Chapter 5.2 - Malaria issues in special hosts - pregnancy and breastfeeding: Canadian recommendations for the prevention and treatment of malaria

Updated 2019

What's new

  • Updated references and surveillance data where appropriate
  • New evidence that the rate of adverse effects on the fetus due to doxycycline may be similar to the baseline rate. However, at this point, CATMAT does not feel there is enough evidence to change recommendations and doxycycline remains contraindicated during pregnancy.

Contents

Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. The Agency acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Background

Malaria increases the risk of maternal and neonatal death, miscarriage and stillbirth. Malaria parasites adhere to the placental vasculature, leading to impairment of the micro circulation and eventually placental insufficiencyFootnote 1Footnote 2. In addition, low birth-weight infants and premature births are more common in pregnant women with malariaFootnote 3Footnote 4Footnote 5Footnote 6. Malaria caused by P. falciparum is associated with the highest rate of adverse outcomes, although recent case reports highlighted complications with P. vivax and P. knowlesi Footnote 7Footnote 8Footnote 9. The burden of P. vivax malaria in pregnant women is increasingly recognizedFootnote 10. Congenital malaria, although rare, is another possible complicationFootnote 11Footnote 12. Furthermore, pregnant women are twice as likely to be bitten by mosquitoes, probably as a result of increased body surface temperature, increased CO2 production and the greater chance of leaving the protection of the bed net at night due to increased urinary frequencyFootnote 13.

Malaria prevention in pregnancy and during breastfeeding

Surveillance data from the US indicated that malaria in pregnant travellers represented 6% of cases in women, 22% of which were severe and needed hospitalization. In cases where the information was known, most were visiting friends and relatives (VFRs) and had travelled to AfricaFootnote 14.  A review of 631 cases of imported malaria in pregnant women in the US, Europe, and Japan showed similar results. In this review, 46 of the cases had severe malaria and 54 reported complications such as severe anemia, acute respiratory distress syndrome, renal insufficiency etcFootnote 15. A recent study found that the majority of pregnant or breastfeeding women seen in a Swiss clinic planned to travel to a malaria-endemic areaFootnote 16. Another study showed that only 25% of pregnant women travelling to malarious areas had taken chemoprophylaxisFootnote 17.

Pregnant women should defer travel to malaria-endemic areas and particularly to those regions with drug-resistant falciparum malaria. If travel cannot be avoided, special care should be taken. Personal protective measures (PPM) to avoid mosquito bites are the same for pregnant women as for other adults—use topical repellents and insecticide-treated bed netsFootnote 18 (see Chapter 3). In addition, effective chemoprophylaxis (outlined below) should be selected. Chemoprophylaxis has been shown to reduce the risk of severe anemia, placental parasitemia, and low-birth weightFootnote 19Footnote 20Footnote 21.

Efforts should be made to reach women VFRs, especially those visiting sub-Saharan Africa, to better inform them on the risk of complications to themselves and to their babies, in order to improve adherence to antimalarials, see section 5.5. Refer to the CATMAT Statement on Pregnancy and Travel for a more detailed description of malaria in pregnant travellers or those who are breastfeedingFootnote 22.

Methods

This chapter of the CATMAT malaria guidelines was developed by a volunteer from the CATMAT committee. Criteria outlined in the CATMAT statement on Evidence based process for developing travel and tropical medicine related guidelines and recommendationsFootnote 23, were used to determine that a Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodological approach would not be required for this chapter. The volunteer, with support from the secretariat, was responsible for: literature retrieval, synthesis and analysis; development of key questions and draft recommendations; and chapter writing.

A narrative literature review was undertaken to identify any new evidence regarding malaria risks, prevention and treatment in pregnant or breastfeeding travellers. The full search strategy is described in the appendix. The literature review yielded 213 studies related to risk and 113 related to prevention and treatment. After screening titles and abstracts for relevance, 47 full text articles were reviewed. Ultimately 33 articles were retained. Based on the evidence compiled as well as expert opinion, recommendations for interventions were made and are summarized in table 5.2.1 and 5.2.2.

