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Description : Check out this medical PowerPoint presentation titled "Drug Safety in Pregnancy-Challenges and Solutions” by Sonia Hernández-Díaz, MD, DrPH.

This medical PowerPoint presentation is about drug safety in pregnancy, a critical topic because many drugs can have harmful effects on a developing fetus. Pregnant women should be cautious when taking any medication and should always consult with their healthcare provider before doing so.

The US Food and Drug Administration (FDA) categorizes drugs based on their potential risks during pregnancy. The categories include:

Category A-Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters.

Category B-Animal reproduction studies have failed to demonstrate a risk to the fetus, but there are no adequate and well-controlled studies in pregnant women.

Category C-Animal reproduction studies have shown an adverse effect on the fetus, but there are no adequate and well-controlled studies in humans. The potential benefits of the drug may outweigh the risks in certain situations.

Category D-There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits of the drug may outweigh the risks in certain situations.

Category X-Studies in animals or humans have demonstrated fetal abnormalities, and the risks of the drug outweigh the potential benefits. The drug should not be used during pregnancy.

Pregnant women should avoid using drugs in category X and should use caution with drugs in categories C and D. In some cases, the benefits of taking a medication during pregnancy may outweigh the risks, and a healthcare provider may recommend its use.

It is also essential for pregnant women to be aware of the potential risks associated with over-the-counter medications, herbal supplements, and other products that are not prescribed by a healthcare provider. Pregnant women should always consult with their healthcare provider before taking any medication or supplement.

Tags : Drug Safety in Pregnancy, The US Food and Drug Administration, FDA, Neonatal-Perinatal Medicine, Neonatal-Perinatal Medicine PowerPoint presentation

