:e102. 46. Integrated preventive chemotherapy for neglected tropical diseases: estimation of the number of interventions required and delivered, 2009–2010. Wkly Epidemiol Rec 2012:17–27. 47. Rikoff H, Tukahebwa EM, Fleming FM, Leslie J, Cole DC. Exploring gender dimensions of treatment programmes for neglected tropical diseases in Uganda. PLoS Negl Trop Dis 2013; 7:e2312. 48. Hotez PJ, Pecoul B. ‘Manifesto’ for advancing the control and elimination of neglected tropical diseases. PLoS Negl Trop Dis 2010;4:e718. 49. Hotez PJ, Bethony JM, Diemert DJ, Pearson M, Loukas A. Developing vaccines to combat hookworm infection and intestinal schistosomiasis. Nat Rev Microbiol 2010;8:814–26. 50. Hotez PJ, Diemert D, Bacon KM, Beaumier C, Bethony JM, Bottazzi ME, et al. The human hookworm vaccine. Vaccine 2013;31(suppl 2):B227–32.
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Helminth Infections A New Global Women’s Health Agenda Peter Hotez,
MD, PhD,
and Megan Whitham
Emerging evidence over the past decade has implicated helminth infections as important yet stealth causes of adverse pregnancy outcomes and impaired women’s reproductive health. The two most important helminth infections affecting women living in poverty in Africa and elsewhere in the developing world are hookworm infection and schistosomiasis. In Africa alone, almost 40 million women of childbearing age are infected with hookworms, including almost 7 million pregnant women who are at greater risk of severe anemia, higher mortality, and experiencing poor neonatal outcome (reduced birth weight and increased infant mortality). Possibly, tens of millions of women in Africa also suffer from female genital schistosomiasis associated with genital itching and pain, stress incontinence, dyspareunia, and infertility and experience social stigma and depression. Female genital schistosomiasis also is linked to horizontal transmission of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) and it may represent one of Africa’s major cofactors in its AIDS epidemic. There is urgency to expand mass drug administration efforts for hookworm and schistosomiasis to include women of reproductive age and to shape new policies and advocacy initiatives for women’s global health to include helminth control. In parallel is a require-
From the Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine at Baylor College of Medicine, and the Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, Houston, Texas; and Virginia Tech Carilion School of Medicine, Roanoke, Virginia. Peter Hotez received support to develop vaccines for helminth infections from the Bill & Melinda Gates Foundation, Dutch Ministry of Foreign Affairs, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Blavatnik Family Foundation, Dr. Gary Michelson, Mort and Chris Hyman, and Texas Children’s Hospital. Corresponding author: Peter Hotez, MD, PhD, Baylor College of Medicine, National School of Tropical Medicine, 1 Baylor Plaza, MS 113, Houston, TX 77030; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2013 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
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ment to better link global health programs for HIV and AIDS and malaria with helminth control and to simultaneously launch initiatives for research and development. (Obstet Gynecol 2014;123:155–60) DOI: 10.1097/AOG.0000000000000025
M
ost obstetricians and gynecologists do not routinely think about parasitic worm (helminth) infections nor see them as central or perhaps even relevant to their clinical practices. However, new information published within the last decade has revealed that helminth infections are responsible for a huge but mostly hidden or stealth burden of morbidity among young women living in Africa and other developing regions. The helminthiases represent some of the most common global health conditions of women living in developing countries (Table 1),1 and two helminth infections in particular—hookworm infection and schistosomiasis— stand out for their devastating effect on reproductive health.2 We summarize some of the current and recently published information on these links and new global approaches to control these neglected tropical diseases in resource-poor countries.
