<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03305991</url>
  </required_header>
  <id_info>
    <org_study_id>LundU-2015</org_study_id>
    <nct_id>NCT03305991</nct_id>
  </id_info>
  <brief_title>Tuberculosis Infection in Women of Reproductive Age and Their Infants</brief_title>
  <official_title>The Role of Maternal TB Infection for Adverse Pregnancy and Infant Health Outcomes in Ethiopia - a Long-term Prospective Cohort Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lund University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Lund University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Women living in low-income countries are at elevated risk of death in connection to&#xD;
      pregnancy, as well as infants born to women in such settings. It is probable that several&#xD;
      factors are involved, such as poverty, lack of education and access to healthcare. Infectious&#xD;
      diseases constitute important threats to maternal health in resource-limited settings.&#xD;
      Tuberculosis (TB) is reported to be the third leading cause of maternal death globally.&#xD;
      Furthermore, TB can be transmitted from mother to child during pregnancy, with high risk of&#xD;
      severe consequences for the infant. Despite these data, neither the role of TB in relation to&#xD;
      co-existing risk factors for adverse pregnancy outcomes, nor the mechanisms involved, are&#xD;
      well understood. It is likely that TB interacts with other characteristics, in particular&#xD;
      socio-economic condition and HIV infection, which could obscure associations between TB and&#xD;
      pregnancy outcomes. For this reason, it is critical to design studies so that the independent&#xD;
      role of TB can be deduced.&#xD;
&#xD;
      This project aims to investigate how TB infection in women affects the risk of adverse&#xD;
      pregnancy outcomes in relation to co-existing factors, and how exposure to TB infection may&#xD;
      impact growth and development of infants born to women with TB. In addition, mechanisms in&#xD;
      which TB and the immune system during pregnancy will be explored.&#xD;
&#xD;
      The project is conducted at public health facilities in Ethiopia, where 2 000 women have been&#xD;
      recruited during antenatal care. These women will be followed until 5 years after delivery,&#xD;
      along with their offspring born during the study period. Detailed data is collected at&#xD;
      inclusion and at study visits during follow-up, with submission of samples for TB testing and&#xD;
      immunological analyses.&#xD;
&#xD;
      Better knowledge on the characteristics of TB infection in association with pregnancy, and&#xD;
      how TB affects maternal and child health, can be used to construct new guidelines for&#xD;
      management of TB in women of fertile age. This may contribute to reductions in adverse&#xD;
      pregnancy outcomes, including maternal and infant deaths.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Objective The overall objective of this project is to investigate longitudinal patterns and&#xD;
      consequences of tuberculosis (TB) infection in a prospective cohort of women recruited during&#xD;
      pregnancy. The relation between maternal TB infection and pregnancy outcomes, as well as&#xD;
      infant health and development, will be evaluated over time.&#xD;
&#xD;
      Specific aims&#xD;
&#xD;
        1. To determine whether maternal TB infection is associated with adverse pregnancy outcomes&#xD;
&#xD;
        2. To determine the excess risk of incident active TB during pregnancy and post-partum,&#xD;
           with regard to the prevalence of latent TB infection at registration in antenatal care&#xD;
&#xD;
        3. To investigate long-term health and survival in infants in relation to maternal TB and&#xD;
           adverse pregnancy outcomes&#xD;
&#xD;
      Methods Study setting and participants This project is conducted in public health facilities&#xD;
      in the city of Adama, Central Ethiopia. Participants are recruited and followed at antenatal&#xD;
      care (ANC) clinics until delivery. After delivery their children are followed at clinics for&#xD;
      extended program for immunization (EPI); continued follow-up of the mothers after the first&#xD;
      post-natal visit also takes place in these clinics.&#xD;
&#xD;
      All study procedures, including interviews, physical examination, and collection of informed&#xD;
      consent, are performed by health facility staff (nurses and midwives) in the respective&#xD;
      clinics. Biological samples including blood and sputum are collected at the respective health&#xD;
      facility laboratory. Study samples are transported to the Adama Regional Laboratory. At this&#xD;
      laboratory, additional analyses and storage of plasma will be done.&#xD;
&#xD;
      For supervision and monitoring of data collection, as well as for data entry, the project&#xD;
      uses staff and infrastructure in a field research station which has been established in Adama&#xD;
      since 2010 by the research group.&#xD;
&#xD;
      Study procedure Both scheduled and unscheduled study visits can occur for participants in&#xD;
      this project. Scheduled study visits coincide with routine antenatal and postnatal visits and&#xD;
      visits at the EPI clinics for the infant's immunization following National guidelines.&#xD;
      Unscheduled visits occur in case of symptoms suggestive of active TB (according to the study&#xD;
      definitions) in the pregnant/postnatal/non-pregnant woman, or in the child, at any time in&#xD;
      between these routine visits.&#xD;
&#xD;
      Antenatal care visits At inclusion, structured information on socio-demographic conditions,&#xD;
      education, occupation, and poverty indicators is collected; as well as medical history (in&#xD;
      particular for obstetric, gynecological and TB-related details). Physical and obstetric&#xD;
      examination is performed. Apart from the study procedures and investigations, participants&#xD;
      will receive care according to current Ethiopian ANC guidelines.&#xD;
&#xD;
      At the inclusion visit blood samples are obtained for routine care and for study specific&#xD;
