Abstract
Tuberculosis (TB) is one of the top 10 causes of death worldwide and is believed to be nearly as old as human history. Tuberculosis remains the most common cause of death from infectious agents in childbearing-age women (14–49 years) worldwide.
In 2017, TB caused an estimated 1.3 million deaths (range 1.2–1.4 million). The progress made in the diagnosis, treatment and control of TB has been offset by the HIV epidemic, the growing challenge of drug resistance and other epidemiological factors like population migration, poverty, overcrowding, poor sanitation and malnutrition in the developing countries.
Six countries, India, Indonesia, China, Nigeria, Pakistan and South Africa, account for 60 per cent of the total burden of new TB cases.
Introduction
Tuberculosis (TB) is one of the top 10 causes of death worldwide and is believed to be nearly as old as human history.1 Tuberculosis remains the most common cause of death from infectious agents in childbearing-age women (14–49 years) worldwide.
In 2017, TB caused an estimated 1.3 million deaths (range 1.2–1.4 million). The progress made in the diagnosis, treatment and control of TB has been offset by the HIV epidemic, the growing challenge of drug resistance and other epidemiological factors like population migration, poverty, overcrowding, poor sanitation and malnutrition in the developing countries.
Six countries, India, Indonesia, China, Nigeria, Pakistan and South Africa, account for 60 per cent of the total burden of new TB cases.
Microbiology and Etiopathogenesis
Tuberculosis (TB) is caused by bacteria called Mycobacterium tuberculosis, a contagious infection that usually attacks the lungs. It can also spread to other parts of the body, such as the brain and spine.2
The name Mycobacterium is derived from the Greek words myk¯es, meaning fungus, and bakt¯erion meaning ‘little rod’, which it resembles when grown on liquid culture media. It was discovered in 1882 by Robert Koch.
Mycobacterium tuberculosis (M. tuberculosis) is an obligate intracellular pathogen. It is an aerobic, non-motile, non-encapsulated spore-forming bacillus and is one of the five members of the M. tuberculosis complex (the others being M. bovis, M. ulcerans, M. africanum and M. microti). It is termed as acid- fast (25 per cent H2SO4) as it retains the colour of the stains (Ziehl–Neelsen and auramine-o) even after an acid-control wash.
Infection is caused mainly by:
a) Inhalation of infectious particles aerosolised by coughing, sneezing, talking or manipulation of infected tissue
b) Ingestion of unpasteurised milk
c) Direct implantation through skin abrasion or the conjunctiva
Tuberculosis and Pregnancy
Incidence
TB is a public health problem and a significant contributor to maternal mortality. It is among the three leading causes of death among women between 15 and 45 years of age. The exact incidence of TB during pregnancy is not readily available for low-resource countries; however, it is expected to be as high as that of the general population.
The incidence of TB during pregnancy reported in the United States between 2003 and 2011 was 26.6 per 100 000 births.3
As a cause of maternal mortality, in the UK, it accounted for 4.2 per 100 000 maternities in 2005–06.4
Effects of Pregnancy on TB
Tuberculosis remains a significant worldwide concern among pregnant or postpartum women, with high maternal mortality rates. In 2008, an estimated 9.4 million new cases of TB occurred, with 1.7 million TB-related deaths, more than half among women.5
Research has proved that pregnancy neither improves nor worsens the course of TB (sputum conversion, stabilisation of the disease and relapse rate), as long as it is diagnosed and treated appropriately and early.6
Rather than pregnancy itself, the course and prognosis of the disease during pregnancy is associated with the current health status of the woman, the disease extent and radiographic pattern.
The diagnosis of TB in pregnancy may be more challenging as the symptoms may initially be attributed to the pregnancy. The weight loss associated with the disease may temporarily be masked by the normal weight gain in pregnancy.
Early postpartum women are twice as likely to develop TB as non-pregnant women, because of the suppression of T-helper 1 (Th1) pro-inflammatory response during pregnancy which reverses post-delivery, resulting in risk of exacerbation.7
Effects of TB on Pregnancy
The effects of TB on pregnancy depend on the severity of the disease, the presence of extrapulmonary spread, HIV co-infection and gestational age at the time of diagnosis. Poor prognosis is seen in cases of advanced disease diagnosed in puerperium and in those with HIV co-infection. Non-compliance with treatment also worsens the prognosis.8, 9
Obstetric Outcomes
Obstetric complications of TB include miscarriage, intrauterine growth retardation, preterm labour, low birthweight and increased neonatal morbidity and mortality. Early start of anti-tuberculous treatment results in better outcomes comparable to that in non-pregnant patients.10
Late diagnosis and care is associated with increased maternal morbidity:11
1. Pre-eclampsia
2. Acute respiratory failure
3. Poor weight gain in pregnancy
4. Postpartum haemorrhage
5. Difficult labour11
Advanced TB is associated with upregulation of pro-inflammatory cytokines such as tumour necrosis factor-alpha which could be the pathogenesis of increased rates of pre-eclampsia.
