STATEMENT ON PREGNANCY AND TRAVEL

Members: Dr. P.J. Plourde (Chair); Dr. S. Houston; Dr. S. Kuhn; Dr. A. McCarthy; Dr. K.L. McClean; Dr. C. Beallor; Ms. A. Henteleff

Ex-Officio Members: Dr. M. Tepper; Dr. J. Given; Dr. R. Weinman; Dr. F. Hindieh; Dr. J.P. Legault; Dr. P. McDonald; Dr. N. Marano; Dr. P. Arguin; Dr. P. Charlebois; Dr. A. Duggan

Liaison Representatives: Dr. C. Greenaway; Mrs. A. Hanrahan; Dr. C. Hui; Dr. P. Teitelbaum; Dr. A. Pozgay

Member Emeritus: Dr. C.W.L. Jeanes.

Consultant: Dr. S. Schofield.

Note:

This correction note was published in the CCDR Volume 40-8 on April 17, 2014

The “Statement on Pregnancy and Travel” by the Committee to Advise on Tropical Medicine and Travel (CATMAT)^† published in March 2010, contained incorrect information. It suggested in the text that Diclectin - a doxylamine-pyridoxine delayed release combination pill - had been studied in over 200,000 pregnant women and, in Table 4, indicated there was good evidence to support its use for motion sickness in pregnant women.

In the text under the sub-heading of Motion Sickness, it should have noted: “Diclectin has not been shown to increase the risk of teratogenicity. Its use for motion sickness is off-label and based on expert opinion.” Likewise in Table 4, the recommendation “Diclectin can be used during pregnancy to prevent and treat motion sickness.” should be given a Category C for strength of evidence (i.e. poor evidence to support a recommendation for or against use) and a Grade III for quality of evidence (i.e. Evidence from opinions or respected authorities on the basis of clinical experience, descriptive studies, or reports of expert committees.)

In a further paragraph in the motion sickness section, a statement regarding the lack of teratogenicity of various H1 antagonists and phenothiazines was incorrectly attributed to the Motherisk Program at the Hospital for Sick Children in Toronto and an incorrect reference was used. The attribution should be removed and the correct reference for this sentence is Mazzotta P, & Magee LA. A risk-benefit assessment of pharmacological and nonpharmacological treatments for nausea and vomiting of Pregnancy. Drugs. 2000;59 (4): 781-800.

Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. PHAC 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.

Introduction

Travelling while pregnant poses many challenges due to the inherent risks and changing physiology in pregnancy; the risk to the fetus in-utero from maternal exposure to medicines and vaccines, and the risks and complications of delivery. At some travel destinations, medical resources to deal with pregnancy-related complications may be significantly different than Canadian standards. Pregnant women may be more susceptible to and/or more severely affected by certain infectious diseases due to changes in immunity and physiology. In addition, pregnancy may increase the risk of acquiring certain infections such as malaria, toxoplasmosis, leprosy and listeriosis (1). Similarly, certain infections such as influenza and varicella may have a more severe clinical course, an increased rate of complications and a higher case fatality rate. Some fungal infections such as coccidiodomycosis and blastomycosis are associated with a higher incidence of disseminated disease in pregnancy especially in the third trimester (2). The other major issue in advising pregnant travellers is that there is very little evidence based on randomized controlled studies and much of the information in the literature is theoretical. The following paper will outline the risks to the pregnant traveller and the current recommendations based upon the existing body of literature.

Safe Time to Travel

According to the American College of Obstetricians and Gynecologists (ACOG), most common obstetric emergencies occur in the first and third trimesters (3). The safest time to travel is between 18 and 24 weeks in the second trimester.

The decision to travel if pregnant is best decided between the pregnant woman and her obstetrical care provider. Many factors come into play including the purpose of travel, destination, perceived risk, underlying medical and/or pregnancy related complications, available medical facilities and insurance.

The following table outlines potential contra-indications to international travel in pregnancy according to the Center for Disease Control and Prevention (CDC) (4).

Table 1. Potential Contraindications to International Travel during Pregnancy.

RISK FACTORS / FACTEURS DE RISQUE		POTENTIALLY HAZARDOUS DESTINATIONS DESTINATIONS POSSIBLEMENT DANGEREUSES
OBSTETRICAL / OBSTÉTRICAUX	MEDICAL / MÉDICAUX
• History of miscarriage      • Incompetent cervix      • History of ectopic pregnancy (ectopic with current pregnancy should be ruled out before travel)      • History of premature labor or premature rupture of membranes      • History of/or existing placental abnormalities      • Threatened abortion or vaginal bleeding during current pregnancy      • Multiple gestation in current pregnancy      • Fetal growth abnormalities      • History of toxemia, hypertension, or diabetes with any pregnancy      • Primigravida at 35 years of age and older, or 15 years of age and younger	• History of thromboembolic disease      • Pulmonary hypertension      • Severe asthma or other chronic lung disease      • Valvular heart disease (if NYHA class III or IV heart failure)      • Cardiomyopathy      • Hypertension      • Diabetes      • Renal insufficiency      • Severe anemia or hemoglobinopathy      • Chronic organ system dysfunction requiring frequent medical interventions	• High altitudes      • Areas endemic for or with ongoing outbreaks of life-threatening food- or insect-borne infections      • Areas where chloroquine-resistant Plasmodium falciparum malaria is endemic      • Areas where live virus vaccines are required and recommended

Immunizations

The decision of whether to vaccinate pregnant women travellers depends on many factors including the destination, the duration of travel, the risk of contracting the disease, the severity of the effect of the disease on the pregnant woman and /or the fetus, the adverse effects of the vaccine on the pregnant woman and/or the fetus and the risk perceptions of the pregnant woman and the health care provider. Most evidence available to support vaccinating pregnant women is based upon historical use with no negative outcomes and outcomes based on inadvertent use. Most major organizations currently providing recommendations, including the CDC, the World Health Organization (WHO), the ACOG, the American Advisory Committee on Immunization Practices (ACIP) and the Canadian National Advisory Committee on Immunization (NACI), are for the most part in agreement with immunization recommendations in pregnant women based upon the same limited body of evidence.

