Diphtheria
Conditions
Keywords
exposed and unexposed cohorts, post-marketing, maternal immunization, neonate related Adverse Events, Congenital anomaly, RefortrixTM, Pregnancy related Adverse Events
Brief summary
The purpose of this study is to assess the safety of RefortrixTM (Tdap) when administered during pregnancy in a maternal immunization program in Brazil.
Detailed description
In this retrospective cohort study the safety of RefortrixTM (Tdap) administered during pregnancy as part of the National immunization program in Brazil will be assessed by comparing the risk of pre-defined adverse events before and after introduction of the RefortrixTM (Tdap) maternal immunization program.
Interventions
BIOLOGICALCombined diphtheria, tetanus and tricomponent acellular pertussis vaccine [Refortrix (Tdap)]
Subjects were included in the Exposed cohort if they received Refortrix as part of the maternal immunization program in Brazil.
Sponsors
GlaxoSmithKline
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Subjects between 18 and 45 years of age at the time of pregnancy under consideration for the study, who deliver in the study centre. * Residents of the study area * Subjects who were compliant with the routine antenatal care including at least one ultrasound assessment report early in the pregnancy. * Subjects with the complete and relevant medical records available. Inclusion criteria for the Exposed cohort: * Subjects who received one dose of Refortrix vaccine in the recommended time period between 27 and 36 completed weeks of pregnancy (or as late as 20 days before delivery due date) as part of the maternal immunization program in Brazil, and according to the program recommendations from May 2015 onwards. * Subjects with appropriate vaccination records. Inclusion criteria for the Unexposed cohort: * Subjects who had delivered in the same hospital (study centre) before 01 September 2014 (September 2012-August 2014) and who did not receive Tdap vaccination during pregnancy to the best knowledge of the investigator.
Exclusion criteria
* Subjects who have been transferred to other specialised centres, where their medical records would be inaccessible for the study (private clinics, psychiatric or prison hospitals, other state hospitals, etc).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Pre-specified Neonate-related Outcomes, Resulting in Neonates Small for Their Gestational Age | After week 27 of pregnancy | Small for gestational age is defined as: Birth weight less than (\<) 10% for infants of same gestational age and gender in same population. |
| Number of Subjects Reporting Pregnancy-related Hypertension, Pre-eclampsia, Eclampsia, and HELLP Syndrome | After week 27 of pregnancy | Pregnancy-related hypertension is defined as: Blood pressure systolic higher than (\>) 140 and/or diastolic \> 90 millimetre of mercury (mmHg), documented in at least two separate measurements after 20 weeks of gestation, without proteinuria or other stigmata of pre-eclampsia, and returning to normal post-partum. Hypertension usually resolves by 12 weeks post-partum, included pre-eclampsia, eclampsia and haemolysis elevated liver enzymes low platelet (HELLP) Syndrome for this study. |
| Number of Subjects Reporting Pregnancy Hemorrhage | After week 27 of pregnancy | Pregnancy vaginal hemorrhage is defined as: excessive blood loss after delivery i.e. estimated blood loss in excess of 500 milliliters (ml) after vaginal delivery and estimated blood loss in excess of 1000 ml after Caesarean delivery. The other symptoms are higher than or equal to (≥) 10 percent (%) drop in hematocrit, need for blood transfusion, symptomatic hypotension, dizziness, pallor and oliguria. Vaginal or intrauterine hemorrhage that encompasses antepartum (i.e. bleeding from the genital tract after 24 weeks of gestation), intrapartum, and postpartum bleeding (i.e. within 24 hours post-delivery). A major obstetric hemorrhage is defined as blood loss from uterus or genital tract \>1500 ml or a decrease. |
| Number of Subjects With Pre-specified Neonate-related Outcomes Resulting in Preterm Birth | From week 27 up to week 37 of pregnancy | Preterm birth is defined as: Birth before 37 weeks of gestation. |
| Number of Subjects Reporting Gestational Diabetes | After week 27 of pregnancy | Gestational diabetes was defined as: Onset or first recognition of abnormal glucose tolerance during pregnancy (the diagnosis is based on administration of glucose challenge test at 24-28 weeks of gestation). Includes Class A1: Euglycaemia achieved with diet and/or exercise and Class A2: Euglycaemia achieved with medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Reporting Cases of Congenital Anomalies in the Neonates | From week 27 of pregnancy up to birth | Congenital anomalies include morphological, functional, chromosomal or genetic anomalies, regardless of whether detected at birth or not, the foetus is delivered dead or alive, or defects are identified by prenatal ultrasound, amniocentesis or examination of the products of conception. |
| Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | After week 27 of pregnancy | Pregnancy related AEs include: gestational diabetes, pregnancy-related hypertension, pre-eclampsia, eclampsia, HELLP Syndrome and pregnancy hemorrhage. Birth outcomes include: preterm birth and small for gestational age. |
| Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | After week 27 of pregnancy | Pregnancy-related AEs of interest and neonate-related events are defined as: premature rupture of membranes, preterm premature rupture of membranes, premature uterine contraction, neonatal death, maternal death, still birth, neonatal hypoxic ischaemic encephalopathy. |
Countries
Brazil
Participant flow
Recruitment details
A total of 2462 subjects were enrolled in the study in one center in Brazil.