Selecting antimalarials for pregnant travellers from specific regions of drug resistance

Chloroquine sensitive destinations

Chloroquine is safe in pregnancyFootnote 24 and is the drug of choice for pregnant travellers travelling to chloroquine-sensitive malaria-endemic destinations (see Appendix I).

Chloroquine resistant destinations

Atovaquone-proguanil: Proguanil has long been considered safe in pregnancy; however, data are lacking on atovaquone. Small malaria treatment trials using atovaquone-proguanil alone or with artesunate have included women in the second and/or third trimesters of pregnancy. Drug tolerability was good, as were the birth outcomesFootnote 25Footnote 26Footnote 27Footnote 28. Until these data are supported with further trials or experience, atovaquone-proguanil is not routinely recommended during pregnancyFootnote 29. However, when other options cannot be used and the potential benefit outweighs the potential risk to the fetus, it may be considered after the first trimester.

Chloroquine–proguanil: While chloroquine and proguanil are both safe in pregnancy, the combination is ineffective in preventing chloroquine-resistant malaria and is not recommended.

Doxycycline: Doxycycline has long been contraindicated for malaria prophylaxis during pregnancy because of adverse effects on the fetus, including discolouration and dysplasia of the teeth, and inhibition of bone growthFootnote 30. However, it has been suggested that the rate of malformations is similar to the baseline rate, and since tooth development occurs during the last half of pregnancy, that tetracyclines could perhaps be used until the 4th month of pregnancyFootnote 31. At this point, CATMAT does not feel there is enough evidence to change recommendations regarding doxycycline use during pregnancy. Attempting to become pregnant should be avoided for a week after completing doxycycline prophylaxis to allow for complete excretion.

Mefloquine: Mefloquine can be used safely for chemoprophylaxis throughout most of pregnancy according to various guidelines and systematic reviewsFootnote 11Footnote 30Footnote 32Footnote 33Footnote 34Footnote 35Footnote 36Footnote 37Footnote 38. While treatment doses five-fold greater than prophylaxis doses may be associated with an increased risk of stillbirthFootnote 39, the majority of observational and clinical trial data have concluded that mefloquine does not lead to an increased risk of either stillbirth or congenital malformations at prophylactic doses when used during the second and third trimestersFootnote 39Footnote 40Footnote 41. Surveillance data of more than 1,500 pregnant women found no evidence of increased risk of either teratogenicity or spontaneous abortion when mefloquine was used at any time from before conception up to and including the third trimesterFootnote 42. A more recent review analyzed 2,506 reports of women having taken mefloquine mainly for chemoprophylaxis, and concluded that the rate of birth defects and fetal loss were comparable to background rates of the general populationFootnote 43. Although there does not appear to be a concern early in pregnancy, the data for the first trimester are limited, and larger sample size would be needed for safety ascertainmentFootnote 44. While the use of mefloquine at the time of conception or during the first trimester has not been associated with adverse effects on the pregnancy, and is not an indication for therapeutic abortionFootnote 40Footnote 45, highly risk-averse travellers may choose to avoid pregnancy for up to three months after discontinuing mefloquine because of the long half-life of the drug (approximately three weeks). For expatriates or other long-term travellers in malaria-endemic areas, it is safer for both fetus and mother if she uses effective chemoprophylaxis, given the ongoing risk of disease and the increased risk of severe disease and death during pregnancyFootnote 46.

Primaquine: Primaquine is contraindicated during pregnancyFootnote 47 because the glucose-6-phosphate dehydrogenase (G6PD) status of the fetus cannot be established and the drug can be passed across the placentaFootnote 48. Whenever radical cure or terminal prophylaxis for vivax malaria is indicated in a pregnant woman, chloroquine can be given once a week until delivery, at which time primaquine may be given postpartum.

Table 5.2.1: Recommendations for selecting antimalarials for pregnant travellers

Pregnant women should avoid travel to areas with significant transmission of malariaFootnote 46.

The use of PPM, including appropriate topical repellents and insecticide-treated bed nets, are strongly encouraged for all pregnant women who travel to malaria-endemic areasFootnote 18.

Pregnant women travelling to or living in chloroquine-sensitive areas should use chloroquine as chemoprophylaxis.