HOOKWORM INFECTION AND PREGNANCY Hookworm infection is one of the most common soiltransmitted helminth infections of humans, affecting up to hundreds of millions of people mostly in areas of ruraly poverty in sub-Saharan Africa, south and east Asia, Oceania, and Central and South America.3 Anemia is the major morbidity resulting from the presence of adult hookworms, which are nematode parasites—either Necator americanus or Ancylostoma duodenale—attached to the inner wall of the small intestine.4 Hookworms can live for years in the intestine where they remove host blood to cause iron and protein losses that ultimately lead to iron deficiency anemia (microcytic hypochromic anemia) and protein malnutrition, respectively.4 Hookworms are important public health threats among women of reproductive age. Whereas other
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Table 1. Helminth Infections Among Women in Africa Disease or Condition Hookworm infection
Schistosomiasis
Lymphatic filariasis
Onchocerciasis
No. of Cases
Major Pathologic Sequelae Relevant to Women’s Health
198 million cases in sub-Saharan Maternal and child Africa, approximately one half anemia among women (99 million cases) 37.7 million women of reproductive age 6.9 million pregnant women 192 million cases in sub-Saharan Female genital Africa, approximately one half schistosomiasis, among women (96 million cases) approximately 20– 150 million cases in sub-Saharan Africa
Alternative estimates indicate that 586–659 million people at any given time live with some form of schistosomiasis, 90% of whom live in sub-Saharan Africa 46–51 million cases in subBreast and vulvar Saharan Africa, approximately lymphoedema one half among women (23–25 million cases) 37 million cases in sub-Saharan Onchocerca skin Africa, approximately one half disease among women (18 million cases)
common intestinal nematodes such as Ascaris lumbricoides or Trichuris trichiura exhibit their highest intensity in early childhood, so that young children tend to harbor the largest number of these worms in their gut, hookworms are exceptional in that adult populations frequently exhibit the highest intensities and worm burdens of hookworm in endemic areas.5 Therefore, hookworm-associated iron deficiency anemia is commonly found among adolescent girls and women of reproductive age.6 In a systematic review, Brooker et al6 found that during pregnancy, increasing hookworm infection intensity is associated with anemia, ie, lower hemoglobin levels. Indeed, in sub-Saharan Africa where almost 200 million cases of hookworm infection occur,3 it was estimated that 37.7 million women of reproductive age are infected with hookworms at any given time.6 Based on the number of live births that occur in sub-Saharan Africa, it was determined that 6.9 million pregnant women are infected with hookworms, ie, between one fourth and one third of pregnancies in sub-Saharan Africa.6 Thus, hookworm infection (and hookworm–malaria coinfections) may represent one of the most common obstetric complications on the African continent. Moreover,
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Additional Comments
Reference
Sub-Saharan Africa only
3,6,42
The differences in the total number of cases in sub-Saharan Africa are based on studies that for every egg-positive individual diagnosed there may be 1 or 2 individuals who are egg-negative at the time of diagnosis yet still infected21 Female genital schistosomiasis estimates are preliminary and nonpeer-reviewed
20,21,28,42
Sub-Saharan Africa only
42
Sub-Saharan Africa only
42,43
hookworm infection is not restricted to Africa, and high rates of hookworm infection in pregnancy have also been found in impoverished areas of South Asia7 and South America.8 An earlier estimate indicated that 44 million pregnant women globally are infected with hookworms.9 The World Health Organization (WHO) recommends annual deworming of children at risk for acquiring hookworm and other intestinal helminth infections.10 Deworming is typically conducted with a single 400-mg tablet of albendazole or a 500-mg tablet of mebendazole, although sometimes twiceyearly treatments are required.10 Mass treatments are given without first conducting individual diagnostic examinations and instead are provided based on the prevalence and intensity of the helminth infections in the community. Currently, the WHO estimates that almost 900 million children are at risk for acquiring intestinal helminth infections, of which approximately one third actually receive deworming medication globally, and only 23% in Africa.11 As a result, programs of advocacy and resource mobilization were launched to expand global deworming coverage.12
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Currently most global deworming activity does not extend to pregnant women or adult women of reproductive age despite its demonstrated benefit (together with iron–folic acid supplementation) in some settings in terms of reducing maternal morbidity and mortality and improving neonatal outcome (in terms of increased birth weight and reduced infant mortality).7,8,13,14 Indeed, there is an expanding evidence base to support use of antenatal anthelminthic treatment in the second or third trimester with either albendazole or mebendazole given that the risks of hookworm in pregnancy appear to outweigh potential toxicities noted in preclinical animal testing with these medications.15,16 However, in other settings, including a study of more than 2,000 pregnant women in Uganda with low-intensity helminth infections, there was no overall benefit of using of anthelminthics during pregnancy,17 and there was even an increased risk of infantile eczema among newborns.18 In the systematic review published in 2008, there were insufficient data to confirm the benefits of deworming on anemia in pregnancy,6 but gradually and cautiously the global health community is moving toward extending coverage of anthelminthic treatment to pregnant women, especially in areas where pharmacovigilance can be assured.19