Participants by arm
| Arm | Count |
|---|---|
| Exposed Cohort Women, 18-45 years of age at the time of pregnancy, who delivered in the hospital (study centre) from May 2015 and who received one dose of Refortrix during 27 to 36 weeks of pregnancy (or as late as 20 days before delivery due date). | 1,203 |
| Unexposed Cohort Women, 18-45 years of age at the time of pregnancy, who delivered in the hospital (study centre) before implementation of the maternal immunization program in Brazil in September 2014 and who did not receive Tdap vaccination during pregnancy. | 1,259 |
| Total | 2,462 |
Baseline characteristics
| Characteristic | Exposed Cohort | Unexposed Cohort | Total |
|---|---|---|---|
| Age, Continuous | 26.49 Years STANDARD_DEVIATION 6.15 | 26.28 Years STANDARD_DEVIATION 6.24 | 26.38 Years STANDARD_DEVIATION 6.2 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 1203 Participants | 1259 Participants | 2462 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Subjects Reporting Gestational Diabetes
Gestational diabetes was defined as: Onset or first recognition of abnormal glucose tolerance during pregnancy (the diagnosis is based on administration of glucose challenge test at 24-28 weeks of gestation). Includes Class A1: Euglycaemia achieved with diet and/or exercise and Class A2: Euglycaemia achieved with medication.
Time frame: After week 27 of pregnancy
Population: Analysis was performed on the Total Cohort (TC), which included all the subjects enrolled in the study with symptom sheets filled-in.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Exposed Cohort | Number of Subjects Reporting Gestational Diabetes | 10 Participants |
| Unexposed Cohort | Number of Subjects Reporting Gestational Diabetes | 22 Participants |
Comparison: The analysis contained only the subjects with vaccination date in the Exposed cohort and subjects from the Unexposed cohort.p-value: 0.114795% CI: [0.259, 1.157]Regression, Logistic
Primary
Number of Subjects Reporting Pregnancy Hemorrhage
Pregnancy vaginal hemorrhage is defined as: excessive blood loss after delivery i.e. estimated blood loss in excess of 500 milliliters (ml) after vaginal delivery and estimated blood loss in excess of 1000 ml after Caesarean delivery. The other symptoms are higher than or equal to (≥) 10 percent (%) drop in hematocrit, need for blood transfusion, symptomatic hypotension, dizziness, pallor and oliguria. Vaginal or intrauterine hemorrhage that encompasses antepartum (i.e. bleeding from the genital tract after 24 weeks of gestation), intrapartum, and postpartum bleeding (i.e. within 24 hours post-delivery). A major obstetric hemorrhage is defined as blood loss from uterus or genital tract \>1500 ml or a decrease.