Where exposure to chloroquine-resistant falciparum malaria is unavoidable, mefloquine is recommended from conception through the first trimester after a careful discussion of the benefits and risks, as well as during the second and third trimestersFootnote 39Footnote 40Footnote 41.

There are no currently approved antimalarials for pregnant women travelling to mefloquine-resistant regions. Atovaquone–proguanil after the first trimester in women who cannot avoid travel to mefloquine-resistant areas (e.g. border areas between Thailand and Cambodia or Burma [Myanmar], see Appendix I) may be considered after careful discussion of the benefits and risksFootnote 25Footnote 26.

Although safe in pregnancy, the combination of chloroquine and proguanil is inadequate as an antimalarial and cannot be recommended for chloroquine-resistant areasFootnote 49.

Abbreviation: PPM, personal protective measures.

Prophylaxis while breastfeeding

The availability of antimalarial medication in breast milk is insufficient to protect breastfeeding infants against malaria; therefore, infants requiring chemoprophylaxis should receive a recommended dose of appropriate antimalarial drug. Breastfeeding is not contraindicated for the use of medications that are safe in infancy (chloroquine, mefloquine and atovaquone-proguanil in infants weighing ≥5 kg).

There is no information on the amount of primaquine that enters human breast milk; therefore, the infant should be tested for G6PD deficiency before primaquine is administered to a breastfeeding woman.

Because of the lack of data on the safety and efficacy of atovaquone in infants weighing less than 5 kg, atovaquone-proguanil should not be given to a woman who is breastfeeding an infant of this size unless the potential benefit to the woman outweighs the potential risk to the infant.

Limited data are available on the safety of doxycycline during breastfeeding, but the American Academy of Pediatrics states that no observable effect has been noted in infants of lactating women using tetracyclines, and absorption by the infant is negligibleFootnote 50.

Table 5.2.2: Recommendations for selecting antimalarials for infants and travellers who are breastfeeding

Infants who are at risk of malaria and who are being breastfed should receive their own appropriate chemoprophylaxisFootnote 29.

Atovaquone–proguanil should be avoided, if possible, in a woman who is breastfeeding a child weighing less than 5 kgFootnote 29.

Limited data suggest that doxycycline absorption through breast milk is negligible and that breastfeeding is not an absolute contraindication to maternal useFootnote 50.

Acknowledgement

This chapter was prepared by: Bui Y and Brophy J and approved by CATMAT.

CATMAT would like to acknowledge the technical and administrative support from the Office of Border and Travel Health at the Public Health Agency of Canada for the development of this statement.

CATMAT Members: McCarthy A (Chair), Acharya A, Boggild A, Brophy J, Bui Y, Crockett M, Greenaway C, Libman M, Teitelbaum P, Vaughan S.

Liaison Members: Angelo K (US Centers for Disease Control Prevention), Audcent T (Canadian Paediatric Society) and Pernica J (Association of Medical Microbiology and Infectious Disease Canada).

Ex officio members: Marion D (Canadian Forces Health Services Centre, Department of National Defence), McDonald P (Bureau of Medical Science, Health Canada), Rossi C (Medical Intelligence, Department of National Defence) and Schofield S (Pest Management Entomology, Department of National Defence).

References

Appendix

Search strategy

Four electronic databases: Ovid MEDLINE, Embase, Global Health, and Scopus were searched using terms related to malaria in pregnant and breastfeeding travellers in combination with the concepts of risk, prevention, and treatment. The time period covered by the search was from 2006 to June 8, 2016. Following removal of duplicates, the search yielded 213 studies related to risk and 113 related to prevention and treatment. The titles and abstracts of all search results were screened for relevance to the topics and 47 articles were retained for full text review. Papers were excluded if there was no relevant data to questions. Ultimately 33 articles were retained.

In addition a reference librarian conducted an advanced google search and review of the CDC Stacks to identify any relevant grey literature related to malaria and pregnancy. There were 30 publications identified through the search. Results were scanned for relevance and 3 publications from the WHO and 1 from the CDC were retained.

What are the risks associated with malaria and breast-feeding/pregnancy?

Database(s): Embase 1974 to 2016 June 08
Search Strategy:

# Searches Results

1

*pregnancy outcome/ or *pregnancy/

159524

2

(pregnan* or gravidity or gestation).ti.

