DOI: 10.1111/j.1471-0528.2010.02771.x www.bjog.

org

Review article

Tuberculosis in pregnancy
CN Mnyani, JA McIntyre
Anova Health Institute, Johannesburg, South Africa Correspondence: Dr JA McIntyre, Anova Health Institute, 12 Sherborne Rd., Parktown, Johannesburg 2193, South Africa. Email mcintyre@anovahealth.co.za Accepted 17 September 2010. Published Online 18 November 2010.

Tuberculosis (TB) remains an important infection in women globally. It is responsible for 700 000 deaths annually and is a major contributor to maternal mortality. Mycobacterium tuberculosis/HIV co-infection is common in areas of high HIV prevalence, and may be associated with signicant perinatal and maternal morbidity. Improved diagnosis and treatment of TB in pregnant women are important interventions for both maternal

and child health. Controlling TB in pregnancy in high-prevalence areas requires a range of interventions, including active TB screening in pregnant women, TB preventative therapy for HIV-infected pregnant women, treatment of active TB and linking mothers and children to TB care services.
Keywords AIDS, HIV, pregnancy, tuberculosis.

Please cite this paper as: Mnyani C, McIntyre J. Tuberculosis in pregnancy. BJOG 2011;118:226231.

Introduction
The World Health Organization (WHO) estimates that, globally, there were approximately 13.7 million cases of tuberculosis (TB) in 2008. TB incident cases have risen from 6.6 million in 1990 to 9.4 million in 2008, with 3.6 million of the new infections in 2008 occurring in women.1 TB is a leading cause of death in women, accounting for about 700 000 deaths every year, and it is also one of the leading nonobstetric causes of maternal mortality, with an estimated one-third of deaths due to TB occurring in women of child-bearing age, the majority in resource-limited countries.2 Data from sub-Saharan Africa illustrate the signicance of Mycobacterium tuberculosis infection as a major cause of maternal mortality, especially in the context of HIV coinfection.3,4 Mycobacterium tuberculosis/HIV co-infection is common, as areas of high TB incidence and prevalence are also areas of high HIV incidence and prevalence. In an audit of maternal mortality in Johannesburg, South Africa, 70% of deaths in women who were infected with HIV were HIV-related, rather than from obstetric causes, and mainly from TB and pneumonia.4 Although the greatest burden of TB infection is in resource-limited countries, resource-rich countries have seen a resurgence of TB over the past few years, largely as a result of an increase in immigrant populations in these countries. A retrospective study in London over a 5-year period19972001showed an increase in

the number of pregnant women with TB.5 Another study in 2008 estimated that the national incidence of TB in pregnancy in the UK was 4.2 per 100 000 maternities, or approximately 1 per 24 000 maternities.6 All pregnant women with TB in both of these studies were of ethnic minority origin, and a signicant number had recently immigrated into the UK. Although there has been a reported decline in the incidence of TB in the USA, immigrant populations remain at a greater risk of TB infection compared with individuals born in the USAthe risk is up to 11 times higher.7

Epidemiology
In areas with stable or increasing TB transmission rates, the highest incidence rate is in young adults,8 with more men affected than women. In 2007, 1.65 million cases of smearpositive TB notied were in men, compared with 0.9 million in women.9 However, in resource-limited settings, women of child-bearing ageespecially in the 1524-year age groupare disproportionately affected by TB because of the high HIV prevalence rates in this group.1 They bear the brunt of M. tuberculosis/HIV co-infection in these settings. HIV infection increases the risk of infection with TB: results from a large cohort in South Africa showed that this risk increased soon after HIV seroconversion and was sustained for a few years thereafter.10 The extent of immunosuppression inuences the risk of TB. Antiretroviral

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therapy (ART) decreases the risk of TB, but HIV-infected individuals on ART remain at some risk for TB infection, albeit at a lower risk than individuals who are not on treatment.11 Pregnancy on its own has not been found to be associated with an increased risk of TB, but a general increase in the incidence of TB will lead to an increase in TB infection rates in pregnant women.12