FEMALE GENITAL SCHISTOSOMIASIS: AFRICA’S MOST COMMON CHRONIC GYNECOLOGIC DISEASE? Beyond hookworm and the other intestinal nematode infections, schistosomiasis appears to be the next most common helminth infection of humankind.1 The infection is acquired through contact with fresh water contaminated with Schistosome cercariae. The most recent published estimate was that 207 million people are infected worldwide, with greater than 90% of those infections in sub-Saharan Africa.20 However, revised estimates indicate that the actual number of infections may be several times higher21 so that schistosomiasis might emerge as the most common helminth infection in sub-Saharan Africa.22 There are several different species of schistosomes that cause human disease. In Africa, where most of the cases of schistosomiasis occur, approximately two thirds are caused by Schistosoma haematobium, the etiologic agent of urinary tract schistosomiasis.23 This form of schistosomiasis results from adult S haematobium worm pairs living in the small veins draining the bladder; the female worm releases terminal spine-shaped eggs that enter the tissues of the bladder.24 The resulting granulomas produce inflammation and bleeding that can result in hematuria.23,24 In addition, these gran-
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ulomas can coalesce to obstruct the ureteral entrance to the bladder, resulting in higher urinary tract disease and even kidney failure.23,24 Studies of S haematobium infection in Africa reveal that adolescents and young adults on average harbor the highest intensity schistosome infections25 and therefore experience the greatest morbidity from many adult parasites depositing eggs in the urinary tract. Newer evidence indicates that between one third and three fourths of girls and women with S haematobium infection also suffer from parasite egg deposition in the uterus, cervix, vagina, and vulva, a condition known as female genital schistosomiasis or female urogenital schistosomiasis.26 The “classical” lesions of female genital schistosomiasis are so-called “sandy patches” in the female genital tract, which are comprised of eggs and surrounding granulomas associated with increased vascularity and host inflammation.26 Sandy patches often bleed on contact and also cause genital itching and pain, stress incontinence, dyspareunia, and possibly infertility.26,27 Female genital schistosomiasis has also been linked to social stigma and depression.26,27 Based on the number of estimated cases of S haematobium in Africa, one of us (P.H.) has suggested (in a non-peer-reviewed editorial) that female genital schistosomiasis could affect between 20 and 150 million girls and women there.28 If confirmed, female genital schistosomiasis could emerge as one of the most common gynecologic conditions in sub-Saharan Africa.12 Additional evidence from two epidemiologic studies conducted in Zimbabwe and Tanzania indicates that female genital schistosomiasis is linked to a 2.9-fold and fourfold increase in risk of acquiring human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), respectively.27,29,30 It is believed that highly vascular and CD4+ cell-enriched sandy patches in the cervix or elsewhere in the female genital tract may provide host entry routes for sexually transmitted HIV, although other mechanisms are plausible.26 There is an urgent need for expanded studies, but, if these findings are confirmed, female genital schistosomiasis from S haematobium infection also could emerge as one of the most important cofactors of Africa’s AIDS epidemic.28 Such findings are critical for designing potential intervention strategies. The major approach to controlling schistosomiasis in Africa relies on annual anthelminthic treatment with praziquantel, which has been shown to effectively treat human schistosome infections, although it does not effectively prevent posttreatment reinfection.22 Programs of mass drug administration with praziquantel are currently being conducted in
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more than a dozen African countries with efforts being led by Ministries of Health in Africa together with the WHO and its regional office for Africa and several nongovernmental organizations for technical assistance.31 However, there is a need for further studies to determine whether praziquantel administered annually or regularly to young girls in mass treatment programs would actually prevent the onset of female genital schistosomiasis. Although praziquantel destroys the egg-laying adult schistosomes, once genital lesions develop, antihelminthic therapy may not affect the presence of adult sandy patches or contact bleeding.26 Thus, although praziquantel has a beneficial effect in terms of curing schistosomiasis and even resolves schistosomerelated infertility,26 it may not reverse the lesions of female genital schistosomiasis. Therefore, if praziquantel were to be used as a female genital schistosomiasis prevention strategy, it is likely that young girls would