Poor nutritional state of the mother, hypo-proteinuria and anaemia predispose to TB infection in pregnancy and increase the morbidity and mortality.
Extrapulmonary TB is also associated with maternal morbidity in the form of recurrent admissions and disability as well as increased mortality with central nervous system complications.
Maternal Mortality
The risk of mortality is increased both during pregnancy and postpartum. Women co-infected with HIV are at higher risk of mortality. One post-mortem study in Africa on maternal deaths reported TB as a cause of death in 12.9 per cent of deaths overall and 27.7 per cent of deaths among HIV-infected women.12 [EL 2]
Untreated, TB in pregnancy can have a mortality of up to 40 per cent.
Perinatal Outcomes
Preterm labour, low-birthweight babies and neonatal mortality are more prevalent in cases where diagnosis and treatment is delayed.13
Low birthweight is also seen in countries like the UK where TB during pregnancy is much less prevalent, i.e. 62/100 000 pregnancies. [EL 2]
In a recent systematic review and meta-analysis (2016):
Perinatal death was four times more frequent
Preterm birth was 1.6 times greater
Low birthweight was 1.7 times greater
Low APGAR score at 1 minute was five times greater
Acute fetal distress was 2.3 times greater
There was an odds ratio of 3.4 for congenital anomalies14 [EL 1]
Mother-to-Child Transmission and Congenital Infection
Congenital TB is rare but associated with high perinatal mortality. Congenital infection by TB is caused by transplacental transmission via the umbilical vein to the fetal liver and lungs. In late pregnancy, aspiration and swallowing of infected amniotic fluid in utero or during labour causes primary infection of fetal lungs and gut.15
The primary focus develops in the liver with involvement of the periportal lymph nodes following haematogenous spread via umbilical vein. The fetal lungs are infected secondarily.
Dissemination to other systems is carried out via fetal circulation to other organ systems such as TB meningitis.
In a study by Pillay et al. in South Africa, vertical transmission of Mycobacterium tuberculosis was detected in 16 newborns (16 per cent) with no difference between HIV-infected and non-infected mothers.15
The risk of transmission from infected mother to neonate is greater in the first three weeks of life.
Cantwell et al. Modified Criteria for Diagnosis of Congenital Tuberculosis
Lesion during the first week of life.
A primary hepatic complex or caseating granuloma.
Documented tuberculosis infection of placenta or endometrium.
Exclusion of postnatal transmission through contact tracing.
Common clinical presentations of congenital TB include abdominal distension, hepato-splenomegaly, respiratory distress, failure to thrive, fever and lymphadenopathy usually presenting in the second or third week postnatal.
Radiographic abnormality is seen in almost all cases, with nearly half showing a miliary pattern. Overall mortality of congenital TB is 38 per cent in the untreated and 22 per cent in the treated newborns.16
Acquired Newborn TB Infection
A newborn infant is at greater risk of acquiring TB postpartum than congenitally, especially if the mother is sputum-positive or if the maternal condition remains undiagnosed and untreated.
The newborn may acquire postnatal disease by contact:
1. Droplet infection from the mother
2. An infectious adult
3. An infected family member, particularly if they are sputum-positive and not under treatment
Transmission of Tuberculosis through Breastmilk Does Not Occur [EL 2]
About 50 per cent of children born to mothers with active pulmonary TB develop the disease during the first year of life if chemoprophylaxis or Bacillus Calmette–Guérin (BCG) vaccine is not given.
Separation of mother and offspring is indicated only if the mother is non-adherent to medical treatment, needs to be hospitalised or if she has developed drug-resistant TB.
Clinically, signs of neonatal TB are non-specific but are usually marked by multiple organ involvement. The neonate may have fever, is lethargic or may look acutely or chronically ill with respiratory distress or non-responsive pneumonia, hepatosplenomegaly or failure to thrive.
