The Intergenerational Transfer of Mental Disorders: A Population-Based Multigenerational Linkage Study: Le transfert intergénérationnel des troubles mentaux : une étude sur les liens multigénérationnels basée sur la population.

OBJECTIVES: The aetiology of mental disorders involves genetic and environmental factors, both reflected in family health history. We examined the intergenerational transmission of multiple mental disorders from parents and grandparents using population-based, objectively measured family histories. METHODS: This population-based retrospective cohort study used administrative healthcare databases in Manitoba, Canada and included adults living in Manitoba from 1977 to 2020 with linkages to at least one parent and one grandparent. Index date was when individuals turned 18 or 1 April 1977, whichever occurred later. Mental disorder diagnoses (mood and anxiety, substance use and psychotic disorders) were identified in individuals, parents and grandparents from hospitalization and outpatient records. Cox proportional hazards regression models included sociodemographic characteristics, individual's comorbidity and mental disorder history in a grandparent, mother and father. RESULTS: Of 109,359 individuals with no mental disorder prior to index date, 47.1% were female, 36.3% had a mental disorder during follow-up, and 90.9% had a parent or grandparent with a history of a mental disorder prior to the index date. Both paternal and maternal history of a mental disorder increased the risk of the disorder in individuals. Psychotic disorders had the strongest association with parental history and were mostly influenced by paternal (hazards ratio [HR] 3.73, 95% confidence interval [CI] 2.99 to 4.64) compared to maternal history (HR 2.23, 95% CI, 1.89 to 2.64). Grandparent history was independently associated with the risk of all mental disorders but had the strongest influence on substance use disorders (HR 1.42, 95% CI, 1.34 to 1.50). CONCLUSIONS: Parental history of mental disorders was associated with an increased risk of all mental disorders. Grandparent history of mental disorders was associated with a small risk increase of the disorders above and beyond parental history influence. This three-generation study further highlights the need for family-based interventional programs in families affected by mental disorders. PLAIN LANGUAGE SUMMARY TITLE: The Intergenerational Transfer of Mental Illnesses.

ObjectivesBoth genetics and environmental factors, such as poverty, maltreatment and parental education, have a role in the development of mental illnesses. Some genetic and environmental risk factors for mental illnesses are shared within families. We conducted a large study to test the extent to which mental illnesses are passed down through generations.MethodsThis study used healthcare data from Manitoba, Canada captured during the delivery of healthcare services for administrative purposes. These data included all adults from 1977 to 2020 who had at least one parent and one grandparent with linked data. Mental illnesses were diagnosed in individuals, parents and grandparents by doctors during hospitalizations or physician visits. The illnesses included mood and anxiety, substance use, and psychotic illnesses. We estimated the likelihood of developing a mental illness when parents and/or grandparents had a mental illness as well.ResultsThe study included 109,359 individuals; a third developed a mental illness during the study period. The majority had a history of a mental illness in a parent or grandparent. We found that a history of mental illness in a mother and father increased the chance of developing the illness. Psychotic illnesses had the strongest relation with parental history. In particular, having a father with a psychotic illness increased the chance of developing the illness by four times. The likelihood of developing a mental illness was higher if a grandparent had a mental illness, above and beyond parental history influence, particularly for substance use disorders.ConclusionsHaving a parent or grandparent with a mental illness increases an individual's chance of developing a mental illness. Family-based intervention programs are needed to support families affected by mental illnesses in coping with their heavy burden.

Developing a prediction model of children asthma risk using population-based family history health records.

BACKGROUND: Identifying children at high risk of developing asthma can facilitate prevention and early management strategies. We developed a prediction model of children's asthma risk using objectively collected population-based children and parental histories of comorbidities. METHODS: We conducted a retrospective population-based cohort study using administrative data from Manitoba, Canada, and included children born from 1974 to 2000 with linkages to ≥1 parent. We identified asthma and prior comorbid condition diagnoses from hospital and outpatient records. We used two machine-learning models: least absolute shrinkage and selection operator (LASSO) logistic regression (LR) and random forest (RF) to identify important predictors. The predictors in the base model included children's demographics, allergic conditions, respiratory infections, and parental asthma. Subsequent models included additional multiple comorbidities for children and parents. RESULTS: The cohort included 195,666 children: 51.3% were males and 17.7% had asthma diagnosis. The base LR model achieved a low predictive performance with sensitivity of 0.47, 95% confidence interval (0.45-0.48), and specificity of 0.67 (0.66-0.67) using a predicted probability threshold of 0.20. Sensitivity significantly improved when children's comorbidities were included using LASSO LR: 0.71 (0.69-0.72). Predictive performance further improved by including parental comorbidities (sensitivity = 0.72 [0.70-0.73], specificity = 0.69 [0.69-0.70]). We observed similar results for the RF models. Children's menstrual disorders and mood and anxiety disorders, parental lipid metabolism disorders and asthma were among the most important variables that predicted asthma risk. CONCLUSION: Including children and parental comorbidities to children's asthma prediction models improves their accuracy.