need access to the drug early in life to prevent the lesions from developing in the first place. Further epidemiologic studies and prospective clinical trials may be required to confirm such assumptions. It has been further suggested that potentially, mass treatment of girls and young women with praziquantel by preventing female genital schistosomiasis could serve as a surrogate AIDS prevention strategy.32 Indeed, at least one modeling study based on data from Zimbabwe indicates that mass treatment with praziquantel would be highly cost-effective and even costsaving as a means to prevent HIV and AIDS in Africa.33 Possibly this strategy is even more cost-effective than other current approaches such as male circumcision.33 Therefore, there is an urgent need to conduct prospective clinical studies to confirm the ability of praziquantel mass drug administration to prevent female genital schistosomiasis and HIV and AIDS. In the meantime, we advocate for better links between programs of parasite control that use praziquantel and global HIV and AIDS programs such as the President’s Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS, Tuberculosis, and Malaria.34 Beyond female genital schistosomiasis, there is emerging evidence that S haematobium infection is common in pregnancy in Africa35 and, as with hookworm infection, schistosomiasis may exert adverse effects on pregnancy outcome.36 In vitro schistosome egg antigens can activate proinflammatory responses in trophoblasts.37 Accordingly, the WHO now recommends praziquantel to women with schistosomiasis who are pregnant and lactating,26 whereas a WHO informal consultation has further recommended that “women of childbearing age should not be excluded from population-based chemotherapy programmes for schistosomiasis.”38
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OTHER HELMINTH INFECTIONS Other helminth infections can also cause direct and indirect effects. For example, lymphatic filariasis, a tissue helminth infection associated with lymphedema and elephantiasis and transmitted by mosquitoes, can affect the breasts and cause genital deformities of the vulva.2,39,40 Most of the cases of lymphatic filariasis are caused by Wuchereria bancrofti. As with female genital schistosomiasis, lymphatic filariasis is also highly stigmatizing.41 In sub-Saharan Africa it has been estimated that there are approximately 46–51 million cases of lymphatic filariasis.42 Still another important helminth infection of women (transmitted by blackflies) is onchocerciasis.43 In addition, onchocerciasisassociated skin disease has also been demonstrated to be highly stigmatizing for women.2,43
A WOMEN’S HEALTH AGENDA Beginning in 2005 and 2006, global efforts at controlling the morbidity of the helminth infections were integrated through mass drug administration of a “rapid impact package” of medicines that simultaneously targeted hookworm and other intestinal helminth infections as well as lymphatic filariasis and onchocerciasis in addition to blinding trachoma (caused by the bacterial pathogen Chlamydia trachomitis).44,45 Today, under the auspices of the WHO (and their regional offices) and through generous drug donations by multinational pharmaceutical corporations, financial support of the governments of the United States and United Kingdom, and private organizations and foundations such as the Gates Foundation, the Ending Neglected Diseases Fund, and the Global Network for Neglected Tropical Diseases, more than 700 million people receive access annually to essential medicines for these neglected tropical diseases.46 Still unclear is the actual number of pregnant women and women at risk of female genital schistosomiasis who are receiving treatments. Recently the gender dimensions of treatment programs for helminth infections in Uganda were evaluated,47 but there is urgency to expand such studies globally. Helminth infections have been mostly ignored as part of UN Women and other global efforts to ensure gender equality and women’s empowerment2 (Hotez PJ. NTDs V.2.0: ‘Blue marble health’—neglected tropical disease control and elimination in a shifting health policy landscape; unpublished manuscript). The observation that hookworm, schistosomiasis, and other helminth infections have not yet been embraced by the President’s Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS, tuberculosis, and malaria34 is consistent with the lack of acceptance of these diseases as important women’s health threats. Beyond the
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global health policies and advocacy required to better integrate helminth control with other women’s health initiatives is an important research and development agenda, which includes programs of operational research and exploring new diagnostics, drugs, and vaccines for the major helminthiases outlined.48 New vaccines for hookworm and schistosomiasis are under development,49,50 which might one day join vaccines for human papillomavirus and tetanus as important new interventions to improve the health of girls and women who live in poverty. As we march toward 2015 and look beyond the UN Millennium Goals, it will be essential to fully explore the important yet often stealth role helminth infections have on such vulnerable populations. Helminth infections and other neglected tropical diseases may ultimately emerge as a major priority in women’s health alongside HIV and AIDS and other sexually transmitted diseases, nutrition, lack of access to contraception, violence, and poverty.