Published on : Jun 07, 2023 | Views : 1153 | Downloads : 0

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Slide 1-

Drug Safety in Pregnancy: Challenges and SolutionsSonia Hernández-Díaz, MD, DrPH 13th Annual Harry Guess Memorial Lecture
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Disclosure The following personal or financial relationships existed during the past 12 months: SHD consulted for Roche and UCB SHD participated as investigator in projects funded by Takeda SHD was the epidemiologist for the North American Antiepileptic Drugs pregnancy registry and advisor for the Antipsychotics Pregnancy Registry, which are funded my multiple companies The Pharmacoepidemiology Program at the Harvard T.H. Chan School of Public Health is partially supported by training grants from Pfizer, UCB, Bayer and Asisa 2 13-Jun-23 Hernandez-Diaz
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Outline Introduction to Drug Safety in Pregnancy Tools Overview Challenges & Solutions Example Future 3 13-Jun-23 Hernandez-Diaz
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Outline Introduction to Drug Safety in Pregnancy 4 13-Jun-23 Hernandez-Diaz
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Background Once upon a time there was a drug… 5 13-Jun-23 Hernandez-Diaz
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…that entered German market in 1957 as a non-addictive, non-barbiturate sedative Quickly discovered to also be an effective anti‐emetic and used to treat morning sickness in pregnant women Marketing (46 countries; Distaval, Softenon, Contergan): “…drug of choice to help pregnant women” “completely safe for pregnant women” However: No studies in pregnant women (or animals) had been conducted. “Practically nothing was known about the drug at the time of its marketing" 13-Jun-23 Hernandez-Diaz 6
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…that entered German market in 1957 as a non-addictive, non-barbiturate sedative Quickly discovered to also be an effective anti‐emetic and used to treat morning sickness in pregnant women Marketing (46 countries; Distaval, Softenon, Contergan): “…drug of choice to help pregnant women” “completely safe for pregnant women” However: No studies in pregnant women (or animals) had been conducted. Practically nothing was known about the drug at the time of its marketing 13-Jun-23 Hernandez-Diaz 7
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Thalidomide First afflicted child Girl born December 25, 1956 Daughter of employee of Grünenthal Thalidomide embryopathy Limb deformities (phocomelia) Absence of ears 13-Jun-23 Hernandez-Diaz 8
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Thalidomide December 1961, McBride letter in The Lancet: Prevalence after exposure: 20% to 50%, around half of the cases included limb defects Baseline prevalence of congenital malformations: 3% No formal epidemiologic studies were necessary to demonstrate causality However, the lack of a formal surveillance system had a cost…. 13-Jun-23 Hernandez-Diaz 9
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Lessons learned Need active surveillance Recognition of epidemic of rare defects took almost 4 more years Around 10,000 infants were born with deformities worldwide; only about 5,000 survived beyond childhood FDA inspector Frances Kelsey, prevented the drug’s approval within the US 13-Jun-23 Hernandez-Diaz 10
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Lessons learned Need active surveillance Need to focus on etiologically relevant period Critical period 6th and 7th week of pregnancy (35-50 days after LMP) Implications for public health 13-Jun-23 Hernandez-Diaz 11
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12 13-Jun-23 Hernandez-Diaz 12
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Lessons learned Need active surveillance Need to focus on etiologically relevant period Critical period 6th and 7th week of pregnancy (35-50 days after LMP) Implications for public health …& for research Trimethoprim & NTDs by month Hernández-Díaz S et al. Folic Acid Antagonists During Pregnancy and the Risk of Birth Defects. New England Journal of Medicine 2000;343:1608-1614. 13-Jun-23 Hernandez-Diaz 13
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Lessons learned Need active surveillance Need to focus on etiologically relevant period Need to consider specific birth defects Major Malformations, 3-4 per 100 Specific Major Malformations, 1 per 1,000 Correct phenotype 13-Jun-23 Hernandez-Diaz 14
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Lessons learned Need active surveillance Need to focus on etiologically relevant period Need to consider specific birth defects Post-T-Lesson: Not everything is thalidomide 1956: Bendectin (doxylamine + pyridoxine) approved Concerns arose in late 1970s; series of lawsuits “1 of every five malformed infants delivered has been exposed to Bendectin“ Used by 10 to 25% of pregnant women in the US 13-Jun-23 Hernandez-Diaz 15
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Was there enough evidence to withdraw bendectin? In 1983, production was discontinued because of litigation. FDA: “Bendectin was withdrawn by its maker, and not for reasons of safety and efficacy.” 13-Jun-23 Hernandez-Diaz 16
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Drug Safety During Pregnancy 17 13-Jun-23 Hernandez-Diaz
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Drug Safety During Pregnancy 13-Jun-23 Hernandez-Diaz
