Epidemiology and control of malaria during pregnancy

M. James Eliades, MD, MPHCenters for Disease Control and

PreventionDivision of Parasitic Diseases

Objectives of talk

Discuss the epidemiology of malaria during pregnancy in sub-Saharan Africa

Present evidence for current intervention strategies

Mention gaps in our knowledge

Epidemiology

Malaria during pregnancy: bad news 50 million women in malaria endemic areas become

pregnant each year (UNICEF)

Malaria during pregnancy most widely evaluated in sub-Saharan Africa and estimated to account for:• 400,000 cases of severe anemia in pregnant

women (Guyatt 2001)

• ~ 35% of preventable low birth weight (Steketee 2001, Guyatt 2004)

• 3-8% of infant mortality (Steketee 2001, Guyatt 2001)• 75,000 - 200,000 infant deaths annually

(WHO/UNICEF Africa Malaria Report 2003)

Distribution of Malaria

Where in the World is Malaria Found?

Malaria during pregnancy

Maternal and perinatal effects depend on intensity of transmission: Plasmodium falciparum in high transmission areas is most well studied - responsible for most morbidity & mortality

Transmission intensity

“Stable” malaria• Prevalence

persistently high• Transmission can

continue with few vectors

• Collective immunity is high

• P. falciparum• Young children and

pregnant women at greatest risk

• Type: sub-Saharan Africa

“Unstable” malaria• Variability in space

and time• Disease fluctuates

(inc. epidemics)• Collective immunity

is low• P. vivax, also P.

falciparum• All ages at risk• Type: S.E. Asia

Malaria in Pregnancy

Transmission levels effect consequences of disease• Low transmission/little or no immunity

Symptomatic Severe malaria Anemia Adverse birth outcomes

• Moderate to high transmission/immunity Asymptomatic Severe anemia Low birth weight

Malaria during pregnancy:stable transmission areas

Asymptomatic infection

Nutrient transport

Placental sequestration

Low birth weight

Risk of infant mortality

P. falciparum malaria

Anemia

Acquired immunity - high 1st & 2nd pregnancies at

greatest risk Prevention essential

Malaria during pregnancy:unstable transmission areas

P. falciparum malaria

Clinical illness

Severe disease

Risk to mother(death)

Risk to fetus(stillbirth, abortion)

Acquired immunity - low

All pregnancies affected equally

Recognition and case management needed in addition to prevention

Vulnerable groups among pregnant women

Primigravidae Adolescents HIV-positive women Women in rural areas

Placental parasitemia by pregnancy number, Kisumu, Kenya, 1996-98

0

5

10

15

20

25

30

G1 G2 G3+

1-999 1000-9999 >10,000

Parasite density/mm3

% parasitemic

772402 479

Adapted from Van Eijk et al.

Effects on Maternal Health

Severe anemia• Proportion in all gravidities attributable to

malaria: 26%• Approximately 400,000 cases per year

Effects on Birth Outcome

Low Birth Weight 20% of LBW deliveries, 35% of preventable LBW Responsible for at least 100,000 infant deaths

• Intrauterine growth retardation (IUGR)• Preterm delivery

Stillbirth• Twice the risk with placental malaria(OR 2.19)

Low birth weight

Effects on Birth Outcomes: Low Transmission Settings

In Africa• LBW: 9.3%• Preterm delivery: 8.6%• Stillbirths: 3.7%

Outside Africa• LBW: 16.0%• Preterm delivery: 11.0%• Stillbirths: 3.0%

Neonatal Mortality Rates by BirthweightMangochi, Malawi

September 1987 - June 1989

Adapted from Steketee et al.