Vaccines can be divided into two groups, live-attenuated vaccines and inactivated viral and bacterial and toxoid vaccines. Live-attenuated vaccines are generally contraindicated in pregnancy because some of the diseases they prevent are known to have serious effects on the fetus such as rubella or varicella (5). Because live vaccines can multiply in the pregnant woman there is a theoretical risk of transfer of vaccine-derived virus to the fetus and subsequent harm; however, post marketing surveillance of the inadvertent use of live vaccines has not demonstrated any serious adverse reaction to the mother or fetus, including teratogenic effects, therefore termination of the pregnancy is not recommended (5). Maternal viremia post vaccination is felt to wane after one month and therefore it is usually advised to delay conception for at least one month after the administration of any live vaccine (5).

Killed, inactivated and toxoid vaccines generally do not pose any significant risk in pregnancy (5). Many vaccines have not been studied in pregnancy and that is the reason why the recommendations are usually to administer the vaccine if the risk of contracting the disease outweighs the potential adverse effects of the vaccine.

Most data also support an adequate immune response in pregnancy despite the somewhat immune suppressed state of pregnancy (5). In general, vaccination for travel-related illnesses is better if it occurs pre-conception; however this is rarely practical in clinical practice.

Toxoid vaccines

Tetanus and Diphtheria Toxoids Adsorbed (Td)

Based on extensive use in pregnant women there is no evidence that either tetanus or diptheria toxoid are teratogenic (6,7). It is prudent to update tetanus immunization in pregnancy if it is a risk especially as maternal immunity is passed to the baby and can help protect against neonatal tetanus.

Inactivated, killed, and recombinant DNA virus vaccines

In general there is no evidence to suggest a risk to the pregnant woman or to the fetus with maternal vaccination with these vaccines.

Inactivated poliovirus vaccine (IPV)

Problems in humans have not been documented and are unlikely (6). Despite one study in the 1970’s which reported an association between IPV in pregnancy and malignant neoplasm of neural origin in offspring (8), this finding was never confirmed in other studies and the vaccine is felt to be safe when protection from poliomyelitis is required (5). The vaccine is indicated if the risk of contracting the disease outweighs the potential risk of adverse effects of the vaccine.

Hepatitis A Vaccine (Havrix, Vaqta, Avaxim)

Hepatitis A vaccine is not contraindicated in pregnancy and is recommended for those at risk. Hepatitis A infection is generally felt to be no more severe during pregnancy than at other times; however, there are reports of acute fulminant disease during the third trimester as well as an increased risk of premature labour and fetal death (9). One recent study showed acute hepatitis A infection during pregnancy is associated with high risk of maternal complications including premature contractions, placental separation, premature rupture of membranes and pre-term labour (10). There is also possible transmission to the neonate at delivery if the pregnant woman is incubating the virus or is acutely ill at the time of delivery (11).

Hepatitis B Vaccine (Engerix, Recombivax)

Hepatitis B vaccine is not contraindicated in pregnancy and is recommended for those at risk. Hepatitis B infection may increase in severity in the third trimester of pregnancy. It is also possibly associated with an increase in spontaneous abortion rate and pre-term birth. Due to vertical trans-mission, neonatal hepatitis B may occur with high risk of carriage in the newborn (11).

Influenza vaccine (Fluviral, Fluzone)

According to NACI, current evidence indicates that influenza vaccine is safe for pregnant women at all stages of pregnancy and for breastfeeding mothers (12). All pregnant women who wish to avoid morbidity associated with influenza should be encouraged to be vaccinated (13).

Pregnant women are at increased risk for influenza-related complications and morbidity, especially during the third trimester of pregnancy (14,15). Evidence suggests that during past pandemics pregnant women are disproportionately affected compared to non-pregnant women (15). The ACIP estimates that one to two hospitalizations among pregnant women, related to influenza can be averted for each 1000 pregnant women vaccinated (16). Vaccination should especially be considered in those who have chronic conditions that put them at high risk of complications from influenza, as well as those who are close contacts of high risk individuals. Regarding the safety of the vaccine, a study of 252 pregnant women vaccinated at a mean gestational age of 26 weeks had no adverse events and no adverse perinatal outcomes compared with the non-vaccinated group (17). As well, data from the CDC from immunizing 2000 pregnant women with inactivated influenza vaccine did not show an association with adverse fetal effects.

Rabies Vaccine (Imovax [human diploid cell vaccine], Rabavert [purified chick embryo cell], Verorab [purified Vero cell vaccine])

There have been some studies of pregnant women who have received rabies vaccine (human diploid cell vaccine, purified chick embryo cell and purified Vero cell vaccine) with no data supporting vaccine-related maternal or fetal complications (18,19). A study of the outcomes of post-exposure treatment administered to 202 pregnant women in Thailand concluded that tissue culture derived rabies vaccines as well as rabies immune globulin are safe to use for post-exposure prophylaxis during pregnancy (20). Such post-exposure treatment should never be withheld or delayed if the patient possibly was exposed to rabies. Problems with the vaccine in humans have not been documented and are unlikely (6). The vaccine is indicated if the risk of contracting the disease outweighs the potential risk of adverse effects of the vaccine.

Pneumococcal Vaccine (Pneumovax 23, Pneumo 23)

Pneumococcal vaccine has been administered to pregnant women in reported studies to determine if the immunologic response to infants from maternal vaccine is effective in preventing disease in young infants. These studies have shown some protection to infants but also safety of the vaccine in pregnancy (21-23). Problems with the vaccine in humans have not been documented and are unlikely (6). The vaccine is indicated if the risk of contracting the disease outweighs the potential risk of adverse effects of the vaccine. Indications for immunization should mirror those for the non-pregnant traveller.

Meningococcal Quadrivalent Conjugate Vaccine (Menactra)

Mouse reproduction studies using a dose 900 times that of a human dose, adjusted for weight, showed no adverse effects on fertility, maternal health, fetal development, or post natal development (6). There are no adequate controlled studies in pregnant women though the manufacturer does maintain a registry for those pregnant women who are vaccinated. The vaccine should be used if there is a clear indication for risk of disease. Pregnant women who are sanofi pasteur Pregnancy Registry, an organized systematic collection of data on pregnant women vaccinated with Menactra, by calling 1-888-621-1146.