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Outline Introduction to Drug Safety in Pregnancy Tools Overview 19 13-Jun-23 Hernandez-Diaz
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Is this still a problem today?Do pregnant women use drugs? Most women take medications during their pregnancy 20 13-Jun-23 Hernandez-Diaz
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What do we need to know for a given drug? Clinician and patient: Is this drug another thalidomide or isotretinoin? Are there other, less frequent teratogenic risks? Regulatory agencies and public: What is the teratogenic impact on the public health? 21 13-Jun-23 Hernandez-Diaz Mitchell AA. Systematic Identification of Drugs That Cause Birth Defects-- A New Opportunity. New England Journal of Medicine 2003;349:2556-2559.
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Most commonly used drugs Apart from vitamins and minerals, the most used drugs during pregnancy are: Analgesics Cough/cold medications Allergy /asthma Antibiotics/anti-infectives Most commonly used drugs are non-prescription Most commonly used drugs change over time (exposure to opioids, psychotropics and vaccines has increased) 22 13-Jun-23 Hernandez-Diaz
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13-Jun-23 Hernandez-Diaz 23 Secular patterns of selected anti-nausea medications during the first trimester
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24 Desai R, Hernández-Díaz S, Bateman BT, Huybrechts K. Increase in prescription opioid use during pregnancy among Medicaid-enrolled women. Obstet Gynecol. 2014;123(5):997-1002 Opioids epidemic also affecting pregnancy… 13-Jun-23 Hernandez-Diaz
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Where can we identify teratogens? Premarketing Approaches: Pharmacologic or toxicologic studies - poor predictors Animal studies - poor predictors Clinical trials - exclude pregnant women 25 13-Jun-23 Hernandez-Diaz
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Where can we identify teratogens? Post-marketing Approaches: Case reports - clues; false alarms Ecological studies - clues; false alarms Experimental studies - too small Non-experimental (epidemiologic) studies Cohort Case-Control 26 13-Jun-23 Hernandez-Diaz
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Where can we identify teratogens? Designed for Birth Defects Research Cohorts, wide range of exposures - Collaborative Perinatal Project, MoBa Cohorts, specific exposures – Exposure Pregnancy Registries Case control studies – Case Control Surveillance (Slone, BDSTEPS) Designed for Other Purposes Automated claims databases - Medicaid Analytic eXtract, Optum, IBM MarketScan Computerized medical records – UK Clinical Practice Research Datalink (CPRD) Provincial registries - Régie de l'assurance maladie du Québec, Health Services Saskatchewan National Registers - Nordic linked databases 27 13-Jun-23 Hernandez-Diaz
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Surveillance strategy Exposure pregnancy registries To identify drugs with dramatic fetal risks (e.g., thalidomide) New drugs Health care databases To identify drugs with moderate fetal risk Commonly used prescription drugs and/or relatively common outcomes Case control surveillance To identify drugs with moderate fetal risk Suspected specific malformation (or other outcome) & relatively common use 28 13-Jun-23 Hernandez-Diaz
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Outline Introduction to Drug Safety in Pregnancy Tools Overview Challenges & Solutions 29 13-Jun-23 Hernandez-Diaz
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Source Population Mother Pregnancy Fetus (1 or more) Need information on outcome for each fetus or newborn 30 13-Jun-23 Hernandez-Diaz
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Role of multifetal gestations Exposure of interest, e.g. what is the effect of multiple gestation on the risk of adverse perinatal outcomes? Outcome of interest, e.g. what is the effect of infertility treatment on the risk of multiple gestation? Confounder, e.g. what is the effect of delivery via cesarean section on perinatal outcomes? Causal Mediator Source of clustered data structure (Generalized estimating equations) 31 13-Jun-23 Hernandez-Diaz Oberg AS, VanderWeele TJ, Almqvist C, Hernandez-Diaz S. Pregnancy complications following fertility treatment—disentangling the role of multiple gestation. International journal of epidemiology 2018;47(4):1333-134
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Information Bias - Exposure Misclassification False positives (adherence / compliance, stop after conception) More than a quarter of new prescriptions are unfilled, especially when the drugs are for symptomless conditions False negatives (OTC, sharing, missing data, recall) Differential misclassification Recall bias (retrospective interviews) Etiologically relevant period  need timing of pregnancy too 32 13-Jun-23 Hernandez-Diaz
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Information Bias - Solutions Exposure: Filling ≥ 1 prescription during the first trimester Reference: No prescription for index drug in months or filling ≥ 1 prescription for reference drug with same indication Prospective records of drugs Comparable sources of information Other defects as controls Improve algorithms to identify last menstrual period (LMP) 33 13-Jun-23 Hernandez-Diaz
