MATERNAL AND PERINATAL TUBERCULOSIS
A Bekker
Department of Pediatric and Child Health, Desmond TB Tutu centreStellenbosch University,Tygerberg Children’s Hospital
MOM AND BABY S
Born by NVD at peripheral hospital (23 July 2008)
• 38 weeks - male• 2605 g (5 .7 lbs)
Respiratory distress at birth and transferred to TygerbergChildren’s Hospital (level 3)
MOM
18 yrs old , G1P1Uncomplicated pregnancyHIV - , RPR -
ARRIVAL TO NICU
GENERAL
oedematous +
pale
petchecial rash
RESP IPPV
GIT
hepatosplenomegaly
(5 cm liver; 4 cm spleen)
ascites
RADIOLOGY
ULTRASOUND
• Viseromegaly with hyperechogenic lesions in the liver
• Abundant free fluid (ascites)
CONGENITAL INFECTION
• Term baby boy
• Acutely ill
• Abnormal blood results in keeping with infection
• Septic work up
• TORCH infection
• Parvovirus screen
DETERIORATION IN FIRST WEEK
• IV Pen and Gentamycin
• Broad spectrum antibiotic cover + Acyclovir
• Optimal supportive therapy – HFOV and vasopressors
• All test results were coming back negative
…..took a week for the penny to drop…
CASE OF CONGENITAL TB
MOM’S HEALTH?
TB screening questions
• No coughing
• No night sweats
• No fever
• Weight loss (not applicable)
• No other family members or close contacts with TB
• Because of high TB incidence in our area:– CXR
– Sputum specimens for M. tuberculosis
TB symptom screening tool
TB INVESTIGATIONS
Date Type AFB M.tb culture
Mom 01/08/08 Endometriumbiopsy
- Positive 22/09/08
Date Type AFB M.tb culture
Baby 30/07/08 Trachealaspirate
+ Positive 04/09/08
30/07/08 Urine - Positive 12/09/08
01/08/08 Ascitic fluid - Positive 12/09/08
11/08/08 Bone marrow - Positive 16/10/08
OUTLINE
• Burden of TB
• Understanding maternal and perinatal TB
• Approach to the TB-exposed newborn
2015 TB CASES WORLDWIDE
TB INCIDENCE RATES HIV PREVALENCE IN TB CASES
WHO Global Report 2016
3.2 million women fell ill with TB 70% of TB/HIV cases – Africa 480 000 of women with TB died
TB CASE DETECTION AMONG WOMEN
SA - 2015 SUB-SAHARAN AFRICA
Deluca JAIDS 2009WHO Global Report 2016
IMPACT OF MATERNAL TB
Increased mortality
• 6-fold increase in perinatal deaths
• 4-fold increase in TB-exposed newborn deaths (India)
Increased prematurity and low birth weight
• twice as likely
Increased risk for HIV transmission
• Infants from TB/HIV women– 2.5-fold (95% CI, 1.05-6.02) increased odds of acquiring HIV infection*
* Gupta JID 2011
OUTLINE
• Burden of TB
• Understanding maternal and perinatal TB
• Approach to the TB-exposed newborn
MATERNAL TB PRESENTATION
• Asymptomatic
• Endometrial TB
• Typical PTB with cavities
• Primary TB disease - pleural effusions
• Disseminated TB disease (miliary TB and TBM)
Poor sensitivity (28-55% ) and specificity (84-91%) of TB symptom-screening tool was found in HIV-infected pregnant
women *
*Hoffmann PLoS One 2013*Gupta CID 2011
TYPES OF MATERNAL TB ASSOCIATED WITH PERINATAL TB
Bacillaemic phase – in utero transmissionTypical cavitating disease – post-natal transmission
Congenital TB is rare:
• transmitted in utero by haematogenous spread via the umbilical vein or ingestion/aspiration of infected amniotic fluid during birth
Postnatal infection much more common:
• which occurs by inhalation of bacilli spread by the airborne route from a mother or other close source case with infectious pulmonary TB
TERMINOLOGY
• Congenital TB + Postnatal TB = Perinatal TB
TRANSMISSION MODES FOR PERINATAL TB
POSTPARTUM PERIOD
• Postpartum women were twice as likely to develop TB than pregnant women – UK epidemiological study
“Adjusting for age, region, and socioeconomic status