      investigations from all participants. At the health facility laboratory, the following&#xD;
      analyses are performed: HIV rapid test, urine dipstick. Ten mL of venous blood is collected.&#xD;
      This sample is used for analysis of complete blood count, blood/Rh group, syphilis serology,&#xD;
      creatinine and fasting glucose. The remaining plasma is aliquoted and stored at -80° C for&#xD;
      research analyses that are performed at the completion of inclusion. Blood is collected&#xD;
      separately for QuantiFERON TB Plus (QFT) testing, in order to determine the prevalence of&#xD;
      LTBI. For the last 500 women included in the study, QFT testing is repeated at the 3rd&#xD;
      antenatal care visit. From HIV positive women blood for viral load and CD4 count is drawn at&#xD;
      each scheduled visit pre- and post-delivery except from 2nd and 3rd antenatal care visit.&#xD;
&#xD;
      Participants are followed up four times in accordance with WHO recommended focused antenatal&#xD;
      visits until delivery or term of pregnancy. They are also instructed to contact the study&#xD;
      clinic in between these visits in case of health-related events. In case of delivery (or&#xD;
      other unintended termination of pregnancy) in another place than any of the study health&#xD;
      facilities, they are asked to communicate this to their study site for further follow-up&#xD;
      examinations.&#xD;
&#xD;
      All participants with suspected active TB according to the study definition (irrespective of&#xD;
      Quantiferon results) at enrolment and/or during follow up are asked to submit samples for&#xD;
      bacteriological TB investigations. These encompass liquid culture, smear microscopy and PCR&#xD;
      (using Xpert MTB/RIF technique). All these tests are performed on two consecutive morning&#xD;
      sputum samples. Moreover, acquisition of blood for QuantiFERON testing is repeated for all&#xD;
      women investigated for suspected active TB.&#xD;
&#xD;
      Stored aliquots of Mtb-incubated plasma will be analyzed at the end of inclusion for&#xD;
      potential blood biomarkers of TB infection during pregnancy. These analyses will be performed&#xD;
      using ELISA and/or Luminex technique, and they will include the following markers of immune&#xD;
      activation and inflammation: C-reactive protein (CRP), neopterin, soluble&#xD;
      urokinase-plasminogen activator receptor (suPAR), interferon-inducible protein 10 (IP-10).&#xD;
&#xD;
      Postpartum follow-up visits for women Further follow-up visits for women are scheduled for 6&#xD;
      weeks and 9 months after delivery or termination of pregnancy, coinciding with the routine&#xD;
      child visits for immunization. The first postnatal visit takes place at the ANC clinic,&#xD;
      whereas all subsequent visits take place at the respective EPI clinics (where infant&#xD;
      follow-up also occurs). At the 6 week postnatal visit details on delivery outcome are&#xD;
      recorded.&#xD;
&#xD;
      For investigation of long-term health effects after delivery, participants will be asked to&#xD;
      come for further annual visits with similar assessments until 54 months after termination of&#xD;
      pregnancy. At all follow-up visits symptoms and signs on physical examination will be&#xD;
      recorded using structured questionnaires.&#xD;
&#xD;
      At inclusion, and repeatedly on scheduled follow-up visits, participants are informed about&#xD;
      symptoms and signs that may indicate active TB. Study subjects are instructed to contact the&#xD;
      study site clinic (ANC during antenatal period, EPI during postnatal period) directly if they&#xD;
      develop such symptoms for unscheduled study visits (in order to assess incident active TB&#xD;
      during follow-up).&#xD;
&#xD;
      At all visits, whether scheduled or unscheduled, bacteriological testing (smear microscopy,&#xD;
      Xpert MTB/RIF assay, and liquid culture) is performed according to the study protocol in case&#xD;
      study criteria for suspected active TB are met. These tests are performed on two morning&#xD;
      sputum samples.&#xD;
&#xD;
      In case study participants do not come for their scheduled study visits they are contacted by&#xD;
      phone by the study site staff and/or the research study team. If the participant cannot be&#xD;
      reached, her contact person is contacted by phone. At mid-time in between the scheduled&#xD;
      visits, women are contacted by phone by a member of the local research team to assess whether&#xD;
      any health events or symptoms compatible with TB have occurred.&#xD;
&#xD;
      Repeated sampling for QFT testing will be performed for all women at 4 years after inclusion&#xD;
      (irrespective of previous QFT results), with storage of incubated plasma for further analysis&#xD;
      of immune markers of TB infection.&#xD;
&#xD;
      Follow-up visits for infants If consent has been provided by the mother, infants are&#xD;
      registered and included in a separate infant follow-up cohort as soon as possible after&#xD;
      birth. Birth details, including delivery method, weight, length, APGAR score, and head&#xD;
      circumference are registered at inclusion of the infant. Follow-up of included infants takes&#xD;
      place in the EPI clinic at the respective study health facilities. Follow-up visits are&#xD;
      scheduled at the same time interval as the mother, i.e. at 6 weeks and 9 months and&#xD;
      subsequently at annual intervals congruent with the mothers until four and a half year after&#xD;
      birth. The two first visits coincide with routine immunization visits. On all study visits,&#xD;
      parameters of growth, nutritional and neurological development are recorded using structured&#xD;
      questionnaires. In addition, data on socio-demographic characteristics, health-related events&#xD;
      and feeding details are recorded, as well as data on known or suspected exposure to TB.&#xD;
&#xD;
      At inclusion, and repeatedly on scheduled follow-up visits, caretakers are informed about&#xD;
      symptoms and signs that may indicate active pediatric TB. Study infant caretakers are&#xD;