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Information Bias - Outcome Misclassification (e.g. ICD9 codes, maternal report) Suspected diagnoses may be coded to justify the performance of diagnostic tests (rule-out diagnoses) Differential misclassification Diagnostic bias (ultrasounds and minor defects) Comparable “major malformation” definition (CAUTION with external reference) Period of diagnosis (prenatal, birth, life) Inclusion / exclusion criteria 34 13-Jun-23 Hernandez-Diaz
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Information Bias - Solutions Measure outcome in study with accuracy (accurate internal data) Use algorithms with high specificity Validate all potential cases with external data (e.g., medical records) and use “definite cases” Validate a subsample of potential cases, quantify misclassification and evaluate impact on relative risk estimates 35 13-Jun-23 Hernandez-Diaz
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Prevalence of major congenital malformations defined on the basis of a single diagnostic claim (blue bars) or an algorithm requiring multiple codes or a single code plus a corrective procedure and/or infant death Use algorithms that prioritize Specificity Huybrechts KF, Bateman BT, Hernandez-Diaz S. Use of real-world evidence from healthcare utilization data to evaluate drug safety during pregnancy. Pharmacoepidemiology and drug safety 2019. 2 codes or 1+procedure/death 1 code 13-Jun-23 Hernandez-Diaz 36
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37 Specific malformations: >1 date with code 1 date + surgery/procedure 1 date + infant death within 90 days For selected malformations: at least one code documented at >= 6 weeks after DoB Malformations overall: Any of the 13 specific malformations present 13-Jun-23 Hernandez-Diaz
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38 Validation studies Validate Medicaid claims data Hospital medical records Palmsten K, Huybrechts KF, Kowal MK, Mogun H, Hernández-Díaz S. Validity of maternal and infant outcomes within nationwide Medicaid data. Pharmacoepidemiol Drug Saf. 2014; 23:646-55. 13-Jun-23 Hernandez-Diaz
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Not all cases validated  Use plausible misclassification in probabilistic bias analyses Palmsten K, Huybrechts KF, Kowal MK, Mogun H, Hernandez-Diaz S. Validity of maternal and infant outcomes within nationwide Medicaid data. Pharmacoepidemiology and drug safety 2014;23:646-55. Validation studies 13-Jun-23 Hernandez-Diaz 39
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Sensitivity analyses 40 For misspecification Assess robustness of definition, try modifications of phenotype Example: For preeclampsia, estimate the relative risk separately for early-onset (diagnosis between day 141-237) and late-onset (diagnosis after 237 days) 2. For misclassification Assess impact of excluding outcomes designated as “probably occurred” or “likely did not occur” based on review of claims profiles or medical records Correct relative risks for outcome misclassification using sensitivity and specificity derived from PPV estimated in validation studies Fox MP, Lash TL, Greenland S. A method to automate probabilistic sensitivity analyses of misclassified binary variables. International journal of epidemiology 2005;34:1370-6. Lash TF, Fox MP, Fink AK. Missclassification. Applying Quantitative Bias Analysis to Epidemiologic Data. New York: Springer; 2009:79-108. 13-Jun-23 Hernandez-Diaz
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Selection Bias Start of follow up (left-censoring) What would you expect to find if exposed subjects are enrolled during first trimester and unexposed are enrolled later in pregnancy? 41 13-Jun-23 Hernandez-Diaz
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Timing of first interview 13-Jun-23 Hernandez-Diaz 42
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43 43 Pregnancies Differential Timing of Enrollment 13-Jun-23 Hernandez-Diaz
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All enrollees cases/N in AED users: 353/7,029 Non-users: 6/581 Margulis AV, Mittleman MA, Glynn RJ, Holmes LB, Hernández-Díaz S. Effects of gestational age at enrollment in pregnancy exposure registries. Pharmacoepidemiology and Drug Safety. 2015; 24(4):343-52. Impact on Spontaneous Abortions 13-Jun-23 Hernandez-Diaz 44
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Selection Bias Start of follow up (left-censoring) What would you expect to find if subjects are enrolled late in pregnancy, after prenatal screening tests? If diagnoses are included: potential overestimation if preferential enrollment or underestimation if lower participation of cases. If diagnoses are excluded: underestimation 45 13-Jun-23 Hernandez-Diaz
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46 46 Pregnancies Enrollment Impact on Birth Defects 13-Jun-23 Hernandez-Diaz
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47 47 Pregnancies Impact on Birth Defects 13-Jun-23 Hernandez-Diaz
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48 Pregnancies 48 Impact on Birth Defects 13-Jun-23 Hernandez-Diaz
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49 All enrollees Pre-screening enrollees M/N in AED users: 210/6,676 nonusers: 6/575 AED users: 117/3,955 nonusers: 3/206 Impact on Birth Defects 13-Jun-23 Hernandez-Diaz
