Malformations
Conditions
Keywords
varenicline, smoking, smoking cessation, cohort study, drug safety, prospective study
Brief summary
A prospective population-based cohort study to examine whether varenicline use during pregnancy is associated with an increased risk of major congenital malformations in infants above that associated with smoking during pregnancy.
Detailed description
Sampling will not be employed. The data sources record nearly all (\>98.6%) births in Denmark and Sweden.
Interventions
DRUGvarenicline
This is a non-interventional study. Exposure in utero to varenicline is observed, not assigned.
BEHAVIORALcigarette smoke from maternal smoking
This is a non-interventional study. Exposure in utero to cigarette smoke from maternal smoking is observed, not assigned.
OTHERNon-Exposure
This is a non-interventional study. Non-exposure in utero to varenicline and cigarette smoke from maternal smoking is observed, not assigned.
Sponsors
University of Aarhus
Karolinska Institutet
Pfizer
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
All live and stillbirths between May 2007 and December 2012 in Denmark and Sweden.
Exclusion criteria
Births less than 22 weeks of gestation in Denmark and 28 weeks in Sweden are not recorded by the registers.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Infants With Major Congenital Malformations | For 12 months after birth | Major congenital malformations were defined as any codes within the Q-chapter of The Tenth Revision of the International Classification of Diseases (ICD-10), excluding certain minor anomalies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Infants With Stillbirths | At the time of birth | Stillbirth was defined as death at a gestational age of greater than or equal to (\>=) 22 weeks, with the exception that in Sweden prior to 2008 it was defined as death at a gestational age of \>=28 weeks. |
| Number of Infants Born Small for Gestational Age (SGA) | At the time of birth | An infant was defined as SGA if birth weight was below the 10th percentile of its sex-specific national distribution at the respective gestational week. Data on birth weight and gestational age from the medical birth registries were used to calculate the 10th percentiles for each sex based on all Danish and Swedish births during the study observation period. |
| Number of Infants Born Preterm | At the time of birth | Preterm birth was defined as birth before the gestational age of 37 weeks. |
| Number of Infants Born To Mothers Diagnosed With Premature Rupture of Membranes | At the time of birth | — |
| Number of Infants Diagnosed With Sudden Infant Death Syndrome (SIDS) | For 12 months after birth | Sudden Infant Death Syndrome (SIDS) was defined as a sudden unexplained death of an infant less than one year of age. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Varenicline Exposed Cohort Participants included infants who were exposed to varenicline in utero. | 335 |
| Varenicline Unexposed Cohort Participants included infants who were exposed to maternal smoking, but not to varenicline in utero. | 78,412 |
| Reference Cohort Participants included infants who were neither exposed to maternal smoking nor to varenicline in utero. | 806,438 |
| Total | 885,185 |
Baseline characteristics
| Characteristic | Varenicline Exposed Cohort | Total | Reference Cohort | Varenicline Unexposed Cohort |
|---|---|---|---|---|
| Age, Customized 32-36 weeks | 22 infants | 45616 infants | 40457 infants | 5137 infants |
| Age, Customized Greater Than or Equal to (>=) 37 weeks | 310 infants | 832255 infants | 759706 infants | 72239 infants |
| Age, Customized Less Than (<) 32 weeks | 3 infants | 7314 infants | 6275 infants | 1036 infants |
| Sex/Gender, Customized Female | 156 infants | 430955 infants | 392755 infants | 38044 infants |
| Sex/Gender, Customized Male | 179 infants | 453992 infants | 413485 infants | 40328 infants |
| Sex/Gender, Customized Unknown | 0 infants | 238 infants | 198 infants | 40 infants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Infants With Major Congenital Malformations
Major congenital malformations were defined as any codes within the Q-chapter of The Tenth Revision of the International Classification of Diseases (ICD-10), excluding certain minor anomalies.
Time frame: For 12 months after birth
Population: Analysis population included all live born infants in Denmark and Sweden from May 1, 2007 through December 31, 2012.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline Exposed Cohort | Number of Infants With Major Congenital Malformations | 12 infants |
| Varenicline Unexposed Cohort | Number of Infants With Major Congenital Malformations | 3382 infants |
| Reference Cohort | Number of Infants With Major Congenital Malformations | 33950 infants |
Comparison: Crude prevalence odds ratios were estimated along with 95% confidence intervals using logistic regression models.95% CI: [0.46, 1.47]
Comparison: Adjusted prevalence odds ratios were estimated along with 95% confidence intervals using logistic regression models.95% CI: [0.45, 1.42]
Secondary
Number of Infants Born Preterm
Preterm birth was defined as birth before the gestational age of 37 weeks.