Meningococcal Quadrivalent Polysaccharide Vaccine (Menommune)

The manufacturer recommends that this vaccine should not be used in pregnancy especially in the first trimester (24), however, a study in 1998 looked at 34 women who received the vaccine during pregnancy and found no increase in the observed unusual birth events compared with expected rates (25). One child was born with a congenital malformation which was not felt to be attributed to a teratogenic effect. In a 1996 study, 75 pregnant women in third trimester received the vaccine and there were no adverse effects to the newborns observed (22). Problems with the vaccine in humans have not been documented and are unlikely (6). The polysaccharide vaccine is to be administered as per general guidelines for non-pregnant women (12).

Typhoid fever vaccine (Typhim VI, Typherix)

Problems with injectable typhoid vaccines in pregnant women have not been documented and are unlikely (6). The vaccine is indicated if the risk of contracting the disease outweighs the potential risk of adverse effects of the vaccine. An oral live-attenuated vaccine for typhoid is also available (see below).

Tick-borne encephalitis vaccine (FSME-IMMUN Vaccine)

According to the Compendium of Pharmaceuticals and Specialties and the compendium of scientific literature put out by the manufacturer, the safety of the vaccine in pregnancy and lactation has not been established and therefore should be used with caution in these situations (26). No data regarding use in pregnancy could be found in the existing literature.

Japanese encephalitis vaccine (JE-Vax, Ixiaro)

Japanese encephalitis infection acquired during the first or second trimesters of pregnancy may cause intrauterine infection and fetal death. Infections during the third trimester are not associated with any adverse outcomes to the fetus (6). Problems with the JE-Vax vaccine in pregnant women have not been documented and are unlikely. The vaccine is indicated if the risk of contracting the disease outweighs the potential risk of adverse effects of the vaccine. JE-Vax is no longer being produced and limited supplies are available. Ixiaro was approved for use in Canada in 2009 and the risk of using Ixiaro in pregnant women is unknown.

Oral cholera vaccine (Dukoral)

This vaccine is not recommended during pregnancy according to the product monograph and no specific studies have been conducted to investigate its use during pregnancy. However, the vaccine is an inactivated, non-replicating vaccine given orally and it is not taken up by the blood stream. It is therefore likely to be safe (24), and should be used if the risk is tangible.

Live-attenuated Vaccines

Measles, Mumps and Rubella vaccine (M-M-R-II, Priorix)

Measles

There is some evidence to suggest that measles is more common and more severe in pregnant women (27). A study involving an outbreak of measles (>1700 cases) in Houston, Texas from 1988-1989 showed a high rate of serious complications among infected pregnant women (28). There are no adequate studies of measles vaccine in pregnant women. Because of the risk to the fetus during natural measles infection of pregnant women it is contraindicated to give the vaccine during pregnancy; however, this contraindication is not evidence-based. Presently, women who are vaccinated are advised to avoid pregnancy for one month after immunization.

Mumps

Mumps virus can infect the placenta and fetus though there is no good evidence showing it causes congenital malformations. The virus has not been isolated from fetal tissues of pregnant women vaccinated with mumps vaccine who chose to have abortions (6). The vaccine is presently contraindicated in pregnancy and women who are vaccinated are advised to avoid pregnancy for one month after immunization; however, this contraindication is not evidence-based.

Rubella

Rubella infection during pregnancy can significantly affect the fetus and result in congenital rubella syndrome. There is evidence to suggest transmission of the vaccine virus to the fetus but it is not shown to cause any fetal harm when given to pregnant women. Inadvertent vaccinations of 226 pregnant women, which were reported to the CDC between 1971 and 1989, demonstrated sub-clinical infection in one to two percent of fetuses but no evidence of congenital rubella syndrome (29). A prospective study followed 94 women who were immunized three months pre-conception demonstrated no increased rate of fetal malformations compared to a control group (30). The vaccine is contraindicated in pregnancy and women who are vaccinated are advised to avoid pregnancy for one month after immunization.

Varicella vaccine (Varivax III, Varilrix)

Natural infection with chicken pox virus can cause fetal varicella syndrome and therefore the vaccine is contraindicated in pregnancy. There is evidence to suggest that primary varicella infections during pregnancy can be more severe and that varicella pneumonia is more common and more frequently fatal in pregnant women (1). There are no good data on the effects of the vaccine on the fetus at this time. Women who are vaccinated are currently advised to avoid pregnancy for one month after immunization, yet a study of 362 pregnant women inadvertently exposed to the vaccine demonstrated no cases of congenital varicella infection (31). There is a Varivax vaccine registry for those women vaccinated within 3 months before pregnancy or anytime during pregnancy (http://www.merckpregnancyregis-tries.com/varivax.html) (6).

Oral Typhoid Vaccine (Ty21a)

The oral vaccine should not be offered to pregnant women as there are no good data regarding its safety in pregnancy and there is a relatively safe inactivated injectable vaccine which is available (see above).

Yellow Fever Vaccine (YF-Vax)

Yellow fever (YF) vaccine is contraindicated in pregnancy on hypothetical grounds as it is a live vaccine, despite emerging evidence of its safe use in pregnancy. A small study involving 39 women inadvertently administered the YF vaccine in Brazil did show some evidence that women vaccinated with YF vaccine during early pregnancy have an increased risk of having spontaneous abortion (32). However, larger studies showed no significant effects on the fetus. A study of 101 Nigerian pregnant women in various stages of pregnancy, inadvertently administered YF vaccine, demonstrated no significant adverse effects on the fetus or an association with risk of fetal infection (33). In this study the percentage of women who seroconverted after vaccination was significantly less than the non-pregnant group (39% vs. 82%) (33). In a more recent study, 441 Brazilian pregnant women who were inadvertently vaccinated were followed through delivery and no adverse effects were demonstrated. Three hundred and forty one babies were seen at three months and 103 babies were recalled at >24 months and again no significant adverse outcomes were demonstrated. As well, in this study the seroconversion rate was 98% (34). As for the risk of fetal infection in utero there was one study done following 41 pregnant women in Trinidad inadvertently immunized during pregnancy. One infant had positive IgM antibodies to YF indicating congenital infection and was born with no complications (35).