the postpartum TB risk was significantly higher
than outside pregnancy
(IRR, 1.95; 95% confidence interval [CI],1.24–3.07)”
Zenner AJRCCM 2012
TB DISEASE SPECTRUM AND TREATMENT OUTCOMES AMONGST
HIV INFECTED AND -UNINFECTED PREGNANT SOUTH AFRICAN WOMEN
OVERVIEW OF MATERNAL TB CASESN=74
13 (18%)Delivered
elsewhere, but transferred in
to TBH
(N=74)Maternal TB
cases
53 (72%)HIV-infected
21 (28%)HIV-uninfected
61 (82%) Delivered at
TBH
CHARACTERISTICS OF MATERNAL TB CASES (N=74)
Age, years (mean ± SD) 30 ± 5.9
Hb, g/dL (mean ± SD) 9.8 ±1.75
Ethnicity, black, n (%) 48 (65)
HIV infection, n (%) 53 (72)
Duration of TB treatment at delivery, months (median; IQR) 1 (0-3)
Previous TB, n (%) 22 (30)
Intra- and postpartum TB diagnosis, n (%) 33 (45)
Bacteriologically status TB diagnosis, n (%) 49 (66)
Smear positive (9 AFB and 1 Xpert) 10
Culture positive 39
MDR TB, n (%) 6 (8)
Intra-uterine deaths, n (%) 4 (5)
Maternal deaths, n (%) 5* (7)
CHARACTERISTICS OF INFANTS BORN TO MATERNAL TB CASES (N=74)Gestational Age, weeks, (median; IQR) 36 (32-38)
Prematurity (<37 weeks), n (%) 47 (64)
Birth weight, grams, (median; IQR) 2197 (1453-2920)
Low birth weight (<2500 g) 42 (58)
TB treatment decision in infants
TB preventive therapy, n (%) 54 (73)
TB treatment, n (%) 4 (5)**
No TB treatment indicated, n (%) 7 (10)
Perinatal and neonatal deaths, n (%) 9 (12)
HIV status (for 53 HIV-exposed infants)
PCR HIV infected, n (%) 3 (6)
** M.tb confirmed in 2
Total Maternal TB(n=74)
HIV-infected(n=53)
HIV-uninfected(n=21)
OR, 95% CI p-value
Ethnicity, black, n (%) 42 (79) 6 (29) 9.5 (2.5 – 35.9) 0.005
Previous TB, n (%) 16 (30) 6 (29) 1.08 (0.4 – 3.3) 0.89
Intra- and postpartum TB diagnosis, n (%)
25 (47) 8 (38) 0.69 (0.21-2.16) 0.48
EPTB , n (%)* 23 (43) 4 (19) 3.26 (0.9 – 11.5) 0.05
Prematurity (<37 ), n (%) 36 (69) 11 (52) 2.05 (0.7 – 5.90 0.18
LBW (<2500 g), n (%) 30 (58) 12 (57) 1.02 (0.4 – 2.9 ) 0.97
Neonatal deaths and IUDs,n (%)
10 (19) 0 (0) - 0.03
Maternal deaths, n (%) 5 (9) 0 (0) - 0.15
* Includes combined EPTB and PTB
MATERNAL TB TREATMENT OUTCOMES*
N=74
FAVOURABLE
n=41 (55%)
Cured
9 (13%)
TB treatment completed
32(43%)
UNFAVOURABLE
n=33 (45%)
LTFU before entering TB clinic service
13 (18%)
LTFU after entering TB clinic services
13 (18%)
Treatment failure
2 (2%)
Died
5 (7%)*WHO definitions, 2013
Key findings
• High burden of TB and HIV-associated in pregnant women at referral hospital level
• HIV co-infected women presented with severe immune deficiency
• Delayed TB diagnosis
• ⅔ Premature and LBW infants
• High maternal and newborn mortality, associated with maternal HIV infection
• Poor maternal TB treatment outcomes
WHICH INFANTS ARE AT HIGH RISK TO DEVELOP TB?
• Premature babies
• LBW infants
• Growth restricted
• HIV-exposed
WHEN TO CONSIDER TB IN NEONATES?
- nonspecific symptoms but mother (or other source case) diagnosed with TB
- pneumonia not responding to broad spectrum antibiotics, especially in TB endemic settings or if the mother/primary caregiver has TB
- high lymphocyte count in CSF with no identified pathogen;
- fever and hepatosplenomegaly
- abdominal distension with ascites Schaaf Respirology 2010
CLINICAL PRESENTATION• Often acute onset of symptoms.
• Age of onset (n=29): median 24 days (range 1-84)
Signs/symptoms Number (n=55)
Respiratory distress 41 (75%)
Hepato/splenomegaly 38 (69%)
Fever 30 (55%)
Lymphadenopathy 20 (36%)
Lethargy/irritability 17 (31%)
Abdominal distension 14 (25%)
Ear discharge 9 (16%)
Skin lesions 7 (12%)
Hageman. J Perinatol 1998;18:389.