Time frame: At the time of birth
Population: Analysis population included all infants born in Denmark and Sweden from May 1, 2007 through December 31, 2012.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline Exposed Cohort | Number of Infants Born Preterm | 25 infants |
| Varenicline Unexposed Cohort | Number of Infants Born Preterm | 6173 infants |
| Reference Cohort | Number of Infants Born Preterm | 46732 infants |
Comparison: Crude prevalence odds ratios were estimated along with 95% confidence intervals using logistic regression models.95% CI: [0.63, 1.42]
Comparison: Adjusted prevalence odds ratios were estimated along with 95% confidence intervals using logistic regression models.95% CI: [0.61, 1.37]
Secondary
Number of Infants Born Small for Gestational Age (SGA)
An infant was defined as SGA if birth weight was below the 10th percentile of its sex-specific national distribution at the respective gestational week. Data on birth weight and gestational age from the medical birth registries were used to calculate the 10th percentiles for each sex based on all Danish and Swedish births during the study observation period.
Time frame: At the time of birth
Population: Analysis population included all infants born in Denmark and Sweden from May 1, 2007 through December 31, 2012.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline Exposed Cohort | Number of Infants Born Small for Gestational Age (SGA) | 42 infants |
| Varenicline Unexposed Cohort | Number of Infants Born Small for Gestational Age (SGA) | 13433 infants |
| Reference Cohort | Number of Infants Born Small for Gestational Age (SGA) | 73135 infants |
Comparison: Crude prevalence odds ratios were estimated along with 95% confidence intervals using logistic regression models.95% CI: [0.5, 0.96]
Comparison: Adjusted prevalence odds ratios were estimated along with 95% confidence intervals using logistic regression models.95% CI: [0.51, 0.97]
Secondary
Number of Infants Born To Mothers Diagnosed With Premature Rupture of Membranes
Time frame: At the time of birth
Population: Analysis population included all infants born in Denmark and Sweden from May 1, 2007 through December 31, 2012.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline Exposed Cohort | Number of Infants Born To Mothers Diagnosed With Premature Rupture of Membranes | 12 infants |
| Varenicline Unexposed Cohort | Number of Infants Born To Mothers Diagnosed With Premature Rupture of Membranes | 4246 infants |
| Reference Cohort | Number of Infants Born To Mothers Diagnosed With Premature Rupture of Membranes | 30641 infants |
Comparison: Crude prevalence odds ratios were estimated along with 95% confidence intervals using logistic regression models.95% CI: [0.37, 1.16]
Comparison: Adjusted prevalence odds ratios were estimated along with 95% confidence intervals using logistic regression models.95% CI: [0.37, 1.16]
Secondary
Number of Infants Diagnosed With Sudden Infant Death Syndrome (SIDS)
Sudden Infant Death Syndrome (SIDS) was defined as a sudden unexplained death of an infant less than one year of age.
Time frame: For 12 months after birth
Population: Analysis population included all infants born in Denmark and Sweden from May 1, 2007 through December 31, 2012. Here, 'Number of participants analyzed' signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline Exposed Cohort | Number of Infants Diagnosed With Sudden Infant Death Syndrome (SIDS) | 0 infants |
| Varenicline Unexposed Cohort | Number of Infants Diagnosed With Sudden Infant Death Syndrome (SIDS) | 51 infants |
| Reference Cohort | Number of Infants Diagnosed With Sudden Infant Death Syndrome (SIDS) | 58 infants |
Secondary
Number of Infants With Stillbirths
Stillbirth was defined as death at a gestational age of greater than or equal to (\>=) 22 weeks, with the exception that in Sweden prior to 2008 it was defined as death at a gestational age of \>=28 weeks.
Time frame: At the time of birth
Population: Analysis population included all infants born in Denmark and Sweden from May 1, 2007 through December 31, 2012.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Varenicline Exposed Cohort | Number of Infants With Stillbirths | 1 infants |
| Varenicline Unexposed Cohort | Number of Infants With Stillbirths | 384 infants |
| Reference Cohort | Number of Infants With Stillbirths | 2418 infants |
Comparison: Crude prevalence odds ratios were estimated along with 95% confidence intervals using logistic regression models.95% CI: [0.09, 4.34]
Comparison: Adjusted prevalence odds ratios were estimated along with 95% confidence intervals using logistic regression models.95% CI: [0.09, 4.67]