Due to the potentially fatal nature of this disease, vaccination of pregnant women should be considered in those whose risk of disease cannot be avoided. In cases where there is a requirement for an International Certificate of Vaccination for YF for entry into a country but no current risk of the disease, a waiver should be provided.

N.B.: A summary table can be found in the Canadian Immunization Guide, 7^th Edition, 2006 (12), Part 3, Recommended Immunization, Table 7. Indication for Use in Pregnancy.

Breastfeeding and Vaccines

Until recently, no vaccine administered to a breastfeeding mother has been shown to have adverse effects on the breastfed infant (5). Killed, inactivated and toxoid vaccines do not multiply in the mother. Most live vaccines that may multiply in the mother are not known to be secreted in breastmilk. There are two known exceptions to this.

1. rubella vaccine virus:

   In one study, seroconversion of breastfed infants to rubella virus post maternal vaccination was 25% with no evidence of clinical disease (36).

2. YF vaccine:

   Recent case of a breastfed child who developed YF following the vaccination of his mother with the YF vaccine – case study to be published in the near future (4).

Air Travel

According to ACOG, in the absence of medical or obstetrical complications, pregnant women can safely fly up to 36 weeks gestation (3). Most Canadian and US airlines allow pregnant women to fly up to 36 weeks whereas the cut off for international airlines is usually 35 weeks. Any woman with a normal pregnancy and no previous history of premature labour may travel up to and including her 36^th week on Air Canada and Air Canada Jazz (37). It is always best to check with the individual airlines as flying restrictions may vary.

Relative contraindications for air travel include risk of pre-term delivery, pregnancy induced hypertension, poorly controlled diabetes, sickle cell trait or disease, or other serious medical conditions. Due to the changes in cabin air pressure with altitude, there is a decrease in partial oxygen pressure, which should not affect normal pregnant women, yet it could affect those with a compromised cardiovascular system (38). Pregnant women who may be affected by a slightly hypoxic environment may require supplemental oxygen. Entrapped gas tends to expand at higher altitudes therefore causing bloating and gas. This can be prevented somewhat by reducing consumption of gas containing carbonated beverages and gas producing foods especially during long-haul flights.

Long air travel is associated with a certain degree of immobility and venous stasis. That in association with the inherent increased risk of venous thrombosis in pregnancy would suggest an increased overall risk of Deep Vein Thrombosis in pregnant women travellers. There are no specific data supporting this, yet theoretically, certain measures should be used to reduce this risk such as support stockings, and lower extremity leg movements. There is no evidence of an increased risk of spontaneous abortion associated with air travel among pregnant women (39).

Personal Protection Measures to Prevent Insect Bites

Personal protection measures are especially important for the pregnant woman traveller as many insect-borne diseases are not vaccine-preventable and can have deleterious effects on the mother as well as the fetus or newborn infant. For example, in the case of dengue fever infection in a pregnant woman, it has been shown that there is a serious risk of premature birth and fetal death and with infection close to term, there is a risk of hemorrhage for both the mother and the newborn (40).

Pregnant women are at risk of insect bites and the diseases they carry as are all travelers, however; there is some evidence to show pregnant women attract more insects than non-pregnant women. In a study by Lindsay et al., pregnant women attracted twice the number of Anopheles gambiae mosquitoes (the predominant African malaria-carrying mosquito) than did their non pregnant counterparts (41).

It is very important for pregnant women to protect themselves against insect bites using personal protective measures including repellents with N, N-Diethyl-M-Tolumide (DEET), insecticide treated nets and lightly-coloured clothing. North American regulatory and public health authorities report that there is no indication that use of DEET by pregnant or breastfeeding women presents a hazard to the unborn or nursing child (42). This conclusion is supported by credible academic reviews of safety information (43). One double-blind randomized trial in Thailand looked at the use of DEET in second and third trimesters. Eight hundred and ninety seven pregnant women were followed and there were no adverse neurologic, gastrointestinal, or dermatologic effects observed with application of a median total dose of 214.2g DEET per pregnancy (44). DEET crossed the placenta and was detected in 8% of cord blood samples (n=50). No adverse effects were demonstrated on survival, growth or development at birth, or at one year.

Bed nets treated with pyrethroid insecticides including permethrin have been shown to provide significant protection against malaria (45,46). Numerous studies have looked specifically at the use of these nets among pregnant women and they appear to be safe and effective (47,48). Pyrethroid-treated clothing is also thought to be helpful in preventing mosquito bites (49). While data specific to pregnant women are lacking, results from animal studies suggest that pyrethroid-treated materials do not present a specific pregnancy-associated risk (50-52). Hence, as with the more general population, use of treated bed nets and clothing by pregnant women is considered to have a good safety profile.

For further information on use of personal protective measures, see the CATMAT Statement on Personal Protective Measures to Prevent Arthropod Bites (49).

Malaria

Malaria increases the risk of maternal and neonatal death, miscarriage, and stillbirth, and low birth weight is more frequent among women who are taking ineffective prophylaxis (53). Pregnant women should defer travel to malaria-endemic areas, particularly to areas with risk of acquisition of drug-resistant P. falciparum malaria. If travel cannot be avoided, special care should be taken to avoid mosquito bites and chemoprophylaxis should be used.

For a detailed review of malaria prevention and treatment including all drugs and their side effects readers are referred to the CATMAT statement on the Canadian Recommendations for the Prevention and Treatment of Malaria among International Travellers (54).

The following is a summary of drugs used for prevention of malaria in pregnant women travellers.

For travel to chloroquine-sensitive areas, pregnant women should take chloroquine (CQ) as chemoprophylaxis. Many studies have confirmed med the safety of chloroquine in pregnancy (55-57). One study in 1985 looked at 169 infants exposed to CQ in-utero and concluded that it is not a major teratogen, but that a small increase in birth defects could not be excluded (58). CQ has been used for decades in the prevention and treatment of malaria in pregnancy and is felt to be safe in pregnancy by leading world authorities including the CDC and the WHO (4,59). CQ is also considered to be safe during breast-feeding (60).