Familial associations in adolescent substance use disorder: a population-based cohort study.

BACKGROUND AND AIMS: Family history of substance use disorder (SUD) affects a child's risk of the disorder through both genetic and shared environmental factors. We aimed to estimate the association between parental or older sibling SUD history with the risk of adolescent SUD diagnosis. DESIGN, SETTING AND PARTICIPANTS: We conducted a population-based cohort study using administrative health-care databases in the Province of Manitoba, Canada, which has a universal and publicly funded health-care system. We included all children born from 1984 to 2000 who have linkages to both parents and were followed until age 18 years. We used generalized estimating equation models to produce unadjusted and adjusted relative risk (RR) estimates of adolescent SUD risk. The study cohort included 134 389 children and 31 307 full sibling pairs; 51.3% were male and 35.4% first-born. MEASUREMENTS: The exposure was SUD diagnosis in a mother or father in either hospitalization or outpatient physician visit records before the children's age of 13 years. The secondary exposure was an adolescent SUD diagnosis in an older full sibling. The outcome was SUD diagnosis during adolescence (13 and 18 years of age) identified in either hospitalization or physician visit records. Children demographics and characteristics associated with SUD diagnosis were included in the models. FINDINGS: Of the 134 389 children, 9.5% had a mother with a history of SUD, 11.3% had a father and 1.3% had an older sibling with a history of SUD diagnosis; 2566 (1.9%) had an adolescent SUD diagnosis. An increased risk of adolescent SUD was observed with SUD history in mothers [adjusted RR (aRR) = 2.50; 95% confidence interval (CI) = 2.26, 2.79], fathers (aRR = 2.15; 95% CI = 1.95, 2.37), both parents (aRR = 3.74; 95% CI = 3.24, 4.31) and older sibling (aRR = 3.85; 95% CI = 2.53, 5.87). CONCLUSIONS: A family history of substance use disorder in parents or older siblings appears to be associated with increased SUD risk in adolescents.

Record linkage and big data-enhancing information and improving design.

BACKGROUND AND OBJECTIVES: To highlight the potential of multiple file record linkage. Linkage increases the value of existing information by supplying missing data or correcting errors in existing data, through generating important covariates, and by using family information to control for unmeasured variables and expand research opportunities. METHODS: Recent Manitoba papers highlight the use of linkage to produce better studies. Specific ways in which linkage helps deal with different substantive issues are described. RESULTS: Wide data files-files containing considerable amounts of information on each individual-generated by linkage improve research by facilitating better design. Nonexperimental work in particular benefits from such linkages. Population registries are especially valuable in supplying family data to facilitate work across different substantive fields. CONCLUSION: Several examples show how record linkage magnifies the value of information from individual projects. The results of observational studies become more defensible through the better designs facilitated by such linkage.

Transitions between versions of the International Classification of Diseases and chronic disease prevalence estimates from administrative health data: a population-based study.

