Table S1. Number of patients dispensed a statin, by drug, during the 1 st trimester

Transcription

1 Supplementary material Table S1. Number of patients dispensed a statin, by drug, during the 1 st trimester Medication Count Overall 1152 Atorvastatin 538 Cerivastatin * Fluvastatin 47 Lovastatin 132 Pravastatin 75 Rosuvastatin 44 Simvastatin 319 *Indicates cell size less than 11 which cannot be disclosed in accordance with the Data Use Agreement

2 Table S2. Relative risks and 95% confidence intervals comparing the risk for major congenital malformations between statin exposed and unexposed stratified by highdimensional propensity score (Hd-PS). Medicaid Analytic extract Primary analysis (exposure based on 1 dispensing in the first trimester) No of outcomes/no of patients Statin-exposed Statin-unexposed Hd-PS stratified Relative risk (95% CI) 73/1,152 31,416/885, (0.86 to 1.41) Lipophilic statins 66/ / (0.84 to 1.40) Exposure based on days supply overlapping the 1st trimester Exposure based on 2 dispensings in the 1st trimester Malformation based on single diagnosis code in the infant record Require a full year of infant eligibility (ascertain outcomes for 1 year) Malformation based on codes in infant or maternal record Examine only the first pregnancy for women with >1 pregnancy in cohort Restrict to term deliveries (exclude preterm deliveries) 97/ / (0.86 to 1.32) 28/ / (0.81 to 1.80) 155/1, /885, (0.92 to 1.26) 92/ / (0.89 to 1.36) 90/ / (0.88 to 1.36) 67/ / (0.84 to 1.41) 41/ / (0.80 to 1.52)

3 Table S3. Probabilistic bias analysis comparing the risk for any congenital malformations between statin exposed and unexposed women across a range of sensitivities and specificities for the outcome. Lower bound CI Odds ratio Upper bound CI Change in point estimate (%) Conventional Analysis Probabilistic Bias Analysis (1) Conventional analysis is adjusted for the propensity-score from the main analysis (based on pre-specified covariates) as a continuous variable, rather than propensity-score stratification which was used in the main analysis. This facilitates comparison with the probabilistic bias analysis which cannot be performed using propensity-score stratification. (2) The distribution of the bias parameters included in the analysis correspond to measurement of the outcome with a sensitivity that ranges from 0.5 to 1.0 (with mode at 0.75) and specificity that ranges from 0.98 to (with mode at 0.99). This corresponds to conservative positive predictive values for the outcome that range from 47.6% to 99.7%, centered at 73.1%. (3) The confidence interval (CI) represents a simulation interval. The bias parameters are drawn from the pre-specified triangular distribution. The draw is repeated over 100 iterations. Results are accumulated to generate a frequency distribution. The simulation interval represents 5 th and the 95 th percentile of the frequency distribution.

4 Table S4. Relative risks and 95% confidence intervals comparing the risk for major congenital malformations in patients with and without pre-existing diabetes mellitus. Medicaid Analytic extract Relative risk (95% CI) Any congenital malformation 3.09 (2.85 to 3.34) Central nervous system malformations 3.97 (2.87 to 5.49) Eye, ear, neck, and face malformations 1.68 (0.99 to 2.86) Cardiac malformations 5.74 (5.22 to 6.31) Respiratory malformations 1.86 (1.21 to 2.86) Cleft palate and lip 2.00 (1.2 to 3.33) Gastrointestinal malformations 1.88 (1.46 to 2.43) Genitourinary malformations 2.32 (1.85 to 2.91) Musculoskeletal malformations 1.56 (1.25 to 1.94) Other 1.86 (1.35 to 2.57) (1) Outcomes were defined as in the primary analysis (2) Pre-existing diabetes is defined by having diagnostic codes on 2 or more dates in the 90 days prior to pregnancy through the end of the first trimester.