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Selection Bias - Solutions Minimize left truncation (enroll early or detect early pregnancies) When the incidence rate of events changes over pregnancy (e.g., SAB), ensure that the distribution of time at risk for the outcome is comparable between exposure groups When an event may influence enrollment decisions (e.g., prenatal screening), primary analyses must include only subjects who enrolled before this event 50 13-Jun-23 Hernandez-Diaz
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Selection Bias End of follow up (right-censoring & Competing events) Abortion, Preterm delivery  Reduced opportunity for exposure & outcomes Intrauterine survival (Incidence versus prevalence at birth) 51 13-Jun-23 Hernandez-Diaz Exposure (E) may affect the risk of early miscarriages or social terminations during 1st trimester (S), and/or the risk of Malformations (M); Malformation (M) early in pregnancy affect terminations in second trimester (T), when diagnosed prenatally and family decides to induced abortion, and M affects fetal loss if incompatible with fetal survival; which affect observation of malformations at birth (M*).
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Selection Bias What would you expect to find in an analysis of teratogenicity if exposure to drug XX causes early pregnancy losses? a large proportion of malformations (e.g., NTDs) are terminated ? only livebirth have information on malformations? 52 13-Jun-23 Hernandez-Diaz
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53 53 Pregnancies Window of observation at birth Impact on Birth Defects 13-Jun-23 Hernandez-Diaz
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54 Pregnancies 54 Impact on Birth Defects 13-Jun-23 Hernandez-Diaz
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Right truncation Non-differential How common is it ? What is the impact? Differential How likely is it ? What is the impact ? Elisabeth Svensson et al. Estimating the Proportion of all Observed Birth Defects Occurring in Pregnancies Terminated by a Second-trimester Abortion. Epidemiology 2014. Levy A et al. Bias toward the null hypothesis in pregnancy drug studies that do not include data on medical terminations of pregnancy: the folic acid antagonists. J Clin Pharmacol. 2012;52:78–83. Intrauterine survival 13-Jun-23 Hernandez-Diaz 55
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Confounding Smoking, illegal drugs, BMI, etc. Indication (e.g., depression, asthma) 56 13-Jun-23 Hernandez-Diaz
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Effect of antidepressants on the risk of cardiac defects In 2005, the FDA warned against a potential increase in the risk of congenital cardiac malformations associated with paroxetine Adjustment (for smoking, BMI, SES, etc) did not change OR in case-control studies We created the Medicaid Analytic eXtract (MAX) mother-infant cohort (>3M) Huybrechts K, Palmsten K, Avorn J, Cohen LJ, Holmes LB, Franklin JM, Mogun H, Levin R, Kowal M, Setoguchi S, Hernández-Díaz S. Antidepressant Use in Pregnancy and the Risk of Cardiac Defects. New England Journal of Medicine. 2014;370:2397-407). 13-Jun-23 Hernandez-Diaz 57
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58 Mitigate through design  Target trial (e.g., inclusion criteria, active comparator) Adjust for measured confounders External adjustment (e.g., National Health and Nutrition Examination Survey) Negative controls (e.g., Evaluate the effect of exposure during a window other than the suspected etiologically relevant window) Probabilistic bias analyses (Fox et al. Int J Epidemiol 2005) External adjustment of the observed crude relative risk (RRED) using NHANES data. Hernandez-Diaz S, Huybrechts KF, Desai RJ, et al. Topiramate use early in pregnancy and the risk of oral clefts. Neurology. 2018; 90(4):e342-e351 Confounding 13-Jun-23 Hernandez-Diaz
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Alternative explanations 13-Jun-23 Hernandez-Diaz 59
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Pregnancy Registries First line of evidence to identify teratogens because they are able to enroll women soon after drug approval. However, they often fail to produce robust safety data, particularly for newly introduced drugs for relatively rare conditions. Targeted enrollment usually ranges between 100 and 500 pregnancies only 14% of registries achieve target enrolment Is this sample size sufficient to detect meaningful risks? Sahin L. Pregnancy exposure registries and other post-approval studies: current status and observations. Data on file. Center for Drug Evaluation and Research, Office of New Drugs, FDA; 2014. Available at: http://www.fda.gov/downloads/Drugs/NewsEvents/UCM399660.pdf. 13-Jun-23 Hernandez-Diaz 60
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Deciding the minimal sample size: Under null Assuming a baseline risk of 3% for major malformations, a cohort with a ratio of exposed to unexposed 1:3, and about 100 exposed pregnancies would have 80% power to “exclude” relative risks (RRs) of 6.5 based on 95% confidence intervals, if the true RRs equal 1. 13-Jun-23 Hernandez-Diaz 61 Rothman KJ. Available at: http://www.krothman.org/episheet.xls.
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Deciding the minimal sample size: Under alternative If there is an effect, a sample size of 100 exposed would provide power to detect RRs over 3.1. Larger numbers would be needed to study specific defects 13-Jun-23 Hernandez-Diaz 62