      instructed to contact the study site EPI clinic directly if the infants develop such symptoms&#xD;
      for unscheduled study visits (in order to assess incident active TB during follow-up).&#xD;
&#xD;
      If criteria for suspected TB are met at any time during follow-up bacteriological&#xD;
      investigations (liquid culture, PCR and microscopy) will be performed on gastric lavage&#xD;
      specimens (or cerebrospinal fluid in case of suspected meningitis; or fine-needle lymph node&#xD;
      aspirates in case of peripheral lymphadenopathy). These investigations will be performed by&#xD;
      trained health care staff at the Department of Pediatrics, Adama Regional Hospital.&#xD;
&#xD;
      Stored aliquots of plasma will be analyzed at the end of inclusion for potential blood&#xD;
      biomarkers of TB in young children. These analyses will be performed using ELISA and Luminex&#xD;
      technique, and they will include the following markers of immune activation and inflammation:&#xD;
      C-reactive protein (CRP), neopterin, soluble urokinase-plasminogen activator receptor&#xD;
      (suPAR).&#xD;
&#xD;
      In case infant participants do not come for their scheduled study visits their caretakers are&#xD;
      contacted by phone by the study site staff and/or the research study team. If the caretaker&#xD;
      cannot be reached, the contact person is contacted by phone. At mid-time in between the&#xD;
      scheduled visits, caretakers are contacted by phone from a study investigator to assess&#xD;
      whether any health events or symptoms compatible with TB have occurred in the infant.&#xD;
&#xD;
      Study definitions Suspected adult active TB is defined as any of the following symptoms or&#xD;
      findings: Cough, fever, night sweating, weight loss (except following delivery), chest pain,&#xD;
      reduced Karnofsky performance score (after pregnancy), peripheral lymph node enlargement,&#xD;
      abdominal distension and/or abdominal mass (during study periods without pregnancy).&#xD;
&#xD;
      Suspected pediatric active TB is defined as any of the following symptoms or findings: Cough,&#xD;
      fever, night sweating, chest pain, peripheral lymph node enlargement, abdominal distension&#xD;
      and/or mass, weight loss, poor growth development, failure to thrive, acute or chronic&#xD;
      malnutrition, neck stiffness, seizures, and loss of consciousness Latent TB infection is&#xD;
      defined as a positive QuantiFERON® TB Gold Plus result (according to the manufacturer's&#xD;
      reference range), in the absence of confirmed active TB and/or national TB guideline criteria&#xD;
      for clinically diagnosed TB.&#xD;
&#xD;
      Confirmed active TB is defined as any subject with a positive bacteriological result (as per&#xD;
      the national TB guideline), irrespective of clinical manifestations.&#xD;
&#xD;
      Clinically diagnosed active TB is defined as any subject without positive bacteriological&#xD;
      results for TB, but who fulfils national TB guideline criteria for clinically diagnosed TB,&#xD;
      and who are referred for anti-TB treatment.&#xD;
&#xD;
      Adverse pregnancy outcomes are defined as maternal or infant death following inclusion until&#xD;
      3 months after unintended termination of pregnancy; preterm birth (before 37 gestational&#xD;
      weeks); spontaneous abortion; PE (as defined by the International Society for the Study of&#xD;
      Hypertension in Pregnancy; 25); IUGR; peri-partum hemorrhage.&#xD;
&#xD;
      Intra uterine growth restriction is defined as growth deviation of weight below 2 SD (-22% or&#xD;
      below 3rd quartile) at birth.&#xD;
&#xD;
      Post-partum TB is defined as confirmed or clinically diagnosed active TB within the 6 months&#xD;
      period following termination of pregnancy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 1, 2015</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">January 1, 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of adverse pregnancy outcomes</measure>
    <time_frame>2015-2023</time_frame>
    <description>Reports of pregnancy outcomes of participating women, collected and assessed during study follow-up and categorized with regard to normal or adverse pregnancy outcomes</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of active tuberculosis in participants during pregnancy, post-partum period and periods outside pregnancy, respectively</measure>
    <time_frame>2015-2023</time_frame>
    <description>Bacteriologically and/or clinically diagnosed cases of active tuberculosis during study follow-up, categorized with regard to timing in relation to pregnancy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pattern of child growth with regard to maternal tuberculosis infection status during pregnancy</measure>
    <time_frame>2016-2023</time_frame>
    <description>Growth curves of children born to participating women, recorded during study follow-up until 4 years of age</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of tuberculosis infection in Ethiopian infants during the first four years of life</measure>
    <time_frame>2021-2023</time_frame>
    <description>Latent and active tuberculosis at 4 years of age among children born to women in the study cohort</description>
  </secondary_outcome>
  <enrollment type="Actual">2120</enrollment>
  <condition>Tuberculosis</condition>
  <condition>Pregnancy Complications</condition>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Frozen aliquots of plasma samples stored at Adama Regional Laboratory, Ethiopia.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Participants are identified at antenatal care clinics at three public health facilities.&#xD;
        The study population consists of women of reproductive age who are identified and recruited&#xD;
        in antenatal care and followed until delivery and 4 years post-partum. Children born to&#xD;
        participants of the study are followed for 4 years after birth for assessment of survival,&#xD;
        growth and development.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pregnant women attending antenatal care at any of the study facilities&#xD;
&#xD;