For travel to CQ resistant areas the drugs of choice are limited. Mefloquine (MQ) is most often the drug of choice for second and third trimesters provided there are no contraindications and also for travel in first trimester if travel to an area of risk cannot be avoided. (The reader is referred to the CATMAT statement on Malaria prevention for more details on contraindications) (54,56).

According to current data, MQ is safe for chemoprophylaxis after the first trimester, with no evidence of increased teratogenic effects. There are several clinical trials describing the use of MQ during the second and third trimesters of pregnancy. Results of an early study, which examined the pharmacokinetics and birth outcomes in 20 pregnant women in their third trimester, demonstrated no labour complications, normal delivery and normal growth and development in the children for two years following delivery (61). In another large clinical trial examining anti-malarial chemoprophylaxis during the second and third trimesters of pregnancy, similar abortion and stillbirth rates were reported among MQ and CQ users (62). In this same study no adverse fetal or birth outcomes were seen among 14 women inadvertently given MQ during the first trimester.

One double-blind placebo-controlled clinical trial examined the use of MQ prophylaxis during the second and third trimesters of pregnancy. MQ was well-tolerated and provided ≥86% protection against P. falciparum and complete protection against P. vivax (63). No adverse birth outcomes were detected in this study (63). Initially, a statistically significant increase in stillbirth rate among pregnant women on MQ was seen; however, the stillbirths were attributed to a wide variety of apparently unlinked causes. In phase two of the study, more stillbirths were seen among the placebo group. Data pooled from phase one and phase two resulted in no significant difference between stillbirths in the MQ and placebo groups. Infants were followed prospectively for at least two years and no differences in mortality, growth, or developmental milestones were observed.

A substantial body of supportive data exist describing pregnancy outcomes in women either inadvertently consuming MQ during early pregnancy or treated with MQ during pregnancy. Data from the Roche International Spontaneous Reporting System, containing 1,627 spontaneous reports of women exposed to MQ before or during pregnancy (1986-1995), has been examined for spontaneous abortion and congenital malformations (64).

The rates of both spontaneous abortions and congenital malformations were consistent with rates in the general population (64).

Birth outcomes for women inadvertently exposed to MQ during the first trimester of pregnancy were examined among participants in a travel survey and among cases reported to the pharmaceutical monitoring system between 1986 and 1993 (65). In both groups, the rates of spontaneous abortions and anomalies were consistent with previously published background rates. In a case series of 10 pregnancies resulting in 11 babies delivered to women who had taken MQ 250mg weekly in or just before the first trimester of pregnancy, no malformations or perinatal pathological symptoms occurred (66).

One study involving 72 women did show an unexpectedly high rate of spontaneous abortions (67). However, this study involved self-reporting events which were then entered into a registry established to follow pregnancy outcomes for female US soldiers in Somalia after inadvertent exposure to MQ prophylaxis in the first trimester. It is unclear as to the validity of the self-reporting.

Only one published case report describing a congenital malformation was found which involved a case of achalasia-microcephaly syndrome in a baby after mother ingested MQ 250mg weekly for the first 8 weeks of her pregnancy (68).

In Canada, MQ is not routinely recommended for the treatment of malaria; however, there are some additional data on MQ treatment during pregnancy lending some evidence to its over-all safety in pregnancy. In a large retrospective study including chart reviews and interviews, women who received MQ treatment during but not before pregnancy had a significantly greater risk of stillbirth than did women treated with quinine alone, women exposed to other treatments and women who had no malaria (69). In this study, MQ was not associated with abortion, low birth weight, neurological retardation, or congenital malformations. In another treatment study of 194 women treated with MQ in the second and third trimesters, there were no apparent fetal adverse reactions, although the possibility of rare events could not be excluded, and stillbirth rates were similar among women treated with MQ and women treated with quinine (70).

There are limited data on the safety of breastfeeding and MQ. One study showed MQ is excreted into human milk in low concentrations following a dose equivalent to 250mg (71). The estimated amount an infant would receive was 3.8% of the prophylaxis dose taken by the mother, leading the authors to conclude that the amount of MQ that an infant would receive through breast milk is unlikely to be harmful to the infant. The manufacturer states that because there is the potential for serious adverse reactions in breastfed infants, a decision should be made whether to discontinue the drug based on an assessment of the benefits and risk of MQ for the mother (72). However, MQ is recommended in Canada for chemoprophylaxis in infants traveling to malaria areas (54).

For travel to areas with MQ resistant malaria, there is no safe and effective chemoprophylaxis alternative for pregnant women at this time.

Although not approved for use in pregnant women, there is mounting evidence that atovaquone-proguanil (AP) or Malarone is safe in pregnancy. One study of 27 Karen pregnant women in Thailand, 24 of whom were in their second or third trimester, with multiple recrudescent P. falciparum infections, who were treated with a triple combination of artesunate-atovaquone-proguanil (AAP) found that the treatment was well tolerated and there was no evidence of toxicity for the mothers and the fetus (73). Another similar study in 2005 looked at 39 Karen pregnant women treated in second and third trimesters with AAP and found no significant differences in birth weight, duration of gestation, or congenital abnormality rates in newborns, or in growth and developmental parameters of infants monitored for one year (74). These findings lend to the evidence that treatment courses of AAP are safe for the mother and the fetus. A further study of 26 pregnant women in third trimester (24-34 weeks) in Thailand and Zambia also showed no serious adverse effects or unexpected adverse effects and no stillbirths or spontaneous abortions with AP (75). Another study showed that the treatment with AAP was effective and safe in pregnant women for malaria treatment but that the dose of AP might need to be increased (76).

There is very little evidence for the safe use of AP in first trimester at this time.

Malarone is currently not approved for use in breastfeeding women according to the product monograph (77). No reports describing the use of AP in breastfeeding have been found. However, AP is recommended to prevent and treat malaria in children greater than 5kg (54).

Doxycycline is contraindicated in pregnancy because of the adverse effect on fetal teeth and maternal liver toxicity (78). Tetracyclines are excreted into breast milk in very low concentrations (79). There is a theoretical risk of dental staining and bone growth inhibition occurring in breast fed infants; however, because of the low concentrations of tetracyclines in breast milk, the risk is remote (78). The American Academy of Pediatrics classifies tetracyclines as compatible with breastfeeding (60).