0

200

400

600

800

1000

<1500 1500-1999 2000-2499 2500

Death

s p

er

1000 L

ive B

irth

s

800

300

49 26

31 11.7 2.4 1.0Relative Risk

Pathophysiology

Placenta

Sequestration of parasites in the placenta• Red blood cells infected with P. falciparum

attach to placenta

Can be present without peripheral parasitemia

Increased susceptibility of primigravidae

Congenital Malaria

Can occur with all four species Parasites cross the placenta and enter

the fetal circulation Immunity of mother affects severity

• Non-immune: stillbirth, perinatal death, fever/anemia/jaundice/splenomegaly up to six weeks post-delivery

• Immune: usually asymptomatic; parasties rapidly cleared

HIV Among Pregnant Women in sub-Sahara Africa

Estimated 27 million people in Africa living with HIV/AIDS

55% of sub-Sahara Africa adult HIV infection in reproductive-age women

Estimated increase in MIP attributable to HIV is 5.5% and 18.8% for populations with HIV prevalence of 10% and 40%

0

10

20

30

40

50

60

Botswana Swaziland Zimbabwe South Africa

HIV Seroprevalence Among Women Attending Antenatal Clinics in Urban

Areas

UNAIDS, Report on the Global HIV/AIDS Epidemic, 2002

HIV+ women have higher prevalences

and densities of parasitemia

All parities affected

Risk of infant mortality higher in

babies born to mothers co-infected

with HIV and placental malaria

• Increased vertical transmission of HIV?

HIV & Malaria During Pregnancy

Study 2. Placental parasitemia by HIV status and pregnancy number, Kisumu, Kenya,

1996-98

0

5

10

15

20

25

30

35

40

G1 G2 G3 G1 G2 G3

1-999 1000-9999 >10,000

Parasite density/mm3

% parasitemic

HIV (+) HIV (-)

231 159 197 772 402 479

Total n = 2263Summary RR = 1.63 (1.41-1.89), p<0.001

Intermittent preventive therapy by HIV status and SP efficacy

05

101520253035404550

Case 2-dose Monthly

Per

cent

par

asite

mia

HIV (+)

HIV (-)

Management

Current strategies

Options for malaria control during pregnancy

Drugs• Chemoprophylaxis

• Intermittent preventive treatment during pregnancy (IPTp)• Febrile case management

Insecticide Treated Nets (ITNs) Prevention and treatment of anemia

• Hematinic supplementation• Nutritional counseling

Vaccines?

Chemoprophylaxis: no longer a recommended strategy in high

transmission areas Most regimens require weekly or more frequent dosing

• Chloroquine (CQ) is the most commonly used drug Usefulness limited by:

• Difficulty in delivering and sustaining intervention

• Poor adherence to regimen

• Side effects of CQ (especially itching)

• Rising levels of P. falciparum resistance to CQ

• Poor program effectiveness of CQ chemoprophylaxis

Intermittent Preventive Treatment for pregnancy (IPTp)

Intermittent preventive treatment (IPTp): an alternative strategy

Most studied regimen: Sulfadoxine-pyrimethamine (SP) 2 curative courses (3 tablets)• One course during second trimester• One course during third trimester

Inexpensive Easily deliverable (can be given under direct

observation) Safe Efficacious

Intermittent preventive treatment-- the two dose SP strategy

Weeks of gestationConception Birth

20 3010

Course 124-28 wks

Course 230-36 wks

Fetal growth velocity

Intermittent preventive treatment (IPTp) with SP: results of clinical trials

Site, Date, Author

Regimens Anemia Placental parasitemia

Birth weight

Malawi, 1994 Shultz

(1) CQ trt/weekly (2) SP then CQ weekly (3) SP/SP (IPT)

NE Decreased NS

Kenya, 1998 Parise

(1) SP/SP (IPT) (2) Monthly SP (IPT) (3) CM

Decreased Decreased LBW – NS; Mean BW increased

Kenya, 1999 Shulman

(1) SP (dose variable) (IPT)

(2) Placebo

Decreased NS NE

Kenya, 2003 Njagi

(1) SP/SP (IPT) (2) Placebo

Decreased Decreased* NS

Mali, 2005, Kayentao

(1) CQ trt/weekly (2) CQ/CQ (IPT) (3) SP/SP (IPT)

Decreased Decreased LBW decreased, Mean BW increased

NE = not evaluated; NS = not statistically significant (p > 0.05)* Data in thesis; not included in published manuscript)