          -  First antenatal care visit for current pregnancy&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
          -  Accepts HIV testing&#xD;
&#xD;
          -  Residence in uptake area during pregnancy period&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        -&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Pregnant women are eligible for inclusion</gender_description>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Per Bjorkman, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Lund University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Adama Health Center</name>
      <address>
        <city>Adama</city>
        <country>Ethiopia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adama Regional Hospital</name>
      <address>
        <city>Adama</city>
        <country>Ethiopia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gheda Health Center</name>
      <address>
        <city>Adama</city>
        <country>Ethiopia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Ethiopia</country>
  </location_countries>
  <reference>
    <citation>Getahun H, Sculier D, Sismanidis C, Grzemska M, Raviglione M. Prevention, diagnosis, and treatment of tuberculosis in children and mothers: evidence for action for maternal, neonatal, and child health services. J Infect Dis. 2012 May 15;205 Suppl 2:S216-27. doi: 10.1093/infdis/jis009. Epub 2012 Mar 22.</citation>
    <PMID>22448018</PMID>
  </reference>
  <reference>
    <citation>Grange J, Adhikari M, Ahmed Y, Mwaba P, Dheda K, Hoelscher M, Zumla A. Tuberculosis in association with HIV/AIDS emerges as a major nonobstetric cause of maternal mortality in Sub-Saharan Africa. Int J Gynaecol Obstet. 2010 Mar;108(3):181-3. doi: 10.1016/j.ijgo.2009.12.005. Epub 2010 Jan 13.</citation>
    <PMID>20070964</PMID>
  </reference>
  <reference>
    <citation>Jana N, Vasishta K, Saha SC, Ghosh K. Obstetrical outcomes among women with extrapulmonary tuberculosis. N Engl J Med. 1999 Aug 26;341(9):645-9. doi: 10.1056/NEJM199908263410903.</citation>
    <PMID>10460815</PMID>
  </reference>
  <reference>
    <citation>Mathad JS, Bhosale R, Sangar V, Mave V, Gupte N, Kanade S, Nangude A, Chopade K, Suryavanshi N, Deshpande P, Kulkarni V, Glesby MJ, Fitzgerald D, Bharadwaj R, Sambarey P, Gupta A. Pregnancy differentially impacts performance of latent tuberculosis diagnostics in a high-burden setting. PLoS One. 2014 Mar 21;9(3):e92308. doi: 10.1371/journal.pone.0092308. eCollection 2014.</citation>
    <PMID>24658103</PMID>
  </reference>
  <reference>
    <citation>Kothari A, Mahadevan N, Girling J. Tuberculosis and pregnancy--Results of a study in a high prevalence area in London. Eur J Obstet Gynecol Reprod Biol. 2006 May 1;126(1):48-55. doi: 10.1016/j.ejogrb.2005.07.025. Epub 2005 Sep 9.</citation>
    <PMID>16154251</PMID>
  </reference>
  <reference>
    <citation>Rustveld LO, Kelsey SF, Sharma R. Association between maternal infections and preeclampsia: a systematic review of epidemiologic studies. Matern Child Health J. 2008 Mar;12(2):223-42. doi: 10.1007/s10995-007-0224-1. Epub 2007 Jun 19.</citation>
    <PMID>17577649</PMID>
  </reference>
  <reference>
    <citation>Rowe JH, Ertelt JM, Way SS. Foxp3(+) regulatory T cells, immune stimulation and host defence against infection. Immunology. 2012 May;136(1):1-10. doi: 10.1111/j.1365-2567.2011.03551.x.</citation>
    <PMID>22211994</PMID>
  </reference>
  <reference>
    <citation>Espinal MA, Reingold AL, Lavandera M. Effect of pregnancy on the risk of developing active tuberculosis. J Infect Dis. 1996 Feb;173(2):488-91. doi: 10.1093/infdis/173.2.488.</citation>
    <PMID>8568319</PMID>
  </reference>
  <reference>
    <citation>Whittaker E, Kampmann B. Perinatal tuberculosis: new challenges in the diagnosis and treatment of tuberculosis in infants and the newborn. Early Hum Dev. 2008 Dec;84(12):795-9. doi: 10.1016/j.earlhumdev.2008.09.005. Epub 2008 Sep 27.</citation>
    <PMID>18823726</PMID>
  </reference>
  <reference>
    <citation>Bekker A, Du Preez K, Schaaf HS, Cotton MF, Hesseling AC. High tuberculosis exposure among neonates in a high tuberculosis and human immunodeficiency virus burden setting. Int J Tuberc Lung Dis. 2012 Aug;16(8):1040-6. doi: 10.5588/ijtld.11.0821. Epub 2012 Jun 12.</citation>
    <PMID>22691968</PMID>
  </reference>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>October 2, 2017</study_first_submitted>
  <study_first_submitted_qc>October 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 10, 2017</study_first_posted>
  <last_update_submitted>April 5, 2022</last_update_submitted>
  <last_update_submitted_qc>April 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 13, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Lund University</investigator_affiliation>
    <investigator_full_name>Per Bjorkman</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>tuberculosis</keyword>
  <keyword>pregnancy</keyword>
  <keyword>ethiopia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Pregnancy Complications</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03305991
org study id: LundU-2015
nct id: NCT03305991
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Women living in low-income countries are at elevated risk of death in connection to
      pregnancy, as well as infants born to women in such settings. It is probable that several
      factors are involved, such as poverty, lack of education and access to healthcare. Infectious
      diseases constitute important threats to maternal health in resource-limited settings.
      Tuberculosis (TB) is reported to be the third leading cause of maternal death globally.
      Furthermore, TB can be transmitted from mother to child during pregnancy, with high risk of
      severe consequences for the infant. Despite these data, neither the role of TB in relation to
      co-existing risk factors for adverse pregnancy outcomes, nor the mechanisms involved, are
      well understood. It is likely that TB interacts with other characteristics, in particular
      socio-economic condition and HIV infection, which could obscure associations between TB and
      pregnancy outcomes. For this reason, it is critical to design studies so that the independent
      role of TB can be deduced.