Primaquine is not recommended in pregnancy because of the theoretical risk of hemolysis to the fetus that may be glucose-6 phosphate dehydrogenase (G6PD) deficient (4,80). There are no data on primaquine use in pregnancy for malaria prevention. There are also no data available on the use of primaquine in breastfeeding women. It would seem that if the mother and child were both G6PD sufficient than there should be no reason why it could not be used.

Women who plan to conceive following malaria chemoprophylaxis with CQ and MQ do not need to wait any specific amount of time as there is no significant risk of congenital effects with these drugs (see discussion above). Table 2 provides information on the elimination half-lives of anti-malarial drugs for those wishing to calculate when their drug will be out of their systems. After 2, 4, and 6 half-lives, approximately 25%, 6%, and 2% of the drug remain in the body (4).

Table 2. Elimination Half-lives of Selected Antimalarial Drugs.

DRUG	HALF LIFE
	HOURS	DAYS	WEEKS
Atovaquone	---	2 to 3	---
Chloroquine	---	6 to 60	---
Doxycyclinc	12 to 24	---	---
Mefloquine	---	---	2 to 3
Primaquine	4 to 7	---	---
Proganil	14 to 21	---	---

Diving

Diving is generally thought to be contraindicated in pregnancy because of the unknown risk to fetal development. There is a potential risk of gas bubble formation within fetal tissues upon ascent, travelling to the brain and causing ischemia and hypoxia. A recent review of the literature shows that there are no good data to confirm or refute an increased risk of birth defects from diving (81). Pregnant women divers have been exposed to hyperbaric oxygen therapy for decompression illness (DCI) and there have been no reports of ill effects on the fetus, therefore pregnant women who suffer from DCI should be treated this way just as non-pregnant divers. Based on their research and review of the literature, Fife and Fife recommend pregnant women not dive (81). Those who do so should be advised of the potential risk to the fetus due to air bubble injury and that the risk likely increases with depth of diving. Previous diving prior to the discovery of a pregnancy is not per se an absolute indication for termination as current data fail to show teratogenic risk in humans.

Altitude Exposure

The exposure of a pregnant woman to hypoxia associated with high altitude results in maternal acclimatization responses, which act to preserve the fetal oxygen supply. Similarly the fetus uses compensatory mechanisms to cope with short periods of hypoxia. The limited data on maternal exercise at high altitude suggests good tolerance in most pregnancies (82); however, short-term abnormalities in fetal heart rate and subsequent complications of pregnancy have been reported. A survey of Colorado obstetrical care providers showed that preterm labour and bleeding complications were the most commonly encountered pregnancy complications due to high altitude pregnant women visitors (82).

There are not many good studies of pregnant travellers ascending to altitude especially high altitudes (>3500m). The limited research does seem to suggest short-term exposure to altitudes of up to 2500m is safe in normal pregnancy (83). Risk factors for poorer outcomes at high altitude include underlying maternal or fetal complications, dehydration, and rapid ascent with inadequate acclimatization, strenuous activity, and high trauma risk activities. Women with pregnancy-related complications should avoid unnecessary altitude exposure.

According to the CDC, all pregnant women should avoid altitudes >3,658 meters (>12,000 feet). In addition, altitudes >2,500 meters (>8,200 feet) should be avoided in late or high-risk pregnancy (4).

Acetazolamide is a drug commonly used to help with acclimatization and the symptoms of altitude illness. There has been a case report of a preterm infant developing metabolic acidosis, hypocalcemia and hypomagnesemia whose mother was treated with acetazolamide throughout pregnancy (84). The metabolic acidosis was transient and resolved spontaneously despite breastfeeding and continued administration of acetazolamide to the mother. Hypocalcemia and hypomagnesemia resolved quickly with appropriate treatment with calcium gluconate and magnesium sulphate, respectively. Follow-up of the baby at ages 1, 3 and 8 months showed mild hypertonicity of the lower limbs requiring physiotherapy. In another study, twelve patients were treated with acetazolamide for idiopathic intracranial hypertension during pregnancy and there were no adverse pregnancy outcomes (85). The authors, having reviewed the literature as well concluded that acetazolamide at high doses may produce birth defects in animals, but there is little clinical or experimental evidence to support any adverse effect of the drug on pregnancy outcomes in humans. If the clinical situation warrants the use of acetazolamide then the drug probably can be offered to pregnant women after appropriate informed consent. The American Academy of Pediatrics classifies acetazolamide as compatible with breastfeeding (60).

Motion Sickness

Diclectin®, a doxylamine-pyridoxine delayed release combination pill is the only drug specifically labeled for use in nausea and vomiting of pregnancy in Canada and it may be used for motion sickness as well. It has been studied in over 200 000 pregnant women and has not been shown to increase the risk of teratogenicity (86). It contains 10 mg of vitamin B6 and 10 mg of doxylamine succinate and has been used for over 40 years in pregnancy. It does not increase the risk of birth defects above the baseline risk of one to three percent that is present in any pregnancy (87).

According to the Motherisk Program, a clinical, research and teaching program at the Hospital for Sick Children in Toronto, Ontario, H1 antagonists including dimenhydrinate (Gravol), hydroxyzine (Atarax), meclizine (Bonamine) as well as phenothiazines including chlorpromazine (Largactil), prochlorperazine (Stemetil), and promethazine (Phenergan) have not demonstrated teratogenicity although many fewer pregnant patients have been studied with these drugs (88). An association has been reported between exposure during the last 2 weeks of pregnancy to antihistamines including H1 antagonists and retrolental fibroplasia in premature infants (89).

Transderm-V® or scopolamine patch 1.5mg is indicated for the prevention of nausea and vomiting associated with motion sickness in adults. The patch should be applied only to skin in the post auricular area. Scopolamine does cross the placenta readily (90). When administered at term fetal effects have been seen including tachycardia, decreased heart rate variability and heart rate decelerations (91). During a clinical study among women undergoing cesarean section treated with Transderm V® in conjunction with epidural anesthesia and opiate analgesia, no evidence of CNS depression was found in the newborns. There are no other adequate and well-controlled studies in pregnant women. Other than in the adjunctive use for delivery by cesarean section, Transderm V® should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus (92).

