Tuberculosis kills more than 500,000
women annually [WHO 2014] and
remains the leading cause of death from
infection in women of childbearing age.
The disease preys disproportionately on
expectant mothers, with an estimated
200,000 diagnoses among pregnant
women globally each year [Sugarman
Lancet GH 2014]. TB increases the rate
of miscarriages and the risk of death for
both the mother and her baby [Mathad
CID 2012].
Photo by Charles Wanga, Jhpiego
The recent emergence of drug-resistant
TB presents terrible challenges to health care providers around the world, particularly when
treating expectant mothers, because we know so little about the safety and efficacy of the few
available treatments during pregnancy. Multi-drug resistant TB (MDR-TB) bacteria are resistant
to two of the most common and effective TB drugs (isoniazid and rifampicin). Extremely drug
resistant TB (XDR-TB) adds resistance to an additional drug (fluoroquinolone) and at least one
of the injectable second-line drugs, leaving vanishingly few treatment options.
The World Health Organization and most national TB programs do not routinely collect
information regarding the incidence or prevalence of TB, including drug-resistant TB, in
pregnant women. Without routine data collection, the extent of the burden of TB in
pregnancy is uncertain, making it too easy for overburdened governments to ignore the
problem.
There are currently no clinical guidelines for the management of drug-resistant TB in
pregnant women. As a result, health care professionals have no choice but to: (1) delay
treatment of the patient until after pregnancy, raising the risk of pre-term labor and maternal and
infant mortality; (2) offer termination of the pregnancy; or (3) continue treatment without solid
data to guide decision-making.
Why are there no guidelines for treatment of drug-resistant TB in pregnancy?
A small number of drugs used for MDR-TB treatment, such as streptomycin and other
aminoglycosides, entail known risks during pregnancy. For most MDR-TB drugs, however, there
are no human data for pregnant patients (Table 1). Without that data, it is impossible to predict
the risk for adverse events in pregnant women and their fetuses or even the appropriate dose.
During pregnancy, a woman undergoes many physiologic changes which alter the way drugs are
metabolized, including increased body fat, slowed transit through the digestive tract, and changes
in how the liver processes the drug [Frederiksen Semin Perinatol 2001, Anderson Clin Pharm
2005].
The few published articles about MDR-TB
treatment among pregnant women are typically
anecdotal reports describing various drug
regimens tried by health care providers around
the world. The largest of these case series—a
cohort of 38 pregnant Peruvian women with
MDR-TB—showed no birth defects attributable
to the drugs themselves. A majority of the
women were cured, and most of their newborns
were delivered healthy. The results are
encouraging, but the cohort was far too small to
draw conclusions.
Table 1. FDA Pregnancy Categories for drugs
used in MDR-TB treatment
Drug
FDA
Category
Aminoglycosides
D
Fluoroquinolones
C
Ethionamide/Prothionamide
C
Cycloserine
C
PAS
C
Linezolid
C
Clofazamine
C
Because pregnant women have been excluded
from every prospective MDR-TB drug trial
Bedaquiline
B
to date, there is an urgent need for wellFDA Pharmaceutical Pregnancy Categories:
controlled clinical trials in this population.
B-Animal studies demonstrate no risk, no human studies;
The alternative is to leave treatment of the everC-Animal studies demonstrate risk; no human studies;
increasing number of MDR-TB cases in
D-Human studies demonstrate risk
pregnant women to individual practitioners with
no data or guidance from competent authorities, resulting in heterogeneous outcomes based
solely on clinician experience.
What can we do?
In order to decrease morbidity and mortality from MDR-TB in mothers and their children
we need to:
 Implement reliable monitoring programs to record the incidence and prevalence of
TB in pregnant women. It is vital that we measure the extent of the problem and provide
baseline data to identify progress.
 Develop safety and efficacy data to inform treatment policies. Drug developers often
choose not to perform reproductive toxicity testing for cost reasons. This data is required
before pregnant women can participate in clinical trials. Supportive incentives should be
considered to encourage this crucial step in drug development for pregnant women.
 Include pregnant women in clinical trials involving TB medications. Consider
bedaquiline, a new MDR-TB drug. Although animal testing showed no reproductive
toxicity, all clinical trials that include bedaquiline in the MDR-TB regimen have
excluded pregnant women. There is no scientific basis for this policy.
 Improve the collection of anecdotal reports and opportunistic data to provide
valuable information, which poses no risk to expectant mothers. When non-pregnant
women participating in new MDR-TB drug trials become pregnant while in the study,
data collection on the safety and metabolism of the drugs will improve understanding and
management of the disease in pregnancy. A pregnancy exposure registry is an example of
an observational study that could collect standardized information on pregnancy
outcomes in women exposed to TB drugs. A similar approach has been successfully used
for antiretrovirals in the management of HIV in pregnancy.
Conclusion
The proportion of new MDR-TB cases in the United States that come from foreign-born persons
has increased from 30.8% to 89.5% in the last 10 years [CDC Reported TB in US, 2014], making
this an increasingly important priority even in the United States. MDR-TB in pregnancy poses a
significant risk to the life of the mother and young children in her home. Insufficient data forces
clinicians to err on the side of caution and undertreat pregnant women with MDR-TB—even
with no data suggesting that treatment poses a special risk to expectant mothers or their fetuses.
As we consider the risks and benefits of including pregnant women in MDR-TB drug trials, we
must consider not only the potential risks of MDR-TB drugs in pregnancy, but also the risks of
inadequate treatment with currently available regimens if we continue to deny them access to
clinical trials. The lives of thousands of women and children worldwide depend on this data.