BACKGROUND: Diagnosis codes in administrative health data are routinely used to monitor trends in disease prevalence and incidence. The International Classification of Diseases (ICD), which is used to record these diagnoses, have been updated multiple times to reflect advances in health and medical research. Our objective was to examine the impact of transitions between ICD versions on the prevalence of chronic health conditions estimated from administrative health data. METHODS: Study data (i.e., physician billing claims, hospital records) were from the province of Manitoba, Canada, which has a universal healthcare system. ICDA-8 (with adaptations), ICD-9-CM (clinical modification), and ICD-10-CA (Canadian adaptation; hospital records only) codes are captured in the data. Annual study cohorts included all individuals 18 + years of age for 45 years from 1974 to 2018. Negative binomial regression was used to estimate annual age- and sex-adjusted prevalence and model parameters (i.e., slopes and intercepts) for 16 chronic health conditions. Statistical control charts were used to assess the impact of changes in ICD version on model parameter estimates. Hotelling's T2 statistic was used to combine the parameter estimates and provide an out-of-control signal when its value was above a pre-specified control limit. RESULTS: The annual cohort sizes ranged from 360,341 to 824,816. Hypertension and skin cancer were among the most and least diagnosed health conditions, respectively; their prevalence per 1,000 population increased from 40.5 to 223.6 and from 0.3 to 2.1, respectively, within the study period. The average annual rate of change in prevalence ranged from -1.6% (95% confidence interval [CI]: -1.8, -1.4) for acute myocardial infarction to 14.6% (95% CI: 13.9, 15.2) for hypertension. The control chart indicated out-of-control observations when transitioning from ICDA-8 to ICD-9-CM for 75% of the investigated chronic health conditions but no out-of-control observations when transitioning from ICD-9-CM to ICD-10-CA. CONCLUSIONS: The prevalence of most of the investigated chronic health conditions changed significantly in the transition from ICDA-8 to ICD-9-CM. These results point to the importance of considering changes in ICD coding as a factor that may influence the interpretation of trend estimates for chronic health conditions derived from administrative health data.

Association Between Parental Type 1 and Type 2 Diabetes Diagnosis and Major Osteoporotic Fracture Risk in Adult Offspring: A Population-Based Cohort Study.

OBJECTIVES: Previous research suggests an intergenerational influence of diabetes on bone health. We examined the association between parental diabetes and major osteoporotic fracture (MOF) risk in offspring. METHODS: This population-based cohort study used de-identified administrative health data from Manitoba, Canada, which capture population-level records of hospitalizations, physician visits and drug dispensations. The cohort included individuals ≥40 years of age with at least 1 parent identified in the data between 1997 and 2015. The exposure was parental diagnosis of diabetes since 1970; the outcome was offspring incident MOF diagnosis of the hip, forearm, spine or humerus. Both measures were identified from hospital and physician visit records using validated case definitions. Multivariable Cox proportional hazards regression models tested the association of parental diabetes and offspring MOF risk. RESULTS: The cohort included 279,085 offspring; 48.5% were females and 86.8% were ≤44 years of age. Both parents were identified for 89.4% of the cohort; 36.7% had a parental diabetes diagnosis. During a median follow up of 12.0 (interquartile range, 6.0 to 18.0) years, 8,762 offspring had an MOF diagnosis. After adjusting for fracture risk factors, parental diabetes diagnosis was not associated with MOF risk, whether diagnosed in fathers (adjusted hazard ratio [aHR], 1.02; 95% confidence interval [CI], 0.97 to 1.08), mothers (aHR, 1.02; 95% CI, 0.97 to 1.07) or both parents (aHR, 1.01; 95% CI, 0.93 to 1.11). The results remained consistent in a stratified analysis by offspring sex, secondary analysis based on MOF site and sensitivity analyses. CONCLUSIONS: The results indicate parental diabetes is not associated with offspring MOF risk.

Multigenerational health research using population-based linked databases: an international review.

Family health history is a well-established risk factor for many health conditions but the systematic collection of health histories, particularly for multiple generations and multiple family members, can be challenging. Routinely-collected electronic databases in a select number of sites worldwide offer a powerful tool to conduct multigenerational health research for entire populations. At these sites, administrative and healthcare records are used to construct familial relationships and objectively-measured health histories. We review and synthesize published literature to compare the attributes of routinely-collected, linked databases for three European sites (Denmark, Norway, Sweden) and three non-European sites (Canadian province of Manitoba, Taiwan, Australian state of Western Australia) with the capability to conduct population-based multigenerational health research. Our review found that European sites primarily identified family structures using population registries, whereas non-European sites used health insurance registries (Manitoba and Taiwan) or linked data from multiple sources (Western Australia). Information on familial status was reported to be available as early as 1947 (Sweden); Taiwan had the fewest years of data available (1995 onwards). All centres reported near complete coverage of familial relationships for their population catchment regions. Challenges in working with these data include differentiating biological and legal relationships, establishing accurate familial linkages over time, and accurately identifying health conditions. This review provides important insights about the benefits and challenges of using routinely-collected, population-based linked databases for conducting population-based multigenerational health research, and identifies opportunities for future research within and across the data-intensive environments at these six sites.