      This project aims to investigate how TB infection in women affects the risk of adverse
      pregnancy outcomes in relation to co-existing factors, and how exposure to TB infection may
      impact growth and development of infants born to women with TB. In addition, mechanisms in
      which TB and the immune system during pregnancy will be explored.

      The project is conducted at public health facilities in Ethiopia, where 2 000 women have been
      recruited during antenatal care. These women will be followed until 5 years after delivery,
      along with their offspring born during the study period. Detailed data is collected at
      inclusion and at study visits during follow-up, with submission of samples for TB testing and
      immunological analyses.

      Better knowledge on the characteristics of TB infection in association with pregnancy, and
      how TB affects maternal and child health, can be used to construct new guidelines for
      management of TB in women of fertile age. This may contribute to reductions in adverse
      pregnancy outcomes, including maternal and infant deaths.
Objective The overall objective of this project is to investigate longitudinal patterns and
      consequences of tuberculosis (TB) infection in a prospective cohort of women recruited during
      pregnancy. The relation between maternal TB infection and pregnancy outcomes, as well as
      infant health and development, will be evaluated over time.

      Specific aims

        1. To determine whether maternal TB infection is associated with adverse pregnancy outcomes

        2. To determine the excess risk of incident active TB during pregnancy and post-partum,
           with regard to the prevalence of latent TB infection at registration in antenatal care

        3. To investigate long-term health and survival in infants in relation to maternal TB and
           adverse pregnancy outcomes

      Methods Study setting and participants This project is conducted in public health facilities
      in the city of Adama, Central Ethiopia. Participants are recruited and followed at antenatal
      care (ANC) clinics until delivery. After delivery their children are followed at clinics for
      extended program for immunization (EPI); continued follow-up of the mothers after the first
      post-natal visit also takes place in these clinics.