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63 For a relatively common defect such as oral cleft(baseline 1 per 1,000 births): 13-Jun-23 Hernandez-Diaz
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64 Conclusion The typical pregnancy registry would detect strong teratogenicity, but low- risk teratogens will not be identifiable Most registries are inadequately powered to study associations for specific major malformations Complementary approaches should be considered before concluding that “there is no increased risk in birth defects,” or that “drug A causes specific defect X” Gelperin K, Hammad H, Leishear K, Bird ST, Taylor L, Hampp C, et al. A systematic review of pregnancy exposure registries: examination of protocol-specified pregnancy outcomes, target sample size, and comparator selection. Pharmacoepidemiol Drug Saf. 2017 Feb;26(2):208-14. 13-Jun-23 Hernandez-Diaz
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Consequences of small numbers False Negatives: Most studies lump together all major malformations even when teratogens tend to cause specific defects  dilution of effect Wrong interpretation of evidence when non statistical significance is used as evidence of no effect  DO NOT USE p-values for safety It is not a yes/no question, it is about establishing the level of risk and discussing whether it is acceptable given the benefits, risks and costs 13-Jun-23 Hernandez-Diaz 65
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Incorrect use of p-values and confidence intervals Example: “… we found an adjusted hazard ratio [HR] of 1.59 [95% CI, 1.17-2.17]). After adjustment the association was not significant (HR, 1.61 [95% CI, 0.997-2.59]). In conclusions, in utero XXXXX exposure was not associated with YYYYY Just wrong 13-Jun-23 Hernandez-Diaz 66
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Consequences of small numbers + multiple comparisons False Positives when the estimated prevalence for the first specific malformation identified in enrollees (e.g., an oral cleft) is compared with the expected prevalence in the population (e.g., 0.1%)  no cherry picking or when results are selectively reported only if the number of exposed cases is >5  publication bias 13-Jun-23 Hernandez-Diaz 67
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Selective reporting renders false the meanings of statistical significance, P values, and confidence intervals 1 2 .5 3 null 13-Jun-23 Hernandez-Diaz 68
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Solution Careful Interpretation Replication Strategies to increase the power Healthcare Databases International collaborations
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Outline Introduction to Drug Safety in Pregnancy Tools Overview Challenges & Solutions Example 70 13-Jun-23 Hernandez-Diaz
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Background: One report had suggested an increased risk of oral clefts after in utero exposure to topiramate Aim: To estimate the risk of oral clefts in infants whose mothers had taken topiramate as monotherapy during the first trimester of pregnancy Hunt S et al. Topiramate in pregnancy: Preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 2008;71;272-276 Example: Topiramate 13-Jun-23 Hernandez-Diaz 71
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72 http://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm134848.htm 13-Jun-23 Hernandez-Diaz
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73 http://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm134848.htm 13-Jun-23 Hernandez-Diaz
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Established in 1997 at Mass. General Hospital, Boston Enrolls pregnant women taking AEDs, and a reference group of friends and family members not taking AED Women call Consent is obtained verbally for interview. Written consent obtained for maternal and infant’s medical records North American AED Pregnancy Registry 13-Jun-23 Hernandez-Diaz 74
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Three telephone interviews: Enrollment (10-15 min.) 7 Months GA (5 min.) 2 Months postpartum (5 min.) Ask about AED use, demographic characteristics, epilepsy, vitamin use and the presence of malformations For any AED data is collected on indication, dose, and start and stop dates Presence of malformations confirmed by medical records Findings in infant reviewed by teratologist blinded to exposure status North American AED Pregnancy Registry 13-Jun-23 Hernandez-Diaz 75
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Exposed (to other AED) internal reference group Lamotrigine, the most commonly reported AED Unexposed internal reference group Friends and family members not taking AED enrolled in the Registry External reference group Active Malformations Surveillance Program, BWH, 1972 – 2000 206,244 livebirths, stillbirths and elective terminations Malformations identified before 5 days of age Reference groups 13-Jun-23 Hernandez-Diaz 76
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Topiramate 13-Jun-23 Hernandez-Diaz 77
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Risk of major malformations among infants exposed to specific AED in monotherapy during the first trimester Hernández-Díaz S, Smith CR, Shen A, Mittendorf R, Hauser WA, Yerby M, Holmes BH. Comparative Safety of Antiepileptic Drugs during Pregnancy. Neurology 2012;78:1692-1699. 13-Jun-23 Hernandez-Diaz 78