Diagnosis
TB infection in pregnancy may present with diagnostic challenges, mainly because of the often nonspecic nature of the early symptoms of the infection, such as malaise and fatigue, which may be attributed to pregnancy and not raise the suspicion of TB infection.1214 Despite this, the presentation of TB in pregnant women is similar to that in nonpregnant individuals, with pulmonary TB the most common manifestation of the disease.14 The most important step in making the diagnosis in pregnancy is the identication of the risk factors for TB infection and specic enquiry about the symptoms which may be suggestive of infection.1214 Routine screening for TB in pregnancy is not standard practice in many settings, and this is one of the factors thought to delay the diagnosis and also contribute to maternal mortality.4 In studies performed in Soweto, South Africa, TB screening by the use of a limited number of questions during routine antenatal care was found to be feasible, and added very little time to the routine consultation.15,16 Recommendations have been made that routine questioning for TB screening should be implemented in settings of high HIV prevalence, as the rates of TB infection in pregnant women are high in these settings.1618 The usual diagnostic modalitiessputum microscopy for acid-fast bacilli, culture of sputum and other specimens for M. tuberculosis and chest radiographyremain the mainstay of diagnosis. The tuberculin skin test is of value in the diagnosis of latent TB infection, except in areas in which there is a high prevalence and incidence of TB.14,19 Conrmation of M. tuberculosis infection remains a difcult issue, with outdated and inaccurate technology, especially in low-resource settings. Improved diagnostic technology remains a priority area for development.20,21 Interferon-c release assays and the Quanti-FERON-TB Gold In-Tube assay have been used for the diagnosis of latent TB infection. They have increased the specicity and diagnostic accuracy, and are not affected by previous bacillus rin (BCG) vaccination or infection with nonCalmetteGue tuberculous mycobacteria.19 The Quanti-FERON-TB Gold In-Tube assay is safe for use in pregnancy, but has not been validated in pregnancy. HIV infection modies the expression of active TB infection. Smear-negative TB is common in HIV-infected

individuals as they tend to produce fewer bacilli, and microscopy alone should not be used to make the diagnosis.22 Chest radiography and sound clinical judgement are essential aids in making a rapid diagnosis of smear-negative TB; however, chest radiography may also be normal in up to 14% of individuals with culture-conrmed TB.23 Extrapulmonary TB is not uncommon in pregnancy, and clinicians should have a high index of suspicion in individuals with atypical symptoms.5,6,22 Infection control is important in controlling the spread of TB, which is infectious only when it occurs in the lungs or larynx, and is not usually spread by brief contact.24 Staff and family members dealing with infected pregnant women should be provided with information on transmission and the need for screening.

Management of active TB
WHO recommends that the treatment of TB in pregnant women should be the same as that in nonpregnant women; the only exception being that streptomycin should be avoided in pregnancy as it is ototoxic to the fetus.25 The standard treatment is ethambutol, isoniazid, rifampicin and pyrazinamide for 2 monthsthe intensive phasefollowed by 4 months of isoniazid and rifampicinthe continuation phase. If pyrazinamide is not used in the rst 2 months of therapy, isoniazid and rifampicin are given for 7 months. Directly observed therapy is recommended, especially if compliance to treatment is a concern. The safety of the rst-line drugs for the management of active TB in pregnancy has been established, and therapy improves both maternal and neonatal outcomes.12,26 The management of multidrug-resistant TB (MDR-TB) in pregnancy is complex, and there are limited data on the safety of second-line drugs in pregnancy. However, several cases of successful treatment of MDR-TB in pregnancy, with good maternal and neonatal outcomes, have been reported.2730 In a retrospective review of treatment and pregnancy outcomes in a cohort of pregnant women infected with MDR-TB in Peru, treatment outcomes were comparable with those in nonpregnant women.30 Pregnancy outcomes in this cohort were also comparable with those in the general population, and the suggestion is that pregnant women diagnosed with MDR-TB should have an option to continue with MDR-TB treatment during pregnancy, rather than terminating the pregnancy or discontinuing treatment. Although good outcomes have been reported in pregnant women infected with MDR-TB, co-infection with HIV may be associated with signicant perinatal and maternal morbidity. In a prospective study of pregnant women co-infected with MDRTB and HIV, conducted in KwaZulu Natal, South Africa, multiple adverse maternal and neonatal outcomes were