13. Casey GJ, Sartori D, Horton SE, Phuc TQ, Phu LB, Thach DT, et al. Weekly iron-folic acid supplementation with regular deworming is cost-effective in preventing anaemia in women of reproductive age in Vietnam. PLoS One 2010;6:e23723.
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21. King CH Parasites and poverty: the case of schistosomiasis. Acta Trop 2010;113:95–104. 22. Hotez PJ, Fenwick A. Schistosomiasis in Africa: an emerging tragedy in our new global health decade. PLoS Negl Trop Dis 2009;3;e485. 23. Van der Werf MJ, de Vlas SJ, Brooker S, Looman CW, Nagelkerke NJ, Habbema JD, et al. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop 2003;86:125–39.
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8. Larocque R, Casapia M, Gotuzzo E, MacLean JD, Soto JC, Rahme E, et al. A double-blind randomized controlled trial of antenatal mebendazole to reduce low birthweight in a hookworm-endemic area of Peru. Trop Med Int Health 2006;11:1485–95. 9. Bundy DAP, Chan MS, Savioli L. Hookworm infection in pregnancy. Trans R Soc Trop Med Hyg 1995;89:521–2. 10. Hotez PJ. Mass drug administration and the integrated control of the world’s high prevalence neglected tropical diseases. Clin Pharmacol Ther 2009;85:659–64. 11. Soil-transmitted helminthiases: number of children treated in 2011. Wkly Epidemiol Rec 2013;88:145–52. 12. Barry MA, Simon G, Mistry N, Hotez PJ. Global trends in neglected tropical disease control and elimination: impact on child health. Arch Dis Child 2013;98:635–41.
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27. Downs JA, Mguta C, Kaatano GM, Mitchell KB, Bang H, Simplice H, et al. Urogenital schistosomiasis in women of reproductive age in Tanzania’s Lake Victoria region. Am J Trop Med Hyg 2011;84:364–9. 28. Hotez P. Africa’s lowest cost AIDS prevention strategy? PLoS Med. Available at: http://blogs.plos.org/speakingofmedicine/2013/08/ 01/africas-lowest-cost-aids-prevention-strategy/. Retrieved August 10, 2013. 29. Kjetland EF, Ndhlovu PD, Gomo E, Mduluza T, Midzi N, Gwanzura L, et al. Association between genital schistosomiasis and HIV in rural Zimbabwean women. AIDS 2006;20: 593–600. 30. Mbabazi PS, Andan O, Fitzgerald DW, Chitsulo L, Engels D, Downs JA. Examining the relationship between urogenital schistosomiasis and HIV infection. PLoS Negl Trop Dis 2011; 5:e1396.