Seabands® or wrist bands with a pressure point to be placed on the P6 point (about 3 fingers from the beginning of the wrist) may be helpful for motion sickness and they are safe in pregnancy (93).

Food and Water Protection

It is highly necessary for pregnant women travellers to take precautions against food and water contamination. Pregnant women may be more susceptible to some food and water-borne diseases and many diseases are more severe in pregnancy and can have significant negative outcomes to the mother and fetus. Examples include toxoplasmosis, listeriosis and hepatitis E (1). Toxoplasma gondii is a parasite that infects humans primarily through ingestion of infected raw or undercooked meat and, less frequently, by exposure to infected cat feces and it can be transmitted transplacentally to the fetus. Listeria monocytogenes is a food-borne pathogen whose infections are more common during pregnancy. One quarter to one third of all cases of listeriosis occur in pregnant women and can lead to miscarriage or stillbirth, premature delivery, or severe infection of the newborn.

Hepatitis E virus (HEV) is a major cause of outbreaks and sporadic cases of viral hepatitis in tropical and subtropical countries but is infrequent in industrialized countries. The virus is transmitted by the fecal-oral route with fecally contaminated drinking water being the usual vehicle. Hepatitis resulting from HEV infection is a moderately severe jaundice that is self-limiting in most patients. Young adults, 15 to 30 years of age, are the main targets of infection, and the overall death rate is 0.5 to 3.0%. However, the death rate during pregnancy approaches 15 to 33%. Death of the mother and fetus, abortion, premature delivery, or death of a live-born baby soon after birth are common complications of hepatitis E infection during pregnancy (94).

Recommendations for food and water precautions remain much the same as those for the general population and the reader is referred to the CATMAT statement on travellers’ diarrhea for more detailed guidelines (95). One significant point is to avoid prolonged iodine usage for water purification because of the potential negative effect on the fetal thyroid gland. Iodine readily crosses the placenta to the fetus and when used for prolonged periods, it may cause hypothyroidism and goiter in the fetus and newborn (78). Short term use of iodine for approximately ten days is considered to be safe (96). There are not much data available on the effects of the maternal use of iodine on the breastfed infant. The American Academy of Pediatrics states it is compatible with breastfeeding but does not give a duration (60); however, as other purification systems using chlorine-based products, boiled water and bottled water are available with no apparent risk to the infant, it seems prudent to recommend these instead.

Traveller’s Diarrhea

The general guidelines for the non-medical prevention and management of travellers’ diarrhea (TD) are similar for pregnant women travellers as for the general population. Readers are advised to refer to the CATMAT Statement on TD for more detailed guidelines (95).

Specific issues pertaining to pregnancy and diarrhea include the safety of medications for the prevention and treatment of diarrhea as well as the need to prevent and treat dehydration, which can affect the mother and fetus.

Oral rehydration should be the foundation of treatment for TD. Bismuth subsalicylate compounds such as Pepto Bismol® are contraindicated because of the theoretical risks of fetal bleeding from salicylates and teratogenicity from the bismuth (4). According to Briggs, Freeman and Yaffe, inorganic bismuth salts present little or no risk to the fetus from normal therapeutic doses, whereas adverse fetal effects may be associated with chronic salicylate exposure (78). For these reasons, it is recommended that, if it must be used, bismuth subsalicylate should be restricted to the first half of pregnancy and only in the recommended dose (78). Kaopectate® or other combinations of kaolin and pectin may be used (78), but are generally not so effective. Loperamide or Imodium® may be used by pregnant women, but should be used only when necessary (4,78).

Fluoroquinolones have been generally contraindicated in pregnancy due to arthropathy in dog studies; however, human studies have shown no clear adverse reactions including fetal and neonatal toxicity and birth defects due to in utero exposure to fluoroquinolones (97,98). The authors of one study prudently conclude that given the limitations of the study and the fact that diseases urgently requiring fluoroquinolone treatment are rare, it appears advisable to choose from cephalosporins and erythromycin based drugs as antibiotics of choice (98).

As azithromycin has been shown to be safe in pregnancy (99-104) and has broad-spectrum activity against the organisms causing severe TD it is a good first choice when antibiotics are required. A third generation cephalosporin like cefixime may be the next best option although it is not effective against campylobacter and may not be effective against shigellosis (105).

Miscellaneous

Pregnant women travellers must ensure that they have proper travel health insurance. Many insurance policies do not cover pregnancy-related complications and it is up to the traveller to inform the insurer of the pregnancy and inquire if any additional coverage is required. Similarly, some insurance policies specify that treatment may be provided in the country where the illness occurs. One might prefer to obtain insurance giving the option of evacuating to a place with better quality of care.

If the baby will be born when travelling either intentionally or unintentionally then it is prudent to look into available obstetrical and post-natal care in the destination country in advance.

RECOMMENDATIONS

Table 3 presents evidence-based medicine categories for the strength and quality of the evidence for the recommendations that follow in Table 4.

Table 3. Strength and quality of evidence summary sheet*.

Categories for the strength of each recommendation
CATEGORY	DEFINITION
A	Good evidence to support a recommendation for use.
B	Moderate evidence to support a recommendation for use
C	Poor evidence to support a recommendation for or against use
D	Moderate evidence to support a recommendation against use.
E	Good evidence to support a recommendation against use.
Categories for the quality of evidence on which recommendations are made
GRADE	DEFINITION
I	Evidence from at least one properly randomized, controlled trial.
II	Evidence from at least one well designed clinical trial without randomization, from cohort or case-controlled analytic studies, preferably from more than one centre, from multiple time series, or from dramatic results in uncontrolled experiments.
III	Evidence from opinions or respected authorities on the basis of clinical experience, descriptive studies, or reports of expert committees.
* From: Macpherson DW. Evidence-based medicine. CCDR 1994;20:145-47

Table 4. Recommendations for travel and pregnancy.