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observed.31 The adverse outcomes included prematurity, intrauterine growth restriction, and maternal drug- and diseaserelatedcomplications. Treatment of TB in pregnant women co-infected with HIV presents several challenges. For those pregnant women who have not yet started ART, there is the question of timing of ART initiation and what regimen to use, taking into account the potential for maternal and fetal toxicities. Although TB treatment and ART can be started concomitantly, the current recommendation is to start combination ART after starting TB treatment, preferably within 8 weeks.25 With ART, TB may be aggravated, and there is also the risk of immune reconstitution syndrome, especially in the rst 2 months of treatment, and in individuals with signicant immune suppression.14 Delaying the initiation of ART decreases the risk of overlapping drug toxicities and complications, especially immune reconstitution inammatory syndrome, but the delay needs to be balanced against the risk of morbidity and mortality associated with not starting ART.32 The administration of TB treatment and ART is complicated by a high pill burden, potential drug toxicities and drug interactions.14,33 Rifampicin may reduce plasma concentrations of commonly used antiretrovirals, especially non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors.34,35 With NNRTIs, studies have found decreased plasma levels of nevirapine in individuals on concomitant rifampicin-based TB treatment; levels of efavirenz at standard doses appear to be largely unaffected, and hence it is the preferred NNRTI.34,35 Efavirenz is contraindicated, however, in the rst trimester of pregnancy because of concerns about teratogenicity. Rifampicin also causes a marked reduction in the levels of protease inhibitors, and there have been reports of hepatotoxicity in individuals initiated on rifampicin prior to the initiation of a boosted protease inhibitor-based regimen.34,35 The recommendation is to monitor liver function. An alternative is to use rifabutin for the treatment of TB, as this may decrease the risk of drug interactions with antiretroviral drugs.36 Management of M. tuberculosis/HIV co-infection remains complex, and there are still a number of unresolved questions.28,37

available, but should be used by clinicians experienced in the management of TB.36 There has been much debate regarding the management of latent TB during pregnancy, with some recommendations that treatment should be deferred during pregnancy and in the immediate postpartum period unless there is a high risk of progression to active disease.41,42 The main concern is the risk of hepatotoxicity associated with isoniazid use during pregnancy and in the immediate postpartum period. This risk of isoniazid toxicity must be weighed against the consequences of active TB developing during pregnancy and in the postpartum period. For HIV-infected pregnant women, the current recommendation remains that they should receive isoniazid preventative therapy during pregnancy, as the benets of preventing active TB infection far outweigh the risks of isoniazid-associated toxicity. Pregnant and breast-feeding women receiving isoniazid therapy should routinely receive pyridoxine as they are at risk of isoniazid-associated peripheral neuropathy.25

Effect of TB on maternal and neonatal outcomes

There are conicting data on the effects of TB on maternal and neonatal outcomes. Some studies have suggested that, with timely and appropriate treatment, TB infection does not have a negative effect on pregnancy outcomes, whereas others have suggested that TB infection in pregnancy is associated with adverse pregnancy outcomes. In a prospective study in India, there were no statistically signicant differences in pregnancy complications and pregnancy outcomes in women diagnosed with and treated for TB in pregnancy relative to matched controls who were pregnant and had no TB.26 The only exception was in women who started TB treatment late in pregnancy; neonatal mortality and extreme prematurity were signicantly higher in this group. TB was diagnosed and treatment was initiated between 13 and 24 weeks of gestation in the majority of cases (64.7%). Treatment outcomessputum conversion, disease stabilisation and rates of relapsewere similar to those of matched controls who had TB and were not pregnant, but none of the pregnant women with TB in this study were infected with HIV. In HIV-infected pregnant women, the effect on TB appears to be related more to HIV disease rather than to the pregnancy itself. In contrast with the ndings of the above study, a retrospective review in Taiwan found that women who were diagnosed with TB in pregnancy had an increased risk of adverse pregnancy outcomes compared with unaffected mothers.43 There was a signicantly higher percentage of low-birth-weight and small-for-gestational-age infants in pregnant women diagnosed with TB, but no signicant difference in preterm birth between the two groups.