CQ = chloroquine; SP = sulfadoxine-pyrimethamine; CM = case management; LBW Low birth weight

Intermittent preventive treatment (IPTp) with SP: program effectiveness evaluations

Site Study design Anemia Placental parasitemia

Birth weight

Malawi, Verhoeff 1998

Observational: Delivering women: comparing 2 or 3 doses of SP vs. 1 dose

Mean Hb increased (multigrav.

only)

NS LBW decreased, Mean BW increased

Malawi, Rogerson, 2000

Observational: Delivering women; number of doses of IPTp/SP vs. outcome measures

Mean Hb increased,

anemia decreased

(2-dose only

Reduced (1 and 2

doses)

LBW decreased, Mean BW increased

Kenya, Van Eijk, 2004

Observational: Delivering women; number of doses of IPTp/SP vs. outcome measures

NA Reduced LBW decreased, Mean BW increased

Burkina Faso, Sirima 2006

Program evaluation: ANC/DU; number of doses of IPTp/SP vs. outcome measures

NS Reduced (2 and 3

doses)

LBW decreased (3

doses)

NS = not statistically significant (p > 0.05)

SP = sulfadoxine-pyrimethamine; Hb Hemoglobin; LBW Low birth weight

IPTp with SP: summary of evidence and benefits

2 doses of IPT with SP is associated with: • Reduction in 3rd trimester maternal anemia • Reduction in placental malaria parasitemia• Reduction in low birth weight

At least 2 doses required for optimal benefit Monthly dosing more beneficial in HIV+

women Regimen is safe and well tolerated

Insecticide treated bed nets (ITNs)

ITNs-efficacy in pregnancy: design

Study Trans-

mission

Group vs individual

randomization Trim ester Comments ANC

Mass Effect

Dolan Thailand

Low Seasonal

Individual 2-3 G-ALL Yes Yes

D’Alessandro

Gambia Low Seasonal

Village ALL G1 No Yes

Shulman Kenya

Intermed. Seasonal

Village ALL G1 Both Yes

Brown Ghana

High Seasonal

Village P:2-3 M:ALL

G-ALL No Yes

Marchant Tanzania

High Perennial

Not random ALL G-ALL NO +/-

ter Kuile Kenya

High Perennial

Village ALL G-ALL No Yes

Njagi Kenya

High Perennial

Individual 2-3 G1+2 Yes No

ITNs during pregnancy

Meta analyses of 5 RCTs (4 from Africa, 1 from Thailand)

In Africa, ITNs reduced• placental parasitemia in all pregnancies

(RR=0.79 [0.63-0.98])• LBW (RR=0.77 [0.61-0.98]) and

stillbirths/abortions in G1-4 (RR=0.67 [0.47-0.97])*

In Thailand, ITNs reduced anemia and stillbirth/abortions in all pregnancies

Source: Gamble 2006

Case management of malaria and anemia

Case management of malaria in pregnancy

Safe drugs

Chloroquine Quinine / quinidine Proguanil, chlorproguanil Pyrimethamine Sulfonamides Dapsone (+pyrimethamine=

Maloprim) Mefloquine (prophylaxis) Clindamycin (300 mg qid, 5-

7 days) Artemisinins (2nd and 3rd)

Drugs with questionable safetyor insufficient data Mefloquine (treatment dose) Artemisinins (1st) Amodiaquine Azithromycin Lumefantrine (component of

coartem/Riamet) Combination therapy

• Artemisinin derivative with other drugs

• Lapdap (chlorproguanil-dapsone)• Atovaquone-proguanil (Malarone)• Amodiaquine-SP

Antimalarials contra-indicated in pregnancy

Tetracycline Doxycycline Halofantrine Primaquine Tafenoquine Note: if serious illness, and where limited

number of drugs are available, it is necessary to balance the risk of maternal death with the hypothetical risks to the infant

Antimalarial drug policy

An antimalarial drug policy must balance between:

Access Rational use

Reduces development of resistance

Emphasis on regulation and controlled use (e.g. prescription only drugs)

• Equitable access to reduce mortality and morbidity

• Emphasis on community management (e.g. use of lay persons for distributing drugs)

High transmission areas• Women don’t feel sick- need prevention of

adverse effects• Prevention by IPT and nets

Low transmission areas• IPT will not necessarily keep the woman well• Prevention by nets• Any role for chemoprophylaxis in select areas?