      All study procedures, including interviews, physical examination, and collection of informed
      consent, are performed by health facility staff (nurses and midwives) in the respective
      clinics. Biological samples including blood and sputum are collected at the respective health
      facility laboratory. Study samples are transported to the Adama Regional Laboratory. At this
      laboratory, additional analyses and storage of plasma will be done.

      For supervision and monitoring of data collection, as well as for data entry, the project
      uses staff and infrastructure in a field research station which has been established in Adama
      since 2010 by the research group.

      Study procedure Both scheduled and unscheduled study visits can occur for participants in
      this project. Scheduled study visits coincide with routine antenatal and postnatal visits and
      visits at the EPI clinics for the infant's immunization following National guidelines.
      Unscheduled visits occur in case of symptoms suggestive of active TB (according to the study
      definitions) in the pregnant/postnatal/non-pregnant woman, or in the child, at any time in
      between these routine visits.

      Antenatal care visits At inclusion, structured information on socio-demographic conditions,
      education, occupation, and poverty indicators is collected; as well as medical history (in
      particular for obstetric, gynecological and TB-related details). Physical and obstetric
      examination is performed. Apart from the study procedures and investigations, participants
      will receive care according to current Ethiopian ANC guidelines.

      At the inclusion visit blood samples are obtained for routine care and for study specific
      investigations from all participants. At the health facility laboratory, the following
      analyses are performed: HIV rapid test, urine dipstick. Ten mL of venous blood is collected.
      This sample is used for analysis of complete blood count, blood/Rh group, syphilis serology,
      creatinine and fasting glucose. The remaining plasma is aliquoted and stored at -80° C for
      research analyses that are performed at the completion of inclusion. Blood is collected
      separately for QuantiFERON TB Plus (QFT) testing, in order to determine the prevalence of
      LTBI. For the last 500 women included in the study, QFT testing is repeated at the 3rd
      antenatal care visit. From HIV positive women blood for viral load and CD4 count is drawn at
      each scheduled visit pre- and post-delivery except from 2nd and 3rd antenatal care visit.

      Participants are followed up four times in accordance with WHO recommended focused antenatal
      visits until delivery or term of pregnancy. They are also instructed to contact the study
      clinic in between these visits in case of health-related events. In case of delivery (or
      other unintended termination of pregnancy) in another place than any of the study health
      facilities, they are asked to communicate this to their study site for further follow-up
      examinations.

      All participants with suspected active TB according to the study definition (irrespective of
      Quantiferon results) at enrolment and/or during follow up are asked to submit samples for
      bacteriological TB investigations. These encompass liquid culture, smear microscopy and PCR
      (using Xpert MTB/RIF technique). All these tests are performed on two consecutive morning
      sputum samples. Moreover, acquisition of blood for QuantiFERON testing is repeated for all
      women investigated for suspected active TB.

      Stored aliquots of Mtb-incubated plasma will be analyzed at the end of inclusion for
      potential blood biomarkers of TB infection during pregnancy. These analyses will be performed
      using ELISA and/or Luminex technique, and they will include the following markers of immune
      activation and inflammation: C-reactive protein (CRP), neopterin, soluble
      urokinase-plasminogen activator receptor (suPAR), interferon-inducible protein 10 (IP-10).

      Postpartum follow-up visits for women Further follow-up visits for women are scheduled for 6
      weeks and 9 months after delivery or termination of pregnancy, coinciding with the routine
      child visits for immunization. The first postnatal visit takes place at the ANC clinic,
      whereas all subsequent visits take place at the respective EPI clinics (where infant
      follow-up also occurs). At the 6 week postnatal visit details on delivery outcome are
      recorded.

      For investigation of long-term health effects after delivery, participants will be asked to
      come for further annual visits with similar assessments until 54 months after termination of
      pregnancy. At all follow-up visits symptoms and signs on physical examination will be
      recorded using structured questionnaires.

      At inclusion, and repeatedly on scheduled follow-up visits, participants are informed about
      symptoms and signs that may indicate active TB. Study subjects are instructed to contact the
      study site clinic (ANC during antenatal period, EPI during postnatal period) directly if they
      develop such symptoms for unscheduled study visits (in order to assess incident active TB
      during follow-up).