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31. Schistosomiasis Control Initiative. Available at: http://www3. imperial.ac.uk/schisto/wherewework. Retrieved August 10, 2013. 32. Hotez PJ, Fenwick A, Kjetland EF. Africa’s 32 cents solution for HIV/AIDS. PLoS Negl Trop Dis 2009;3:e430. 33. Ndeffo Mbah ML, Poolman EM, Atkins KE, Orenstein EW, Ancel Meyers L, Townsend JP, et al. Potential cost-effectiveness of schistosomiasis treatment for reducing HIV transmission in Africa—the case of Zimbabwean women. PLoS Negl Trop Dis 2013;7:e2346. 34. Hotez PJ, Mistry N, Rubinstein J, Sachs JD. Integrating neglected tropical diseases into AIDS, tuberculosis, and malaria control. N Engl J Med 2011;364:2086–9. 35. Salawu OT, Odaibo AB. Schistosomiasis among pregnant women in rural communities in Nigeria. Int J Gynaecol Obstet 2013;122:1–4. 36. Friedman JF, Mital P, Kanzaria HK, Olds GR, Kurtis JD. Schistosomiasis and pregnancy. Trends Parasitol 2007;23: 159–64. 37. McDonald EA, Kurtis JD, Acosta L, Gundogan F, Sharma S, Pond-Tor S, et al. Schistosome egg antigens elicit a proinflammatory response by trophoblast cells of the human placenta. Infect Immun 2013;81:704–12. 38. World Health Organization. Report of the WHO informal consultation on the use of praziquantel during pregnancy/ lactation and albendazole/mebendazole in children under 24 months. 2002. p. 1–34. Available at: http://whqlibdoc.who. int/hq/2003/WHO_CDS_CPE_PVC_2002.4.pdf. Retrieved September 14, 2013. 39. Adesiyun AG, Samaila MO. Huge filarial elephantiasis vulvae in a Nigerian woman with subfertility. Arch Gynecol Obstet 2008;278:597–600. 40. Christiana O, Olajumoke M, Oyetunde S. Lymphatic filariasis and associated morbidities in rural communities of Ogun State, Southwestern Nigeria. Travel Med Infect Dis 2013 Mar 18. pii: S1477-8939(13)00017-3. doi: 10.1016/j.tmaid.2013.02.006. [Epub ahead of print].
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41. Person B, Bartholomew LK, Gyapong M, Adiss DG, van den Borne B. Health-related stigma among women with lymphatic filariasis from the Dominican Republic and Ghana. Soc Sci Med 2009;68:30–8. 42. Hotez PJ, Kamath A. Neglected tropical diseases in Sub-Saharan Africa: review of their prevalence, distribution, and disease burden. PLoS Negl Trop Dis 2009;3:e412. 43. Amazigo U, Noma M, Bump J, Benton B, Liese B, Yaméogo L, et al. Onchocerciasis. In: Jamison DT, Feachem RG, Makgoba MW, Bos Er, Bingana FK, Hoffman KJ, et al, editors. Disease and mortality in sub-Saharan Africa. Washington (DC): World Bank; 2006. p. 215–22. Available at: http://www.ncbi. nlm.nih.gov/books/NBK2287/. Retrieved September 14, 2013. 44. Molyneux DH, Hotez PJ, Fenwick A. ‘Rapid-impact interventions’: how a policy of integrated control for Africa’s neglected tropical diseases could benefit the poor. PLoS Med 2005;2:e336. 45. Hotez PJ, Molyneux DH, Fenwick A, Ottesen E, Ehrlich Sachs S, Sachs JD. Incorporating a rapid-impact package for neglected tropical diseases with programs for HIV/AIDS, tuberculosis, and malaria. PLoS Med 2006;3:e102. 46. Integrated preventive chemotherapy for neglected tropical diseases: estimation of the number of interventions required and delivered, 2009–2010. Wkly Epidemiol Rec 2012:17–27. 47. Rikoff H, Tukahebwa EM, Fleming FM, Leslie J, Cole DC. Exploring gender dimensions of treatment programmes for neglected tropical diseases in Uganda. PLoS Negl Trop Dis 2013; 7:e2312. 48. Hotez PJ, Pecoul B. ‘Manifesto’ for advancing the control and elimination of neglected tropical diseases. PLoS Negl Trop Dis 2010;4:e718. 49. Hotez PJ, Bethony JM, Diemert DJ, Pearson M, Loukas A. Developing vaccines to combat hookworm infection and intestinal schistosomiasis. Nat Rev Microbiol 2010;8:814–26. 50. Hotez PJ, Diemert D, Bacon KM, Beaumier C, Bethony JM, Bottazzi ME, et al. The human hookworm vaccine. Vaccine 2013;31(suppl 2):B227–32.
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