Both areas need prompt appropriate febrile case management

Interventions depend on level of transmission

The Results of Preventing Infection

Reduce the risk of severe maternal anemia: 38%

Reduce the risk of LBW: 43% Reduce the risk of perinatal mortality:

27%

From Research to Policy to Implementation

African summit on Roll Back Malaria (RBM) – Abuja 2000

At least 60 percent of those at risk of malaria, particularly pregnant women and children under 5 years of age, benefit from the most suitable combination of personal and community protective measures such as insecticide-treated mosquito nets …

At least 60 percent of all pregnant women who are at risk of malaria, especially those in their first pregnancies, have access to intermittent preventive treatment.

Malaria during pregnancy: Research to program - a continuous

cycle

Programmatically relevant research

Policy changeProgram implementation

Monitoring & evaluation

Status of IPTp policy and implementation in Africa (2001)

IPTp policy (5)

Very little or no malaria (7)

No known IPT policy

Rapid assessment of burden of malaria during pregnancy

Survey at antenatal care:• peripheral malaria parasitemia and anemia

Survey at delivery units• Peripheral and placental parasitemia, birth

weight, and gestational age

Other modules: severe disease, health facility assessment, rapid ethnographic evaluation

Example: Burkina Faso Joint collaboration of CDC with JHPIEGO and

Burkina Faso Ministry of Health Baseline 2001 rapid assessment examined:

rates of peripheral and placental parasitemia, maternal anemia, and low birth weight • >22% of women had placental parasitemia despite

widespread use of chloroquine chemoprophylaxis Pilot intervention of IPTp with 3 doses of SP

begun in 2003; ITN distribution through NGO programs

Repeat rapid assessment (program evaluation) conducted in 2004

Burkina Faso – 2004 program evaluation

High coverage with IPTp at delivery units (DU) 3 doses: 46.9% 2 doses: 78.6% 1 dose: 93.5 %

High coverage with IPTp at antenatal clinics (ANC) - includes dose given on day of interview

3 doses: 20.9% 2 doses: 57.6% 1 dose: 96.2%

Burkina Faso Delivery Units2001 vs. 2004

2001 2004 Risk ratio P-value

Peripheral parasitemia (delivery)

29.4% 19.4% 0.66 <0.0001

Placental parasitemia

22.6% 15.9% 0.71 0.0002

Low birth weight

14.4% 12.2% 0.85 0.15

Note: Unadjusted

Burkina Faso ANC 2001 vs. 2004

2001 2004 Risk ratio P-value

Peripheral parasitemia (ANC)

32.0% 15.7% 0.49 <0.0001

Any anemia (Hb < 11 g/dL)

79.9% 59.3% 0.74 <0.0001

Moderate-to-severe-anemia

13.0% 3.5% 0.27 <0.0001

Note: Unadjusted; women with 1 prior ANC visit; women in 3rd trimester only

Burkina Faso – Conclusions and recent events

Package of ITNs and IPTp with SP (3 dose strategy) may have resulted in decreased proportion of women with anemia, peripheral parasitemia, and placental parasitemia when comparing pre-program (2001) and post program (2004) assessments

In February 2005, based on data from Koupéla, Burkina MoH adopted IPTp as national policy (2 doses of sulfadoxine-pyrimethamine)

Status of IPTp policy and implementation in Africa (January 2005)

IPTp policy and widespreadIPTp program implementation (5)

IPTp policy and IPTp program implementation in progress (7)

IPTp policy but no implementation yet (3)

IPTp policy but extent of implementation unknown (4)

IPTp implemented on small scale by NGOs but no national policy: Liberia and Somalia