Time frame: After week 27 of pregnancy
Population: Analysis was performed on the Total Cohort (TC), which included all the subjects enrolled in the study with symptom sheets filled-in.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Exposed Cohort | Number of Subjects Reporting Pregnancy Hemorrhage | 4 Participants |
| Unexposed Cohort | Number of Subjects Reporting Pregnancy Hemorrhage | 19 Participants |
Comparison: The analysis contained only the subjects with vaccination date in the Exposed cohort and subjects from the Unexposed cohort.p-value: 0.012795% CI: [0.086, 0.746]Regression, Logistic
Primary
Number of Subjects Reporting Pregnancy-related Hypertension, Pre-eclampsia, Eclampsia, and HELLP Syndrome
Pregnancy-related hypertension is defined as: Blood pressure systolic higher than (\>) 140 and/or diastolic \> 90 millimetre of mercury (mmHg), documented in at least two separate measurements after 20 weeks of gestation, without proteinuria or other stigmata of pre-eclampsia, and returning to normal post-partum. Hypertension usually resolves by 12 weeks post-partum, included pre-eclampsia, eclampsia and haemolysis elevated liver enzymes low platelet (HELLP) Syndrome for this study.
Time frame: After week 27 of pregnancy
Population: Analysis was performed on the Total Cohort (TC), which included all the subjects enrolled in the study with symptom sheets filled-in.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Exposed Cohort | Number of Subjects Reporting Pregnancy-related Hypertension, Pre-eclampsia, Eclampsia, and HELLP Syndrome | Pre-eclampsia | 10 Participants |
| Exposed Cohort | Number of Subjects Reporting Pregnancy-related Hypertension, Pre-eclampsia, Eclampsia, and HELLP Syndrome | HELLP syndrome | 0 Participants |
| Exposed Cohort | Number of Subjects Reporting Pregnancy-related Hypertension, Pre-eclampsia, Eclampsia, and HELLP Syndrome | Eclampsia | 2 Participants |
| Exposed Cohort | Number of Subjects Reporting Pregnancy-related Hypertension, Pre-eclampsia, Eclampsia, and HELLP Syndrome | Pregnancy-related hypertension | 11 Participants |
| Unexposed Cohort | Number of Subjects Reporting Pregnancy-related Hypertension, Pre-eclampsia, Eclampsia, and HELLP Syndrome | Eclampsia | 0 Participants |
| Unexposed Cohort | Number of Subjects Reporting Pregnancy-related Hypertension, Pre-eclampsia, Eclampsia, and HELLP Syndrome | Pre-eclampsia | 30 Participants |
| Unexposed Cohort | Number of Subjects Reporting Pregnancy-related Hypertension, Pre-eclampsia, Eclampsia, and HELLP Syndrome | Pregnancy-related hypertension | 31 Participants |
| Unexposed Cohort | Number of Subjects Reporting Pregnancy-related Hypertension, Pre-eclampsia, Eclampsia, and HELLP Syndrome | HELLP syndrome | 1 Participants |
Comparison: The analysis contained only the subjects with vaccination date in the Exposed cohort and subjects from the Unexposed cohort.p-value: 0.015595% CI: [0.215, 0.851]Regression, Logistic
Primary
Number of Subjects With Pre-specified Neonate-related Outcomes, Resulting in Neonates Small for Their Gestational Age
Small for gestational age is defined as: Birth weight less than (\<) 10% for infants of same gestational age and gender in same population.
Time frame: After week 27 of pregnancy
Population: Analysis was performed on the Total Cohort (TC), which included all the subjects enrolled in the study with symptom sheets filled-in.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Exposed Cohort | Number of Subjects With Pre-specified Neonate-related Outcomes, Resulting in Neonates Small for Their Gestational Age | 69 Participants |
| Unexposed Cohort | Number of Subjects With Pre-specified Neonate-related Outcomes, Resulting in Neonates Small for Their Gestational Age | 62 Participants |
Comparison: The analysis contained only the subjects with vaccination date in the Exposed cohort and subjects from the Unexposed cohort.p-value: 0.093195% CI: [0.952, 1.89]Regression, Logistic
Primary
Number of Subjects With Pre-specified Neonate-related Outcomes Resulting in Preterm Birth
Preterm birth is defined as: Birth before 37 weeks of gestation.