244960

3

1 or 2

297428

4

breast feeding/

40005

5

(breastfeeding or breast feeding or (nursing adj5 women)).ti.

14300

6

4 or 5

42059

7

3 or 6

336539

8

exp *malaria/

53527

9

malaria.ti.

44707

10

8 or 9

60740

11

7 and 10

1811

12

((risk or risks or (side* adj2 (react* or event* or effect*)) or (fatal* or lethal* or safety or mortal* or hazard* or adverse* or (risk adj2 asses*) or (health adj2 (effect? or impact* or implicat* or human?)))) adj5 (pregnan* or breastfeed*)).tw.

53528

13

((risk or risks or (side* adj2 (react* or event* or effect*)) or (fatal* or lethal* or safety or mortal* or hazard* or adverse* or (risk adj2 asses*) or (health adj2 (effect? or impact* or implicat* or human?)))) adj5 malaria).tw.

6071

14

and/11-13

181

15

limit 14 to (yr="2006-2016" and (english or french))

141

Database(s): Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present 
Search Strategy:

# Searches Results

1

*pregnancy/ or *pregnant women/

32523

2

breast feeding/

31735

3

(pregnan* or gravidity or gestation).ti.

204247

4

(breastfeed* or breast feed* or (nursing adj5 women)).ti.

13183

5

or/1-4

245567

6

exp *malaria/

47400

7

malaria.ti.

39534

8

6 or 7

54464

9

5 and 8

1399

10

((risk or risks or (side* adj2 (react* or event* or effect*)) or (fatal* or lethal* or safety or mortal* or hazard* or adverse* or (risk adj2 asses*) or (health adj2 (effect? or impact* or implicat* or human?)))) adj5 (pregnan* or breastfeed* or breast feed*)).tw.

41262

11

((risk or risks or (side* adj2 (react* or event* or effect*)) or (fatal* or lethal* or safety or mortal* or hazard* or adverse* or (risk adj2 asses*) or (health adj2 (effect? or impact* or implicat* or human?)))) adj5 malaria).tw.

4891

12

and/9-11

142

13

limit 12 to ((english or french) and yr="2006-2016")

105

Database(s): Global Health 1973 to 2016 Week 21 
Search Strategy:

# Searches Results

1

(pregnan* or gravidity or gestation).ti.

27316

2

(breastfeeding or breast feeding or (nursing adj5 women)).ti.

6347

3

malaria.ti.

32962

4

((risk or risks or (side* adj2 (react* or event* or effect*)) or (fatal* or lethal* or safety or mortal* or hazard* or adverse* or (risk adj2 asses*) or (health adj2 (effect? or impact* or implicat* or human?)))) adj5 (pregnan* or breastfeed*)).tw.

15780

5

((risk or risks or (side* adj2 (react* or event* or effect*)) or (fatal* or lethal* or safety or mortal* or hazard* or adverse* or (risk adj2 asses*) or (health adj2 (effect? or impact* or implicat* or human?)))) adj5 malaria).tw.

5406

6

1 or 2

33437

7

and/3-6

134

8

limit 7 to ((english or french) and yr="2006-2016")

94

Scopus

TITLE ( pregnan* OR breastfeed* OR "breast feed*" ) AND TITLE ( malaria ) AND TITLE-ABS-KEY ( ( risk OR risks OR exposure OR "side effect" OR hazard OR fatal OR mortal* OR lethal* OR safety ) W/5 ( pregnan* OR breastfeed OR breastfeeding ) ) AND TITLE-ABS-KEY ( ( risk OR risks OR exposure OR "side effect" OR hazard OR fatal OR mortal* OR lethal* OR safety ) W/5 ( malaria ) ) AND PUBYEAR > 2005 AND ( LIMIT-TO ( LANGUAGE , "English" ) ) 131 Results

What preventative measures and prophylaxis should be used?

Database(s): Embase 1974 to 2016 June 08 
Search Strategy:

# Searches Results

1

*pregnancy/ or *pregnancy outcome/

159524

2

(pregnan* or gravidity or gestation).ti.