      At all visits, whether scheduled or unscheduled, bacteriological testing (smear microscopy,
      Xpert MTB/RIF assay, and liquid culture) is performed according to the study protocol in case
      study criteria for suspected active TB are met. These tests are performed on two morning
      sputum samples.

      In case study participants do not come for their scheduled study visits they are contacted by
      phone by the study site staff and/or the research study team. If the participant cannot be
      reached, her contact person is contacted by phone. At mid-time in between the scheduled
      visits, women are contacted by phone by a member of the local research team to assess whether
      any health events or symptoms compatible with TB have occurred.

      Repeated sampling for QFT testing will be performed for all women at 4 years after inclusion
      (irrespective of previous QFT results), with storage of incubated plasma for further analysis
      of immune markers of TB infection.

      Follow-up visits for infants If consent has been provided by the mother, infants are
      registered and included in a separate infant follow-up cohort as soon as possible after
      birth. Birth details, including delivery method, weight, length, APGAR score, and head
      circumference are registered at inclusion of the infant. Follow-up of included infants takes
      place in the EPI clinic at the respective study health facilities. Follow-up visits are
      scheduled at the same time interval as the mother, i.e. at 6 weeks and 9 months and
      subsequently at annual intervals congruent with the mothers until four and a half year after
      birth. The two first visits coincide with routine immunization visits. On all study visits,
      parameters of growth, nutritional and neurological development are recorded using structured
      questionnaires. In addition, data on socio-demographic characteristics, health-related events
      and feeding details are recorded, as well as data on known or suspected exposure to TB.

      At inclusion, and repeatedly on scheduled follow-up visits, caretakers are informed about
      symptoms and signs that may indicate active pediatric TB. Study infant caretakers are
      instructed to contact the study site EPI clinic directly if the infants develop such symptoms
      for unscheduled study visits (in order to assess incident active TB during follow-up).

      If criteria for suspected TB are met at any time during follow-up bacteriological
      investigations (liquid culture, PCR and microscopy) will be performed on gastric lavage
      specimens (or cerebrospinal fluid in case of suspected meningitis; or fine-needle lymph node
      aspirates in case of peripheral lymphadenopathy). These investigations will be performed by
      trained health care staff at the Department of Pediatrics, Adama Regional Hospital.

      Stored aliquots of plasma will be analyzed at the end of inclusion for potential blood
      biomarkers of TB in young children. These analyses will be performed using ELISA and Luminex
      technique, and they will include the following markers of immune activation and inflammation:
      C-reactive protein (CRP), neopterin, soluble urokinase-plasminogen activator receptor
      (suPAR).

      In case infant participants do not come for their scheduled study visits their caretakers are
      contacted by phone by the study site staff and/or the research study team. If the caretaker
      cannot be reached, the contact person is contacted by phone. At mid-time in between the
      scheduled visits, caretakers are contacted by phone from a study investigator to assess
      whether any health events or symptoms compatible with TB have occurred in the infant.

      Study definitions Suspected adult active TB is defined as any of the following symptoms or
      findings: Cough, fever, night sweating, weight loss (except following delivery), chest pain,
      reduced Karnofsky performance score (after pregnancy), peripheral lymph node enlargement,
      abdominal distension and/or abdominal mass (during study periods without pregnancy).

      Suspected pediatric active TB is defined as any of the following symptoms or findings: Cough,
      fever, night sweating, chest pain, peripheral lymph node enlargement, abdominal distension
      and/or mass, weight loss, poor growth development, failure to thrive, acute or chronic
      malnutrition, neck stiffness, seizures, and loss of consciousness Latent TB infection is
      defined as a positive QuantiFERON® TB Gold Plus result (according to the manufacturer's
      reference range), in the absence of confirmed active TB and/or national TB guideline criteria
      for clinically diagnosed TB.

      Confirmed active TB is defined as any subject with a positive bacteriological result (as per
      the national TB guideline), irrespective of clinical manifestations.

      Clinically diagnosed active TB is defined as any subject without positive bacteriological
      results for TB, but who fulfils national TB guideline criteria for clinically diagnosed TB,
      and who are referred for anti-TB treatment.

      Adverse pregnancy outcomes are defined as maternal or infant death following inclusion until
      3 months after unintended termination of pregnancy; preterm birth (before 37 gestational
      weeks); spontaneous abortion; PE (as defined by the International Society for the Study of
      Hypertension in Pregnancy; 25); IUGR; peri-partum hemorrhage.

      Intra uterine growth restriction is defined as growth deviation of weight below 2 SD (-22% or
      below 3rd quartile) at birth.