5 Table S5 Number of organ-specific malformations in statin exposed and unexposed. Medicaid Analytic extract (N=886,996) Exposed Unexposed Central nervous system malformations * 1265 Eye, ear, neck, and face malformations * 1080 Cardiac malformations Respiratory malformations * 1468 Cleft palate and lip * 976 Gastrointestinal malformations * 4224 Genitourinary malformations * 4300 Musculoskeletal malformations * 6770 Other * 2655 *Indicates cell size less than 11 which cannot be disclosed in accordance with the Data Use Agreement

6 Table S6. International Classification of Diseases, 9 th revision Clinical Modification (ICD 9 CM) Codes used to Define Malformations Code Definition Central Nervous System Malformations 7400 ANENCEPHALUS 7401 CRANIORACHISCHISIS 7402 INIENCEPHALY 7410 SPINA BIFIDA WITH HYDROCEPHALUS 7419 SPINA BIFIDA WITHOUT MENTION OF HYDROCEPHALUS 7420 ENCEPHALOCELE 7421 MICROCEPHALUS 7422 CONGENITAL REDUCTION DEFORMITIES OF BRAIN 7423 CONGENITAL HYDROCEPHALUS 7424 OTHER SPECIFIED CONGENITAL ANOMALIES OF BRAIN 7425 OTHER SPECIFIED CONGENITAL ANOMALIES OF SPINAL CORD 7428 OTHER SPECIFIED CONGENITAL ANOMALIES OF NERVOUS SYSTEM 7429 UNSPECIFIED CONGENITAL ANOMALY OF BRAIN SPINAL CORD AND NERVOUS SYSTEM Cardiac Malformations 7450 COMMON TRUNCUS 7451 TRANSPOSITION OF GREAT VESSELS 7452 TETRALOGY OF FALLOT 7453 COMMON VENTRICLE 7454 VENTRICULAR SEPTAL DEFECT 7455 OSTIUM SECUNDUM TYPE ATRIAL SEPTAL DEFECT 7456 ENDOCARDIAL CUSHION DEFECTS 7457 COR BILOCULARE 7458 OTHER BULBUS CORDIS ANOMALIES AND ANOMALIES OF CARDIAC SEPTAL CLOSURE 7459 UNSPECIFIED DEFECT OF SEPTAL CLOSURE 7460 ANOMALIES OF PULMONARY VALVE CONGENITAL 7461 TRICUSPID ATRESIA AND STENOSIS CONGENITAL 7462 EBSTEIN'S ANOMALY 7463 CONGENITAL STENOSIS OF AORTIC VALVE 7464 CONGENITAL INSUFFICIENCY OF AORTIC VALVE 7465 CONGENITAL MITRAL STENOSIS 7466 CONGENITAL MITRAL INSUFFICIENCY 7467 HYPOPLASTIC LEFT HEART SYNDROME 7468 OTHER SPECIFIED CONGENITAL ANOMALIES OF HEART 7469 UNSPECIFIED CONGENITAL ANOMALY OF HEART 7470 PATENT DUCTUS ARTERIOSUS 7471 COARCTATION OF AORTA 7472 OTHER CONGENITAL ANOMALIES OF AORTA 7473 CONGENITAL ANOMALIES OF PULMONARY ARTERY 7474 CONGENITAL ANOMALIES OF GREAT VEINS

7 7475 ABSENCE OR HYPOPLASIA OF UMBILICAL ARTERY 7476 OTHER CONGENITAL ANOMALIES OF PERIPHERAL VASCULAR SYSTEM 7478 OTHER SPECIFIED CONGENITAL ANOMALIES OF CIRCULATORY SYSTEM 7479 UNSPECIFIED CONGENITAL ANOMALY OF CIRCULATORY SYSTEM Respiratory Malformations 7480 CHOANAL ATRESIA 7481 OTHER CONGENITAL ANOMALIES OF NOSE 7482 WEB OF LARYNX 7483 OTHER CONGENITAL ANOMALIES OF LARYNX TRACHEA AND BRONCHUS 7484 CONGENITAL CYSTIC LUNG 7485 CONGENITAL AGENESIS HYPOPLASIA AND DYSPLASIA OF LUNG 7486 OTHER CONGENITAL ANOMALIES OF LUNG 7488 OTHER SPECIFIED CONGENITAL ANOMALIES OF RESPIRATORY SYSTEM 7489 UNSPECIFIED CONGENITAL ANOMALY OF RESPIRATORY SYSTEM Cleft Palate and Lip Malformations 7490 CLEFT PALATE 7491 CLEFT LIP 7492 CLEFT PALATE WITH CLEFT LIP Gastrointestinal Malformations 7500 ANKYLOGLOSSIA 7501 OTHER CONGENITAL ANOMALIES OF TONGUE OTHER SPECIFIED CONGENITAL ANOMALIES OF MOUTH AND PHARYNX CONGENITAL TRACHEOESOPHAGEAL FISTULA ESOPHAGEAL ATRESIA AND STENOSIS 7504 OTHER SPECIFIED CONGENITAL ANOMALIES OF ESOPHAGUS 7505 CONGENITAL HYPERTROPHIC PYLORIC STENOSIS 7506 CONGENITAL HIATUS HERNIA 7507 OTHER SPECIFIED CONGENITAL ANOMALIES OF STOMACH 7508 OTHER SPECIFIED CONGENITAL ANOMALIES OF UPPER ALIMENTARY TRACT 7509 UNSPECIFIED CONGENITAL ANOMALY OF UPPER ALIMENTARY TRACT 7510 MECKEL'S DIVERTICULUM 7511 CONGENITAL ATRESIA AND STENOSIS OF SMALL INTESTINE 7512 CONGENITAL ATRESIA AND STENOSIS OF LARGE INTESTINE RECTUM AND ANAL CANAL 7513 HIRSCHSPRUNG'S DISEASE AND OTHER CONGENITAL FUNCTIONAL DISORDERS OF COLON 7514 CONGENITAL ANOMALIES OF INTESTINAL FIXATION 7515 OTHER CONGENITAL ANOMALIES OF INTESTINE