Symptoms and signs in congenital TB: combined data from 75 cases of congenital TB
Symptoms and signs Occurrence
Respiratory distress including tachypnoea
Hepatomegaly, splenomegaly
Fever (usually low grade)
Prematurity/low birth weight
Common (i.e. >40%)
Cough – may be acute or chronic
Poor feeding
Failure to thrive
Abdominal distension (including ascites)
Frequent (i.e. 25-40%)
Irritability
Peripheral lymphadenopathy
Sepsis syndrome
Infrequent (i.e. 10-25%)
Skin papular/pustular or ulcerative lesions
TB meningitis
Jaundice (obstructive)
Otorrhoea/mastoiditis
Wheeze or stridor
Apnoea or cyanosis attacks
Facial nervepalsy
Shock
Rare (i.e. <10%)
Schaaf et al. Respirology
2010;15:747-763
Comparison of CXR features in infants with culture-confirmed congenital tuberculosis versus those <3 months of age with mainly
postnatal tuberculosis
Radiographic feature Congenital TB
n = 53 (%)
TB in infants (<3 mo)
n = 27 (%)
Lymphadenopathy
(hilar/paratracheal)
4 (8) 14 (52)
Lobar/segmental opacification
(unilateral or bilateral)
18 (34) 14 (52)
Airtrapping NA 15 (56)
Large airway compression NA 13 (48)
Bronchopneumonia (bilateral) 17 (32) 5 (19)
Miliary TB 16 (30) 7 (26)
Ghon focus NA 2 (7)
Cavities or cystic lesions 4 (8) NA
Lobar collapse NA 4 (15)
Pleural effusion 1 (2) 2 (7)
Normal chest radiograph 4 (8) 1 (4)
Schaaf et al. Respirology 2010;15:747-763
OUTLINE
• Burden of TB
• Understanding maternal and perinatal TB
• Approach to the TB-exposed newborn
APPROACH TO THE TB-EXPOSED NEWBORN
Infectious mother non-infectious mother
Well baby unwell baby
WHICH MOTHERS ARE AN INFECTION RISK?
A recently diagnosed mother with TB
• Received < 2 months of TB treatment at time of delivery
OR
• Sputum smear/culture has not yet converted to negative/ results are
unknown at time of delivery
APPROACH TO THE TB-EXPOSED NEWBORN
Infectious mother non-infectious mother
Well baby unwell baby
Well baby & non-infectious mother
Observe and f/up
Unwell baby
TB-screening
Well baby & infectious mother
TB-screening
Observe and follow-up
1. Well baby and non-infectious mother
– BCG at birth
– Monthly follow-up
– Ask about TB symptoms at each visit
– Screen for TB in the presence of any TB symptoms
Well baby & non-infectious mother
Observe and f/up
Unwell baby
TB-screening
Well baby & infectious mother
TB-screening
Perform TB-screening
2. Unwell baby
TB Screening
• Gastric aspirates (x2)– Xpert and culture
• Chest radiology
• If indicated:
• Abdominal ultrasound
• CSF
• Blood culture
Well baby & non-infectious mother
Observe and f/up
Unwell baby
TB-screening
Well baby & infectious mother
TB-screening
Perform TB-screening
3. Well baby
TB Screening
• Gastric aspirates (x2)– Xpert and culture
• Chest radiology
• If indicated:
• Abdominal ultrasound
• CSF
• Blood culture
Perform TB screening
No TB TB
Prevention versus Observation Treatment
2. Unwell baby 3. Well baby with infectious mother
IPT PREVENTION
– No BCG at birth
– INH 10 mg/kg/day for 6 months -
– Monthly follow-up
– Ask about TB symptoms at each visit
– Screen for TB in the presence of any TB symptoms
– At IPT completion – BCG administration
Perform TB screening
No TB TB
Prevention Treatment
Unwell baby Well baby with infectious mother
TB - TREATMENT
Intensive phase – 2 months (3/4 drugs)
• INH
• RMP
• PZA
• EMB (ETH)
Continuation phase – 4 months (2 drugs)
• INH
• RMP
TREATMENT2009 WHO-RECOMMENDED DOSES
INH 10 (7-15) mg/kg/d
RMP 15 (10-20) mg/kg/d
PZA 25 (20-30) mg/kg/d
EMB 20 (15-25) mg/kg/d
ISONIAZID PHARMACOKINETIC STUDYIN 20 LOW BIRTH WEIGHT INFANTS,
DOSED AT 10 MG/KG
Bekker et al. AAC 2014
FUTURE DIRECTIONS
• Identifying and quantifying the burden of maternal and infant TB
• Improving integration of health care systems (maternal &child; HIV & TB)
• PK/PD information – maternal and infant
ACKNOWLEDGEMENTS
Anneke Hesseling, Simon Schaaf, Robert Gie, Mark CottonDTTC team: BCH PK unit, TBH, KDH and KBHTygerberg neonatal team Harry Crossley fundingFamilies that participated
QUESTION
Of the symptoms below, which ones are most common in congenital TB:
1. Weight loss
2. Night sweats
3. Respiratory distress
4. Jaundice