Mapping three versions of the international classification of diseases to categories of chronic conditions.

INTRODUCTION: Administrative health data capture diagnoses using the International Classification of Diseases (ICD), which has multiple versions over time. To facilitate longitudinal investigations using these data, we aimed to map diagnoses identified in three ICD versions - ICD-8 with adaptations (ICDA-8), ICD-9 with clinical modifications (ICD-9-CM), and ICD-10 with Canadian adaptations (ICD-10-CA) - to mutually exclusive chronic health condition categories adapted from the open source Clinical Classifications Software (CCS). METHODS: We adapted the CCS crosswalk to 3-digit ICD-9-CM codes for chronic conditions and resolved the one-to-many mappings in ICD-9-CM codes. Using this adapted CCS crosswalk as the reference and referring to existing crosswalks between ICD versions, we extended the mapping to ICDA-8 and ICD-10-CA. Each mapping step was conducted independently by two reviewers and discrepancies were resolved by consensus through deliberation and reference to prior research. We report the frequencies, agreement percentages and 95% confidence intervals (CI) from each step. RESULTS: We identified 354 3-digit ICD-9-CM codes for chronic conditions. Of those, 77 (22%) codes had one-to-many mappings; 36 (10%) codes were mapped to a single CCS category and 41 (12%) codes were mapped to combined CCS categories. In total, the codes were mapped to 130 adapted CCS categories with an agreement percentage of 92% (95% CI: 86%-98%). Then, 321 3-digit ICDA-8 codes were mapped to CCS categories with an agreement percentage of 92% (95% CI: 89%-95%). Finally, 3583 ICD-10-CA codes were mapped to CCS categories; 111 (3%) had a fair or poor mapping quality; these were reviewed to keep or move to another category (agreement percentage = 77% [95% CI: 69%-85%]). CONCLUSIONS: We developed crosswalks for three ICD versions (ICDA-8, ICD-9-CM, and ICD-10-CA) to 130 clinically meaningful categories of chronic health conditions by adapting the CCS classification. These crosswalks will benefit chronic disease studies spanning multiple decades of administrative health data.

Prenatal antibiotic exposure and risk of attention-deficit/hyperactivity disorder: a population-based cohort study.

BACKGROUND: Abnormal microbiota composition induced by prenatal exposure to antibiotics has been proposed as a potential contributor to the development of attention-deficit/hyperactivity disorder (ADHD). We examined the association between prenatal antibiotic exposure and risk of ADHD. METHODS: We conducted a population-based retrospective cohort study of children born in Manitoba, Canada, between 1998 and 2017 and their mothers. We defined exposure as the mother having filled 1 or more antibiotic prescriptions during pregnancy. The outcome was diagnosis of ADHD in the offspring, as identified in administrative databases. We estimated hazard ratios (HRs) using Cox proportional hazards regression in the overall cohort, in a separate cohort matched on high-dimensional propensity scores and in a sibling cohort. RESULTS: In the overall cohort, consisting of 187 605 children, prenatal antibiotic dispensation was associated with increased risk of ADHD (HR 1.22, 95% confidence interval [CI] 1.18-1.26). Similar results were observed in the matched cohort of 129 674 children (HR 1.20, 95% CI 1.15-1.24) but not in the sibling cohort (HR 1.06, 95% CI 0.99-1.13). Two negative-control analyses indicated a positive association with ADHD despite the lack of a reasonable biological mechanism, which suggested that the observed association between prenatal antibiotic dispensation and risk of ADHD was likely due to confounding. INTERPRETATION: In our study, prenatal antibiotic exposure was not associated with increased risk of ADHD in children. Although the risk was higher in the overall and matched cohorts, it was likely overestimated because of unmeasured confounding. Future studies are warranted to examine other factors affecting microbiota composition in association with risk of ADHD.

Antibiotic Exposure in the First Year of Life and the Risk of Attention-Deficit/Hyperactivity Disorder: A Population-Based Cohort Study.