8 7516 ANOMALIES OF GALLBLADDER BILE DUCTS AND LIVER 7517 CONGENITAL ANOMALIES OF PANCREAS 7518 OTHER SPECIFIED CONGENITAL ANOMALIES OF DIGESTIVE SYSTEM 7519 UNSPECIFIED CONGENITAL ANOMALY OF DIGESTIVE SYSTEM Genitourinary Malformations 7520 CONGENITAL ANOMALIES OF OVARIES 7521 CONGENITAL ANOMALIES OF FALLOPIAN TUBES AND BROAD LIGAMENTS 7522 DOUBLING OF UTERUS 7523 OTHER CONGENITAL ANOMALIES OF UTERUS 7524 CONGENITAL ANOMALIES OF CERVIX VAGINA AND EXTERNAL FEMALE GENITALIA 7525 UNDESCENDED AND RETRACTILE TESTICLE 7526 HYPOSPADIAS AND EPISPADIAS AND OTHER PENILE ANOMALIES 7527 INDETERMINATE SEX AND PSEUDOHERMAPHRODITISM 7528 OTHER SPECIFIED CONGENITAL ANOMALIES OF GENITAL ORGANS 7529 UNSPECIFIED CONGENITAL ANOMALY OF GENITAL ORGANS 7530 RENAL AGENESIS AND DYSGENESIS 7531 CYSTIC KIDNEY DISEASE 7532 OBSTRUCTIVE DEFECTS OF RENAL PELVIS AND URETER 7533 OTHER SPECIFIED ANOMALIES OF KIDNEY 7534 OTHER SPECIFIED ANOMALIES OF URETER 7535 EXSTROPHY OF URINARY BLADDER 7536 CONGENITAL ATRESIA AND STENOSIS OF URETHRA AND BLADDER NECK 7537 CONGENITAL ANOMALIES OF URACHUS 7538 OTHER SPECIFIED CONGENITAL ANOMALIES OF BLADDER AND URETHRA 7539 UNSPECIFIED CONGENITAL ANOMALY OF URINARY SYSTEM Musculoskeletal Malformations 7540 CONGENITAL MUSCULOSKELETAL DEFORMITIES OF SKULL FACE AND JAW 7541 CONGENITAL MUSCULOSKELETAL DEFORMITIES OF STERNOCLEIDOMASTOID MUSCLE 7542 CONGENITAL MUSCULOSKELETAL DEFORMITIES OF SPINE 7543 CONGENITAL DISLOCATION OF HIP 7544 CONGENITAL GENU RECURVATUM AND BOWING OF LONG BONES OF LEG 7545 CONGENITAL VARUS DEFORMITIES OF FEET 7546 CONGENITAL VALGUS DEFORMITIES OF FEET 7547 OTHER CONGENITAL DEFORMITIES OF FEET 7548 OTHER SPECIFIED NONTERATOGENIC ANOMALIES 7550 POLYDACTYLY 7551 SYNDACTYLY 7552 REDUCTION DEFORMITIES OF UPPER LIMB CONGENITAL