      Post-partum TB is defined as confirmed or clinically diagnosed active TB within the 6 months
      period following termination of pregnancy.
observational model: Cohort
time perspective: Prospective
measure: Incidence of adverse pregnancy outcomes
time frame: 2015-2023
description: Reports of pregnancy outcomes of participating women, collected and assessed during study follow-up and categorized with regard to normal or adverse pregnancy outcomes
measure: Incidence of active tuberculosis in participants during pregnancy, post-partum period and periods outside pregnancy, respectively
time frame: 2015-2023
description: Bacteriologically and/or clinically diagnosed cases of active tuberculosis during study follow-up, categorized with regard to timing in relation to pregnancy
measure: Pattern of child growth with regard to maternal tuberculosis infection status during pregnancy
time frame: 2016-2023
description: Growth curves of children born to participating women, recorded during study follow-up until 4 years of age
measure: Incidence of tuberculosis infection in Ethiopian infants during the first four years of life
time frame: 2021-2023
description: Latent and active tuberculosis at 4 years of age among children born to women in the study cohort
Frozen aliquots of plasma samples stored at Adama Regional Laboratory, Ethiopia.
study pop: 
sampling method: Probability Sample
criteria: 
gender: Female
gender based: Yes
gender description: Pregnant women are eligible for inclusion
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Per Bjorkman, MD, PhD
role: Principal Investigator
affiliation: Lund University
facility: 
facility: 
facility: 
country: Ethiopia
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PMID: 22448018
citation: Grange J, Adhikari M, Ahmed Y, Mwaba P, Dheda K, Hoelscher M, Zumla A. Tuberculosis in association with HIV/AIDS emerges as a major nonobstetric cause of maternal mortality in Sub-Saharan Africa. Int J Gynaecol Obstet. 2010 Mar;108(3):181-3. doi: 10.1016/j.ijgo.2009.12.005. Epub 2010 Jan 13.
PMID: 20070964
citation: Jana N, Vasishta K, Saha SC, Ghosh K. Obstetrical outcomes among women with extrapulmonary tuberculosis. N Engl J Med. 1999 Aug 26;341(9):645-9. doi: 10.1056/NEJM199908263410903.
PMID: 10460815
citation: Mathad JS, Bhosale R, Sangar V, Mave V, Gupte N, Kanade S, Nangude A, Chopade K, Suryavanshi N, Deshpande P, Kulkarni V, Glesby MJ, Fitzgerald D, Bharadwaj R, Sambarey P, Gupta A. Pregnancy differentially impacts performance of latent tuberculosis diagnostics in a high-burden setting. PLoS One. 2014 Mar 21;9(3):e92308. doi: 10.1371/journal.pone.0092308. eCollection 2014.
PMID: 24658103
citation: Kothari A, Mahadevan N, Girling J. Tuberculosis and pregnancy--Results of a study in a high prevalence area in London. Eur J Obstet Gynecol Reprod Biol. 2006 May 1;126(1):48-55. doi: 10.1016/j.ejogrb.2005.07.025. Epub 2005 Sep 9.
PMID: 16154251
citation: Rustveld LO, Kelsey SF, Sharma R. Association between maternal infections and preeclampsia: a systematic review of epidemiologic studies. Matern Child Health J. 2008 Mar;12(2):223-42. doi: 10.1007/s10995-007-0224-1. Epub 2007 Jun 19.
PMID: 17577649
citation: Rowe JH, Ertelt JM, Way SS. Foxp3(+) regulatory T cells, immune stimulation and host defence against infection. Immunology. 2012 May;136(1):1-10. doi: 10.1111/j.1365-2567.2011.03551.x.
PMID: 22211994
citation: Espinal MA, Reingold AL, Lavandera M. Effect of pregnancy on the risk of developing active tuberculosis. J Infect Dis. 1996 Feb;173(2):488-91. doi: 10.1093/infdis/173.2.488.
PMID: 8568319
citation: Whittaker E, Kampmann B. Perinatal tuberculosis: new challenges in the diagnosis and treatment of tuberculosis in infants and the newborn. Early Hum Dev. 2008 Dec;84(12):795-9. doi: 10.1016/j.earlhumdev.2008.09.005. Epub 2008 Sep 27.
PMID: 18823726
citation: Bekker A, Du Preez K, Schaaf HS, Cotton MF, Hesseling AC. High tuberculosis exposure among neonates in a high tuberculosis and human immunodeficiency virus burden setting. Int J Tuberc Lung Dis. 2012 Aug;16(8):1040-6. doi: 10.5588/ijtld.11.0821. Epub 2012 Jun 12.
PMID: 22691968
responsible party type: Principal Investigator
investigator affiliation: Lund University
investigator full name: Per Bjorkman
investigator title: Professor
mesh term: Tuberculosis
mesh term: Pregnancy Complications
sharing ipd: Undecided