Early childhood antibiotic exposure induces changes in gut microbiota reportedly associated with the development of attention-deficit/hyperactivity disorder (ADHD). We conducted a population-based cohort study to examine the association between antibiotic use in the first year of life and ADHD risk. We included children born in Manitoba, Canada, between 1998 and 2017. Exposure was defined as having filled 1 or more antibiotic prescriptions during the first year of life. ADHD diagnosis was identified in hospital abstracts, physician visits, or drug dispensations. Risk of developing ADHD was estimated using Cox proportional hazards regression in a high-dimensional propensity score-matched cohort (n = 69,738) and a sibling cohort (n = 67,671). ADHD risk was not associated with antibiotic exposure in the matched-cohort (hazard ratio = 1.02, 95% confidence interval: 0.97, 1.08) or in the sibling cohort (hazard ratio = 0.96, 95% confidence interval: 0.89, 1.03). In secondary analyses of the matched cohort, ADHD risk increase was observed in those exposed to 4 or more antibiotic courses or a duration longer than 3 weeks. These associations were not observed in the sibling cohort. We concluded that antibiotic exposure in the first year of life does not pose an ADHD risk on a population level.

Prenatal antibiotics exposure and the risk of autism spectrum disorders: A population-based cohort study.

BACKGROUND: Prenatal antibiotic exposure induces changes in infants' gut microbiota composition and is suggested as a possible contributor in the development of autism spectrum disorders (ASD). In this study, we examined the association between prenatal antibiotic exposure and the risk of ASD. METHODS: This was a population-based cohort study utilizing the Manitoba Population Research Data Repository. The cohort included 214 834 children born in Manitoba, Canada between April 1, 1998 and March 31, 2016. Exposure was defined as having filled one or more antibiotic prescription during pregnancy. The outcome was autism spectrum disorder diagnosis. Multivariable Cox proportional hazards regression was used to estimate the risk of developing ASD in the overall cohort and in a sibling cohort. RESULTS: Of all subjects, 80 750 (37.6%) were exposed to antibiotics prenatally. During follow-up, 2965 children received an ASD diagnosis. Compared to children who were not exposed to antibiotics prenatally, those who were exposed had a higher risk of ASD: (adjusted HR 1.10 [95% CI 1.01, 1.19]). The association was observed in those exposed to antibiotics in the second or third trimester (HR 1.11 [95% CI 1.01, 1.23] and 1.17 [95% CI 1.06, 1.30], respectively). In the siblings' cohort, ASD risk estimate remained unchanged (adjusted HR 1.08 [95% CI 0.90, 1.30], although it was not statistically significant. CONCLUSIONS: Prenatal antibiotic exposure is associated with a small increase in the risk of ASD. Given the potential of residual confounding beyond what it was controlled through our study design and because of possible confounding by indication, such a small risk increase in the population is not expected to be clinically significant.

Annual trends in prevalence and incidence of autism spectrum disorders in Manitoba preschoolers and toddlers: 2004-2015.

OBJECTIVES: Autism spectrum disorders (ASD) are among the leading causes of disabilities in children. We examined the annual prevalence and incidence rate of ASD between 2004 and 2015 in children aged 1 to 5 years residing in Manitoba. METHODS: A population-based study was conducted using the Manitoba Population Research Data Repository. The study included children aged 1 to 5 years residing in Manitoba between 2004 and 2015. Standard identification algorithm was used to identify ASD cases from hospital abstracts and medical claims. Annual prevalence and incidence rates were calculated for the overall population and then stratified according to sex, region, and socio-economic status (SES). Multivariable negative binomial regression models, adjusted for sex, region, and SES, were used to examine changes in prevalence and incidence over study years. RESULTS: Among children aged 1 to 5 years, 1685 ASD cases were diagnosed between 2004 and 2015. The crude ASD prevalence increased from 0.46% in 2004 to 0.97% in 2015 (p = 0.002). The crude incidence rate increased from 0.16% in 2004 to 0.39% in 2015 (p = 0.002). The increase in ASD prevalence and incidence was observed in all subgroups based on sex, region, and SES. The adjusted negative binomial model showed an annual relative risk increase, since 2004, for both prevalence and incidence of 1.69 (95% CI 1.56-1.83) and 1.84 (95% CI 1.62-2.09), respectively. CONCLUSION: During the period from 2004 to 2015, both prevalence and incidence rates of diagnosed ASD in preschoolers and toddlers residing in Manitoba increased significantly.