9 7553 CONGENITAL REDUCTION DEFORMITIES OF LOWER LIMB 7554 CONGENITAL REDUCTION DEFORMITIES UNSPECIFIED LIMB 7555 OTHER CONGENITAL ANOMALIES OF UPPER LIMB INCLUDING SHOULDER GIRDLE 7556 OTHER CONGENITAL ANOMALIES OF LOWER LIMB INCLUDING PELVIC GIRDLE 7558 OTHER SPECIFIED CONGENITAL ANOMALIES OF UNSPECIFIED LIMB 7559 UNSPECIFIED CONGENITAL ANOMALY OF UNSPECIFIED LIMB 7560 CONGENITAL ANOMALIES OF SKULL AND FACE BONES 7561 CONGENITAL ANOMALIES OF SPINE 7562 CERVICAL RIB 7563 OTHER CONGENITAL ANOMALIES OF RIBS AND STERNUM 7564 CHONDRODYSTROPHY 7565 CONGENITAL OSTEODYSTROPHIES 7566 CONGENITAL ANOMALIES OF DIAPHRAGM 7567 CONGENITAL ANOMALIES OF ABDOMINAL WALL 7568 OTHER SPECIFIED CONGENITAL ANOMALIES OF MUSCLE TENDON FASCIA AND CONNECTIVE TISSUE Other Malformations 7570 HEREDITARY EDEMA OF LEGS 7571 ICHTHYOSIS CONGENITA 7572 DERMATOGLYPHIC ANOMALIES 7573 OTHER SPECIFIED CONGENITAL ANOMALIES OF SKIN 7574 SPECIFIED CONGENITAL ANOMALIES OF HAIR 7575 SPECIFIED CONGENITAL ANOMALIES OF NAILS 7576 SPECIFIED CONGENITAL ANOMALIES OF BREAST 7578 OTHER SPECIFIED CONGENITAL ANOMALIES OF THE INTEGUMENT 7579 UNSPECIFIED CONGENITAL ANOMALY OF THE INTEGUMENT 7590 ANOMALIES OF SPLEEN CONGENITAL 7591 ANOMALIES OF ADRENAL GLAND CONGENITAL 7592 ANOMALIES OF OTHER ENDOCRINE GLANDS CONGENITAL 7593 SITUS INVERSUS 7594 CONJOINED TWINS 7595 TUBEROUS SCLEROSIS 7596 OTHER CONGENITAL HAMARTOSES NOT ELSEWHERE CLASSIFIED 7597 MULTIPLE CONGENITAL ANOMALIES SO DESCRIBED 7598 OTHER SPECIFIED CONGENITAL ANOMALIES 7599 CONGENITAL ANOMALY UNSPECIFIED Eye, Ear, Neck and Face Malformations 7430 ANOPHTHALMOS 7431 MICROPHTHALMOS 7432 BUPHTHALMOS 7433 CONGENITAL CATARACT AND LENS ANOMALIES 7434 COLOBOMA AND OTHER ANOMALIES OF ANTERIOR SEGMENT 7435 CONGENITAL ANOMALIES OF POSTERIOR SEGMENT

10 7436 CONGENITAL ANOMALIES OF EYELIDS LACRIMAL SYSTEM AND ORBIT 7438 OTHER SPECIFIED ANOMALIES OF EYE CONGENITAL 7439 UNSPECIFIED ANOMALY OF EYE CONGENITAL 7440 CONGENITAL ANOMALIES OF EAR CAUSING IMPAIRMENT OF HEARING 7441 ACCESSORY AURICLE 7442 OTHER SPECIFIED CONGENITAL ANOMALIES OF EAR 7443 UNSPECIFIED CONGENITAL ANOMALY OF EAR 7444 BRANCHIAL CLEFT CYST OR FISTULA; PREAURICULAR SINUS 7445 WEBBING OF NECK 7448 OTHER SPECIFIED CONGENITAL ANOMALIES OF FACE AND NECK 7449 UNSPECIFIED CONGENITAL ANOMALIES OF FACE AND NECK