244960

3

breast feeding/ or lactation/

78658

4

(breastfeeding or breast feeding or lactat* or (nursing adj5 women)).ti.

51042

5

or/1-4

389739

6

plasmodium ovale malaria/ or malaria falciparum/ or malaria/ or Plasmodium knowlesi malaria/ or Plasmodium vivax malaria/

76226

7

malaria.ti.

44707

8

6 or 7

81765

9

5 and 8

2520

10

prophylaxis/ or prevention/ or "prevention and control"/ or malaria control/ or drug therapy/

676974

11

(prophylaxis or prevent* or treat* or medic*).ti.

2325810

12

(prophylaxis or prevent* or treat* or medic*).ab. /freq=2

3637408

13

or/10-12

5346043

14

(travel* or tour* or "vfr").tw. or travel/ or tourism/

89733

15

and/9,13-14

86

16

limit 15 to (yr="2006-2016" and (english or french))

36

Database(s): Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present 
Search Strategy:

# Searches Results

1

*malaria/ or *malaria, cerebral/ or *malaria, falciparum/ or *malaria, vivax/

46920

2

malaria.ti.

39512

3

1 or 2

54184

4

(prophylaxis or prevent* or treat* or medic*).ti.

1869608

5

(prophylaxis or prevent* or treat* or medic*).ab. /freq=2

2621627

6

4 or 5

3779820

7

Pregnancy/ or pregnant women/ or pregnancy complications/

779859

8

(pregnan* or gravidity or gestation).ti.

204144

9

Breast Feeding/ or lactation/

63611

10

(breastfeeding or breast feeding or lactat* or (nursing adj5 women)).ti.

46533

11

or/7-10

853646

12

and/3,6,11

1172

13

(travel* or tour* or "vfr").tw. or travel/

74216

14

12 and 13

123

15

limit 14 to (yr="2006-2016" and (english or french))

44

Database(s): Global Health 1973 to 2016 Week 21 
Search Strategy:

# Searches Results

1

exp pregnancy/

62201

2

(pregnan* or gravidity or gestation).ti.

27316

3

exp breast feeding/

15509

4

(breastfeeding or breast feeding or (nursing adj5 women)).ti.

6347

5

or/1-4

77917

6

malaria/ or cerebral malaria/

45461

7

malaria.ti.

32962

8

6 or 7

52655

9

prophylaxis/ or chemoprophylaxis/ or prevention/ or disease prevention/ or drug therapy/ or treatment/

240334

10

(prophylaxis or prevent* or treat* or medic).ti.

150647

11

(prophylaxis or prevent* or treat* or medic).ab. /freq=2

347442

12

or/9-11

520711

13

(travel* or tour* or "vfr").tw. or travel/ or tourism/

21823

14

and/5,8,12-13

84

15

limit 14 to (yr="2006-2016" and (english or french))

41

Scopus

TITLE ( pregnan* OR breastfeed* OR "breast feed*" ) AND TITLE-ABS-KEY ( malaria ) AND TITLE-ABS-KEY ( prophylaxis OR prevent* OR treat* OR medic* ) AND TITLE-ABS-KEY ( travel* OR tour* OR "vfr" ) AND PUBYEAR > 2005 AND ( LIMIT-TO ( LANGUAGE , "English" ) OR LIMIT-TO ( LANGUAGE , "French" ) ) 33 Results

Grey Literature

CDC Stacks

Search Results for (( Title contains "pregnancy") OR Title contains "pregnant") AND Title contains "malaria" 21

Results

Search Results for (( Title contains "breastfeed") OR Title contains "breast feeding") AND Title contains "malaria" 0

Results

Google

intitle:malaria AND (intitle:pregnancy OR intitle: pregnant) filetype:pdf site:cdc.gov 6 Results (limited to 2006-2016)
intitle:malaria AND (intitle:pregnancy OR intitle: pregnant) filetype:pdf site:.int 11 Results (limited to 2006-2016)
intitle:malaria AND (intitle:breastfeed OR intitle:breastfeeding) filetype:pdf site:cdc.gov 0 Results
intitle:malaria AND (intitle:breastfeed OR intitle:breastfeeding) filetype:pdf site:.int 0 Results

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