Very little or no malaria (7)

No known IPTp policy (25)

Malaria during pregnancy:gaps in knowledge and future

directions

MiP Consortium

Focused on addressing gaps in knowledge regarding all aspects of MiP

Initial funding for meetings and development of review papers from Bill & Melinda Gates Foundation

Full research agenda to be finalized in 2006 Comprehensive reviews (7) published as

part of an LID supplement

Technical Reviews1. Epidemiology and Burden of disease: M Desai, F ter

Kuile, F Nosten, R McGready, K Asamoa, B Brabin, R Newman

2. Pathophysiology and immunology: S Rogerson R Leke, et al

3. Drug safety and kinetics: S Ward, E Sevene et al4. Case management: F Nosten, R McGready, TK

Mutabingwa5. Prevention: C Menendez, F ter Kuile6. Implementation and Policy: J Crawley, A Palmer, K

Asamoa, R Steketee, et al7. Economics of malaria in pregnancy: E Worrall, A Mills8. Summary concept paper: B Greenwood, R Steketee and

P Alonso

Priorities: Epidemiology and Burden

What is the importance of MiP in low transmission areas including areas where P. vivax is the dominant parasite ? What is the impact of malaria in the first trimester ? Is malaria an important cause of maternal mortality in medium to high transmission areas?

Priorities: Pathogenesis and immunity

How does malaria cause severe anemia in pregnancy ? How does malaria cause low birth weight ? What impact will the introduction of effective control measures have on naturally acquired immunity to malaria ?Can malaria in pregnancy be prevented by:

partially effective pre-erythrocytic vaccines a ‘malaria in pregnancy’ vaccine (anti-cytoadherence)

Priorities: Case Management Can the diagnosis of malaria be improved ? Which drugs can be used to replace CQ and SP for the treatment of malaria in pregnancy and how can the efficacy of new drugs best be measured ? How are the pharmacokinetics of anti-malarial drugs (old and new) influenced by pregnancy ? Are there pharmacokinetic interactions between anti-malarials and ARVs ? Are anti-malarials safe in pregnancy (pharmacovigilance) ?

Priorities: Prevention of MiP

How can current preventive strategies (ITNs, IRS, IPT, repellents) be used together most effectively in different epidemiological situations:

low or high transmission areas with P. vivax infection low or high HIV prevalence

What drug(s) can be used to replace SP for IPT? Do they need to be long acting ? Are existing insecticides and new ones under development safe in pregnancy when used for ITNs or IRS ? Pharmacovigilance

Priorities: Economic aspects of MiP

What is the overall economic burden of malaria in pregnancy ? What are the comparative cost efficacies of different control measures in different circumstances ?

Priorities: Health systems research

How can usage of ITNs and IPT be scaled up most effectively and equitably in different situations ? How can malaria control in pregnancy be integrated into reproductive health and HIV management programmes more effectively ? Will new interventions be accessible, affordable and acceptable?

Overall priorities identified from technical reviews

New drugs for treatment New drugs for prevention Clarity on optimal methods of deploying

combinations of interventions in different epidemiological settings

Improved delivery of existing recommendations to achieve high coverage

Areas for PMI to think about

How to get women to attend all their ANC visits and earlier

Integrating MIP with other ANC services (PMTCT, EPI, Reprod, Nutrition)

Creating demand (quality, wanted services) Expanding commodity procurment to include

iron/folate Monitor efficacy of IPTp with SP resistance

rising

Resources MiP

• Strategic framework for malaria prevention and control during pregnancy in the African Region (WHO/2005)

English, French, Portuguese (soon)

• Rapid Assessment of Malaria during Pregnancy Toolkit (CDC/2005)• Malaria during Pregnancy Resource Package (JHPIEGO/2003)

English, French, Portuguese: all soon to be updated Orders@jhpiego.net

• Malaria in Pregnancy: Guidelines for Measuring Key Monitoring and Evaluation Indicators (WHO/Draft): available from CDC

IPTi• IPTi Consortium website: www.ipti-malaria.org

Questions?