11 Appendix 1: The potential impact of analysis based on livebirths The MAX pregnancy cohort only includes information on pregnancies that result in liveborn infants. There is no information about stillbirths, spontaneous or therapeutic abortions related to the presence of malformations. If non-livebirth frequencies are the same in both the exposed and unexposed, then the estimates of risk in our analysis based on liveborns would be unbiased. However, if non-livebirth of offspring with malformations occurred with greater frequency among women with statin exposure compared to the non-exposed (within levels of covariates used for adjustment in the analysis), then our analysis which includes only pregnancies resulting in livebirth would underestimate the relative risk of malformations associated with statin use. We therefore performed a sensitivity analysis to assess the potential impact of missing non-livebirth on the risk estimate for statins and malformations using methods previously described in detail (Huybrechts KF et al., NEJM, 2014)[1]. The assumptions used for the modeling are similar to those used in our group s sensitivity analysis to quantify the potential impact of missing non-livebirths in a study of the association of serotonin reuptake inhibitors and cardiac malformations (Huybrechts KF et al., NEJM, 2014). Namely, we assume that 20% of non-malformed infants are stillborn, spontaneously or therapeutically terminated in the non-exposed. We then model a range of non-livebirth frequencies for malformed infants in the unexposed from 30% (20% stillborn, spontaneously or therapeutically terminated, 10% terminated for malformations) to 50% (20% terminated for social or other reasons, 30% for malformations); this corresponds to a probability of livebirth among fetuses with malformations in the unexposed group that ranges from 0.7 to 0.5. We then examine the effect of potentially different frequencies of non-livebirth in the statin exposed, under the assumption that statin exposure might decrease or increase the frequency of stillbirth/pregnancy termination/spontaneous abortion.. We examine differences in the proportion of malformed infants that are liveborn in the statin exposed compared to in the non-exposed ranging from -20% to +20% (assuming a comparable reduction or increase in the probability of livebirth, compared to the non-exposed, in the statin exposed fetuses that are not malformed). The relative risk for malformations associated with statin exposure derives from our propensity score stratified estimate from the primary analysis (RR 1.07). Figure 1 shows the corrected estimate of relative risk across a range of selection probabilities (i.e., probability of being liveborn in malformed fetuses) in the unexposed that ranges from 0.7 to 0.5 (assuming the probability of livebirth in the non-malformed is 0.8). Fives lines are shown, corresponding to livebirth probabilities for fetuses in the statin exposed group that are (1) 20% lower than in the unexposed, (2) 10% lower, (3) the same, (4) 10% higher, and (5) 20% higher. Even in the extreme scenario that the frequency of non-livebirth of a malformed fetus was 50% in the unexposed and 70% in the statin exposed, the corrected RR estimate was

12 Corrected Relative Risk only In reality, we expect that non-livebirth rates are likely to be similar in the exposed and unexposed, particularly within levels of covariates included in the propensity score (which included a broad range of demographic, medical/obstetric conditions and healthcare utilization variables). While this sensitivity analysis is useful in putting bounds on the risk estimate associated with missing non-livebirths which might be possible, in reality the risk estimate for statins and malformation from the primary analysis is unlikely to be significantly affected by the missing information on nonlivebirths. Figure % % 0% +10% +20% Probability of livebirth among fetuses with malformations in the unexposed

13 Appendix 2. Method for probabilistic bias analysis We performed a probabilistic assessment to explore the effect of potential outcome misclassification across a range of potential sensitivities and specificities for the malformations and an assessment of the potential impact of analysis based only on live births.[1-3] The distribution of the bias parameters included in the analysis correspond to measurement of the outcome with a sensitivity that ranges from 0.5 to 1.0 (with mode at 0.75) and specificity that ranges from 0.98 to (with mode at 0.99). This corresponds to conservative positive predictive values for the outcome that range from 47.6% to 99.7%, centered at 73.1%. The bias parameters are drawn from the prespecified triangular distribution. The draw is repeated over 100 iterations. Results are accumulated to generate a frequency distribution. The percentage change in the point estimate of risk generated in the probabilistic bias analysis was compared with that of the conventional analysis. The conventional analysis used for this comparison is adjusted for the propensity-score from the main analysis (based on pre-specified covariates) as a continuous variable, rather than propensity-score stratification which facilitates comparison with the probabilistic bias analysis which cannot be performed using propensity-score stratification. References 1. Khoury MJ, Flanders WD, James LM, et al. Human teratogens, prenatal mortality, and selection bias. Am J Epidemiol 1989;130(2): Greenland S. Basic methods for sensitivity analysis of biases. Int J Epidemiol 1996;25(6): Huybrechts KF, Palmsten K, Avorn J, et al. Antidepressant use in pregnancy and the risk of cardiac defects. The New England journal of medicine 2014;370(25):