Diagnosis can be confirmed by chest X-ray, culture of tracheal aspirate, gastric washings, urine, and cerebrospinal fluid or sometimes skin testing.
Evaluation and Diagnosis
Antenatal clinics present an opportunity for evaluation and management of TB among individuals with risk of TB who may not have previously presented for medical care.
Risk factors for TB infection during pregnancy include close contact with infectious cases, living in or travelling to places where TB is prevalent, having a condition associated with low immunity (HIV, diabetes or other medical disorders), substance and alcohol abuse, migrant worker and overcrowding.
Evaluation and treatment of TB in pregnancy depend on two types of presentations:
Latent Tuberculosis Infection (LTBI) in Pregnancy
M. tuberculosis infection is initially contained by host defences and remains latent in most cases. However, this latent infection has the potential to develop into active disease at any time. Identification and treatment of latent TB infection can reduce the risk of development of disease by as much as 90 per cent.18
In countries with low TB infection rates, immigrants from higher-incidence countries are the major pool of infected individuals.
Patients with LTBI are asymptomatic and are not contagious.
There is no risk for vertical transmission of LTBI.19
Screening
There is no role for routine LTBI testing in pregnant women with no risk factors for development of active TB. It is better to test for LTBI prior to pregnancy as this provides an opportunity for counselling about the risk of becoming pregnant while infected with LTBI.
In cohorts of pregnant women tested in the USA, the prevalence of latent infection varied from 14 to 48 per cent,19 hence the antenatal period represents an opportunity for immigrant women to seek medical care. The Centers for Disease Control and Prevention recommend screening all high-risk pregnant women at the beginning of prenatal care. [EL 1]
Currently there does not seem to be any reliable incidence of conversion from latent to active TB during pregnancy.
Diagnosis of LTBI
Tools for LTBI testing include the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs).
1 Tuberculin Skin Test (TST)/Mantoux Test
Identifies individuals with prior sensitisation to mycobacterial antigens.
Tuberculin material is injected intradermally, which stimulates a delayed-type hypersensitivity response mediated by T lymphocytes and causes induration within 48–72 hours.
The transverse diameter of the induration (not erythema) should be demarcated, measured and recorded in millimetres.
Sensitivity is 98 per cent using the 5 mm threshold, 90 per cent using the 10 mm threshold, but only 50–60 per cent using the 15 mm threshold. As the cutoff for mm of induration is increased, the sensitivity decreases and the specificity increases.20
False-positive results can be seen in prior BCG vaccination. False-negative results may occur in immunocompromised patients, or due to improper injection of the tuberculin protein or inaccurate interpretation of the induration.
2 Interferon-Gamma Release Assays (IGRAs)
In vitro blood tests that measure T-cell release of interferon (IFN)-gamma following stimulation by antigens specific to M. tuberculosis.21
IGRA is preferred over TST in cases with low-to-intermediate risk of progression to active disease, for patients who are unlikely to return to have the TST read and for patients with a history of BCG vaccination.21
IGRAs are more expensive than TST.
These tests should not be used for diagnosis of active TB as they cannot distinguish between latent infection and active disease.22
Management of Established LTBI
Patients with a positive TST or IGRA must undergo evaluation to rule out active tuberculosis. [Grade A recommendation]
The role of treatment in latent TB infection, especially in pregnant women, is controversial, as pregnancy itself does not increase the risk of progression of the disease and pregnant and postpartum women are more vulnerable to isoniazid (INH) toxicity. There are no randomised controlled trials on the treatment of LTBI in pregnancy; consequently it is not possible to draw any firm conclusions about the safety of INH therapy antepartum.
If there is no indication for prompt management, LTBI treatment should be deferred until three months after delivery, to minimise the risk of hepatitis. Women who were diagnosed with LTBI prior to pregnancy and started on treatment for an appropriate indication should continue LTBI treatment if they become pregnant. The prior treatment regimen should be modified to a regimen suitable for pregnancy. [Grade B recommendation]
The preferred regimens for treatment of LTBI during pregnancy in non-HIV-infected women are [Grade A recommendation]
○ Isoniazid (5 mg/kg up to 300 mg daily) for nine months
○ Isoniazid (15 mg/kg up to 900 mg twice weekly) for nine months
○ Isoniazid should be administered together with pyridoxine supplementation, 25–50 mg daily. [Grade A recommendation]
Pregnant women with HIV infection and LTBI should be treated with isoniazid with daily dosage schedule for nine months. [Grade A recommendation]
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