Latent TB infection
Latent TB is common and HIV infection increases the risk of reactivation, especially with signicant immunosuppression.38 Latent TB is diagnosed using the tuberculin skin test, and the recommended treatment is 9 months of isoniazid monotherapy, which has been shown to be effective in pregnant women.39,40 Alternative treatment options with varying efcacy and potential for complications are

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Despite the conicting reports, timely diagnosis and treatment of TB in pregnancy are important; TB is still a cause of signicant maternal morbidity and mortality, especially in the context of HIV co-infection.3,4,44,45

Paediatric transmission
In TB-endemic areas, cases of perinatal TB will be more common. In a survey performed in the Western Cape, South Africa, an area with a high prevalence and incidence of TB, infants born to HIV-infected mothers had a high risk of TB exposure, and this exposure may contribute to the high rates of TB infection in this group of infants.46 A prospective study performed in the same area, the Western Cape, showed that the incidence of TB was much higher in HIV-infected infants: 24.2-fold higher rates for any form of TB.47 The mean age at diagnosis was 6 months and, although pulmonary disease was the most common manifestation of TB, extrapulmonary and disseminated TB were not uncommon.47 Both pulmonary and extrapulmonary disease were found in 30.2%, extrapulmonary TB only in 5.3, and 20% had disseminated TB. TB/HIV co-infection in the neonatal period has been shown to carry a poor prognosis, with rapidly progressive HIV infection and early death.48 Mother-to-child transmission of TB may occur in utero through haematogenous spread through the umbilical vein and aspiration or swallowing of infected amniotic uid, and in the intrapartum period through contact with infected amniotic uid or genital secretions. Postpartum infection may occur through aerosol spread, or through infected breast milk from an active tuberculous lesion in the breast. Although transmission through breastfeeding is negligible, an infant of a mother with active TB may still be infected, through aerosol spread, even if formula fed.12 Hence, if the mother has newly diagnosed, untreated, active TB, she should be separated from her infant to prevent exposure, regardless of the mode of infant feeding.19 The diagnosis of TB in the newborn may be challenging; clinical suspicion is important as early symptoms are often nonspecic and may be indistinguishable from those of other congenital infections.14,4951 With congenital TB, symptoms are usually seen in the second and third weeks of the infants life, and a denitive diagnosis rests on the culture of M. tuberculosis from tissues or uids.49 Abnormal ndings on chest radiograph are common, with nearly one-half having a miliary pattern. If active disease is diagnosed, full treatment must be given. If there is no evidence of active disease, isoniazid prophylaxis is given.

child health.52 They are also key strategies towards meeting the Millennium Development Goal target to halt the spread of TB, and to begin to reverse the worldwide TB incidence by 2015, and, in turn, contribute to the reduction in child and maternal mortality covered by Millennium Development Goals 4 and 5. Reversing the adverse effects of TB in pregnancy, particularly in settings in which HIV and M. tuberculosis co-infection is common, will require a range of interventions, including the screening of all pregnant women for TB, preventative therapy for HIV-infected pregnant women after the exclusion of active TB, treatment of active TB and forging stronger links to local TB services for longer term care.14,17,53 WHOs 3 Is Policy is central to this: intensied TB case nding, infection control and isoniazid preventative therapy for the prevention of HIVassociated TB.54

Disclosure of interest
The authors have no competing interests to declare.

Contribution to authorship
CNM and JAMcI contributed to the design and writing of the paper.

Details of ethics approval

Not applicable for this review.

Funding
CM and JMcI are supported in part by the US Presidents Emergency Plan for AIDS Relief (PEPFAR) through the United States Agency for International Development (USAID) under the terms of award no. 674-A-00-0800009-00. The opinions expressed herein are those of the authors and do not necessarily reect the views of USAID. j

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Conclusion
Improved diagnosis and treatment of TB in pregnant women are important interventions for both maternal and

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