Time frame: From week 27 up to week 37 of pregnancy
Population: Analysis was performed on the Total Cohort (TC), which included all the subjects enrolled in the study with symptom sheets filled-in.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Exposed Cohort | Number of Subjects With Pre-specified Neonate-related Outcomes Resulting in Preterm Birth | 64 Participants |
| Unexposed Cohort | Number of Subjects With Pre-specified Neonate-related Outcomes Resulting in Preterm Birth | 121 Participants |
Comparison: The analysis contained only the subjects with vaccination date in the Exposed cohort and subjects from the Unexposed cohort.p-value: 0.003695% CI: [0.471, 0.863]Regression, Logistic
Secondary
Number of Subjects Reporting Cases of Congenital Anomalies in the Neonates
Congenital anomalies include morphological, functional, chromosomal or genetic anomalies, regardless of whether detected at birth or not, the foetus is delivered dead or alive, or defects are identified by prenatal ultrasound, amniocentesis or examination of the products of conception.
Time frame: From week 27 of pregnancy up to birth
Population: Analysis was performed on the Total Cohort (TC), which included all the subjects enrolled in the study with symptom sheets filled-in.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Exposed Cohort | Number of Subjects Reporting Cases of Congenital Anomalies in the Neonates | 3 Participants |
| Unexposed Cohort | Number of Subjects Reporting Cases of Congenital Anomalies in the Neonates | 22 Participants |
Secondary
Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery
Pregnancy-related AEs of interest and neonate-related events are defined as: premature rupture of membranes, preterm premature rupture of membranes, premature uterine contraction, neonatal death, maternal death, still birth, neonatal hypoxic ischaemic encephalopathy.
Time frame: After week 27 of pregnancy
Population: Analysis was performed on the Total Cohort (TC), which included all the subjects enrolled in the study with symptom sheets filled-in.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Exposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Premature uterine contractions | 32 Participants |
| Exposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Maternal death | 0 Participants |
| Exposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Preterm premature rupture of membranes | 17 Participants |
| Exposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Still births | 1 Participants |
| Exposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Neonatal death | 0 Participants |
| Exposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Neonatal hypoxic ischaemic encephalopathy | 0 Participants |
| Exposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Premature rupture of membranes | 190 Participants |
| Unexposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Neonatal hypoxic ischaemic encephalopathy | 0 Participants |
| Unexposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Premature rupture of membranes | 261 Participants |
| Unexposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Preterm premature rupture of membranes | 36 Participants |
| Unexposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Premature uterine contractions | 54 Participants |
| Unexposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Neonatal death | 8 Participants |
| Unexposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Maternal death | 0 Participants |
| Unexposed Cohort | Number of Subjects Reporting Pregnancy-related Adverse Events (AEs) of Interest/Neonate-related Events up to Delivery | Still births | 6 Participants |
Secondary
Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year
Pregnancy related AEs include: gestational diabetes, pregnancy-related hypertension, pre-eclampsia, eclampsia, HELLP Syndrome and pregnancy hemorrhage. Birth outcomes include: preterm birth and small for gestational age.
Time frame: After week 27 of pregnancy
Population: Analysis was performed on the Unexposed Cohort which included women pregnant before implementation of the maternal immunization program, who didn't receive Refortrix, the study vaccine.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Eclampsia, Sep2012-Aug2013 | 0 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Gestational diabetes, Sep2012-Aug2013 | 10 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Gestational diabetes, Sep2013-Aug2014 | 12 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Pregnancy-related hypertension, Sep2012-Aug2013 | 14 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Pregnancy-related hypertension, Sep2013-Aug2014 | 17 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Vaginal hemorrhage, Sep2012-Aug2013 | 16 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Vaginal hemorrhage, Sep2013-Aug2014 | 3 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Preterm birth, Sep2012-Aug2013 | 66 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Preterm birth, Sep2013-Aug2014 | 55 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Small for gestational age, Sep2012-Aug2013 | 31 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Small for gestational age, Sep2013-Aug2014 | 31 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Pre-Eclampsia, Sep2012-Aug2013 | 13 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Pre-Eclampsia, Sep2013-Aug 2014 | 17 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | Eclampsia, Sep2013-Aug 2014 | 0 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | HELLP Syndrome, Sep2012-Aug2013 | 1 Participants |
| Exposed Cohort | Number of Subjects With Pregnancy-related AEs and Birth Outcomes Per Calendar Year | HELLP Syndrome, Sep2013-Aug 2014 | 0 Participants |