Early childhood antibiotics use and autism spectrum disorders: a population-based cohort study.

Background: Changes in microbiota composition as a result of antibiotics use in early life has been proposed as a possible contributor in the aetiology of autism spectrum disorders (ASD). We aimed to examine the association between early life antibiotic exposure and risk of ASD. Methods: This was a population-based cohort study which included all live births in Manitoba, Canada, between 1 April 1998 and 31 March 2016. We used administrative health data from the Manitoba Population Research Data Repository. Exposure was defined as having filled one or more antibiotic prescription during the first year of life. The main outcome was ASD diagnosis. Cox proportional hazards regression models were used to estimate the risk of developing ASD in the overall population and in a sibling cohort. Results: Of all subjects in the cohort (n = 214 834), 94 024 (43.8%) filled an antibiotic prescription during the first year of life. During follow-up, 2965 children received an ASD diagnosis. Compared with children who did not use antibiotics during the first year of life, those who received antibiotics had a reduced risk of ASD [adjusted hazardz ratio (HR) 0.91, 95% confidence interval (CI) 0.84-0.99). Number of treatment courses and cumulative duration of antibiotic exposure were not associated with ASD. In the sibling-controlled analysis, early life antibiotic exposure was not associated with ASD (adjusted HR 1.03, 95% CI 0.86-1.23). Conclusions: Our findings suggested no clinically significant association between early life antibiotics exposure and risk of autism spectrum disorders, and should provide reassurance to concerned prescribers and parents.

Knowledge, attitudes, beliefs, and barriers associated with the uptake of influenza vaccine among pregnant women.

Objective: The purpose of the study was to assess the knowledge, attitudes, beliefs, and factors associated with the uptake of the influenza (flu) vaccination in women within Saudi Arabia during their pregnancy period. Methods: A cross-sectional prospective survey was conducted on 1085 pregnant women at the antenatal clinic over a period of 6 weeks with the provision of influenza vaccination. The questionnaire collected demographic and other data; it included 12 questions on their general knowledge and assessed their attitude toward influenza vaccination, and their awareness of vaccine risk and the potential benefits during pregnancy. The knowledge score obtained was then calculated and compared. Results: A total of 998 patients took part in the questionnaire with a response rate of 92%. There was poor awareness that the flu vaccine is safe to administer during pregnancy (130, 13.1%) and that all pregnant women should receive the flu vaccine (190, 19.1%). Pregnant women with flu vaccine knowledge score of ⩽5 (range 0-12) were significantly less likely to take the vaccine (OR 3.78, 95% CI 2.68-5.26, p < 0.001). There was a low uptake of the vaccine (178, 18.1%) and only 29 (3.0%) had previously been offered the flu vaccine by any doctor during their pregnancy. In addition, 255 (25.8%) were against taking the flu vaccine during pregnancy. Conclusion: The knowledge and uptake of the influenza vaccine among Saudi pregnant women are low. One quarter was against the vaccine during pregnancy. Very few believed the flu vaccine to be safe during pregnancy. Rarely, physicians advise their clients to take flu vaccine.

Knowledge on adherence and safety of the oral contraceptive pill in Saudi women.

OBJECTIVE: To assess knowledge regarding adherence and safety of oral contraceptive pills (OCP) in Saudi women. METHODS: We conducted a cross-sectional prospective study in an outpatient pharmacy at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia from April to September 2011. Participants were healthy women aged greater than or equal to 18 years with an OCP prescription for contraception. We used a validated questionnaire to assess their knowledge regarding adherence and safety of OCPs. RESULTS: Four hundred and sixty women participated. Most (79%) knew to take an extra pill if they missed one in less than 12 hours, but only 6.5% knew they also had to use extra protection for the next 7 days if it was more than 12 hours. Multiple logistic regression analyses indicated that years of contraceptive use and educational level are predictive factors of better knowledge regarding adherence. Few were aware of the action if they experienced diarrhea for more than 12 hours (10%) or vomiting within 2 hours (13.5%) of taking an OCP. Only 30% knew of the adverse effects of smoking while on OCPs. Weight gain (51%) was the most commonly reported side effect. CONCLUSION: Most Saudi women taking OCPs have limited knowledge of its correct use regarding missing pills, vomiting and diarrhea, and poor awareness of the effects of smoking while using OCPs.