Recommandation	EBM   Rating
Vaccinations:
Inactivated Viral and Bacterial Vaccines, Toxoids:
All of the following vaccines are indicated if the risk of the disease clearly outweighs the potential risk of the vaccine: Tetanus & Diphtheria Toxoids Adsorbed vaccine, with or without Polio vaccine (Td, TdP) Poliovirus vaccine inactivated (IPV) Hepatitis A vaccine (Havrix, Vaqta, Avaxim, Twinrix*) Hepatitis B vaccine (Engerix, Recombivax, Twinrix*) Rabies vaccine (Imovax [human diploid cell vaccine], Rabavert [purified chick embryo cell], Verorab [purified Vero cell vaccine]) Pneumococcal vaccine (Pneumovax 23, Pneumo 23) Meningococcal Quadrivalent Polysaccharide vaccine (Menommune) Meningococcal Quadrivalent Conjugate vaccine (Menactra) Typhoid fever vaccine (Typhim Vi, Typherix) Japanese encephalitis vaccine (JE-Vax) Oral Cholera vaccine (Dukoral)	C III
Influenza vaccine (Fluviral, Fluzone) is recommended for all pregnant women in all trimesters (12,13).	B III
Tick-borne encephalitis vaccine (FSME-IMMUN Vaccine): there is insufficient data to comment on the use of this vaccine in pregnancy (26).	C III
Live-Attenuated Vaccines:
Measles, Mumps and Rubella (M-M-R-II, Priorix) vaccine is contraindicated in all pregnant women.	C II
Varicella (Varivax III, Varilrix) vaccine is contraindicated in all pregnant women (1).	C II
Oral Typhoid vaccine (Ty21a): insufficient data available, inactivated injectable vaccine is therefore preferred.	C III
Yellow Fever vaccine (YF-Vax) is recommended if true exposure is unavoidable. Postponement of travel to area of risk is preferred (32-35).	D III
Air Travel:
In the absence of medical or obstetrical complications pregnant women can safely fly up to 36 weeks gestation (3,37,38).	B II
Measures should be used to reduce the risk of deep vein thrombosis such as support stockings and lower extremity leg movements.	C II
Personal Protection Measures:
Insect repellents with N, N-Diethyl-M-Tolumide (DEET) should be used to reduce exposure to insect born diseases (41-44).	B II
Insecticide treated bed nets for sleeping should be used to reduce exposure to insect born diseases (45-52).	A II
Malaria Prevention:
Pregnant women should defer travel to malaria-endemic areas, particularly to areas with risk of acquisition of drug-resistant P. falciparum malaria. If travel cannot be avoided, special care should be taken to avoid mosquito bites and chemoprophylaxis should be used (53).	A I
Chloroquine is the drug of choice for travel to chloroquine sensitive malaria areas (55-59).	A II
Mefloquine is the drug of choice for travel to chloroquine resistant malaria areas (61-72).	A II
There is insufficient data to support the safe use of atovaquone/proguanil to prevent malaria in pregnancy (73-76).	C III
Doxycycline is contraindicated in pregnancy (78).	D II
Primaquine is not recommended in pregnancy because of the theoretical risk of hemolysis to the fetus that may be G6PD deficient (4).	D III
Diving:
Diving is generally thought to be contraindicated in pregnancy because of the unknown risk to fetal development (81). Previous diving prior to the discovery of a pregnancy is not an absolute cause for termination.	C III
High Altitude Exposure:
Short-term exposure to altitudes of up to 2500m is safe in normal pregnancy (82,83).	C III
Women with pregnancy related complications should avoid unnecessary altitude exposure (4).	C III
Acetazolamide should be used to prevent altitude sickness only if absolutely necessary and exposure cannot be avoided (84,85).	C III
Motion Sickness:
Diclectin can be used during pregnancy to prevent and treat motion sickness (86).	A II
H1 antagonists including dimenhydrinate (Gravol), hydroxyzine (Atarax), meclizine (Bonamine) can be used to prevent and treat motion sickness if necessary (88).	C III
Phenothiazines including chlorpromazine (Largactil), prochlorperazine (Stemetil), and promethazine (Phenergan) can be used to prevent and treat motion sickness if necessary.	C III
Scopolamine patches should be avoided in pregnancy (89-91).	C II
Seabands are safe in pregnancy (93).	C III
Food and Water Protection:
Pregnant women need to be especially cautious with food and water protection due to the increased severity of many food borne illnesses in pregnancy (1).	A II
Prolonged iodine usage (greater than 10 days) for water purification should be avoided because of the potential negative effect on the fetal thyroid gland (95).	D II
Traveller’s Diarrhea:
Bismuth subsalicylate compounds such as Pepto Bismol® are contraindicated because of the theoretical risks of fetal bleeding from salicylates and teratogenicity from the bismuth (4,78).	C III
Kaopectate® or other combinations are of kaolin and pectin may be used, but are generally not so effective (78).	C III
Loperamide or Imodium® may be used when necessary (4,78).	B III
Azithromycin is the drug of first choice to treat traveller’s diarrhea in pregnancy (99-104).	B II
Third generation cephalosporins such as cefixime are second line drugs used for the treatment of traveller’s diarrhea in pregnancy (105).	B II
Fluoroquinolones are generally contraindicated in pregnancy (98).	C II
Miscellaneous:
Pregnant women travelers should insure that they have adequate travel health insurance	C III
Pregnant travelers should look into available obstetrical and post-natal care in the destination country in advance.	C III
Breastfeeding::
Breastfeeding is not a contraindication to any vaccine except yellow fever (4,5).	C II
Yellow Fever vaccine is generally not recommended to breastfeeding women.	C III
Chloroquine for malaria chemoprophylaxis is considered to be safe during breastfeeding (60).	C II
Mefloquine can be used for malaria chemoprophylaxis during breastfeeding if necessary (71,72).	C II
Atovaquone/proguanil can be used for malaria chemoprophylaxis during breastfeeding infants greater than 5kg (54).	C II
Doxycycline can be used for malaria chemoprophylaxis during breastfeeding (60,78,79).	C II
Primaquine can be used as malaria chemoprophylaxis during breastfeeding if the mother and infant have been tested and proven to be G6PD sufficient.	C II
Acetazolamide can be used to prevent altitude sickness during breastfeeding (60).	C II

* Twinrix is a combined vaccine providing protection against Hepatitis A and Hepatitis B