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4 of these 11 were oral clefts (13.5/1,000) Frequency in the external control group: 0.7/1,000 Conclusion: Need to replicate Topiramate 13-Jun-23 Hernandez-Diaz 79
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Topamax (topiramate): Label Change - Risk For Development of Cleft Lip and/or Cleft Palate in Newborns Available as generic topiramate AUDIENCE: Neurology, OB/GYN ISSUE: FDA notified healthcare professionals and patients of an increased risk of development of cleft lip and/or cleft palate (oral clefts) in infants born to women treated with Topamax (topiramate) during pregnancy. Because of new human data that show an increased risk for oral clefts, topiramate is being placed in Pregnancy Category D. Pregnancy Category D means there is positive evidence of human fetal risk based on human data but the potential benefits from use of the drug in pregnant women may be acceptable in certain situations despite its risks. The patient medication guide and prescribing information for Topamax and generic topiramate will be updated with the new information. BACKGROUND: Topiramate is an anticonvulsant medication approved for use alone or with other medications to treat patients with epilepsy who have certain types of seizures. Topiramate is also approved for use to prevent migraine headaches. The new data was from the North American Antiepileptic Drug (NAAED) Pregnancy Registry. RECOMMENDATION: Before starting topiramate, pregnant women and women of childbearing potential should discuss other treatment options with their health care professional. Women taking topiramate should tell their health care professional immediately if they are planning to or become pregnant. Patients taking topiramate should not stop taking it unless told to do so by their health care professional. Women who become pregnant while taking topiramate should talk to their health care professional about registering with the North American Antiepileptic Drug Pregnancy Registry, a group that collects information about outcomes in infants born to women treated with antiepileptic drugs during pregnancy. 13-Jun-23 Hernandez-Diaz 80
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Two North American birth defects case control studies Slone Epidemiology Center Birth Defects Study (BDS) Centers for Disease Control and Prevention National Birth Defects Prevention Study (NBDPS) The two studies have many similarities: Study design Data collection methods (e.g. identification of cases and controls; a computer-assisted telephone interview) Case classification (i.e. by expert clinical reviewers) Controls are live born infants without birth defects Replication: Topiramate 13-Jun-23 Hernandez-Diaz 81
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AED, antiepileptic drug; CI, confidence interval; CL/P, cleft lip with or without cleft palate; MCM, major congenital malformations; OR, odds ratio * Conditional on year and region of birth, and study Slone Epidemiology Center Birth Defects Study Centers for Disease Control and Prevention National Birth Defects Prevention Study Results from pooled data Margulis AV, Mitchell AA, Gilboa SM, Werler MM, Mittleman MA, Glynn RJ, Hernández-Díaz S, and the National Birth Defects Prevention Study. Use of topiramate in pregnancy and the risk of oral clefts. Am J Obstet Gynecol 2012;207:405.e1-7. 13-Jun-23 Hernandez-Diaz 82
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Joint state and federal health insurance program for low-income families Covers ~50% of births in the U.S Medicaid enrollment & health care utilization data Demographics, insurance enrollment information Diagnostic and therapeutic procedures (ICD-9/10; CPT) Diagnoses (ICD-9/10) Dispensed outpatient prescription medications (drug, dose, days supply) Cohort Woman-infant linkage 1.3 M pregnancies ending in live birth in which women were enrolled in Medicaid from 3 months before the LMP through 1 month post delivery, and infants were enrolled for ≥3 months Continuously updated as new information released by CMS: 2000-2014, ~1.9 M linked pregnancies Medicaid Analytic eXtract (MAX) Palmsten K, Huybrechts KF, Mogun H, Kowal MK, Williams PL, Michels KB, Setoguchi S, Hernández-Díaz S. Harnessing the Medicaid Analytic eXtract (MAX) to Evaluate Medications in Pregnancy: Design Considerations. PLoS One 2013;8(6):e67405 13-Jun-23 Hernandez-Diaz 83
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Hernandez-Diaz S, Huybrechts KF, Desai RJ, Cohen JM, Mogun H, Pennell PB, Bateman BT, Patorno E. Topiramate use early in pregnancy and the risk of oral clefts. A pregnancy cohort study. Neurology. 2017; 90(4):e342-e351. Replication: Topiramate 13-Jun-23 Hernandez-Diaz 84
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If pooled results represent the “truth”, the absolute risk of CL/P would increase from approximately 1 per 1,000 births to 5 per 1,000 births Replication: Topiramate 13-Jun-23 Hernandez-Diaz 85
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Outline Introduction to Drug Safety in Pregnancy Tools Overview Challenges & Solutions Example Future 86 13-Jun-23 Hernandez-Diaz
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87 Harvard Program on Perinatal and Pediatric Pharmacoepidemiology www.harvardpreg.org 13-Jun-23 Hernandez-Diaz
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88 Sonia Hernandez-Diaz, MD, DrPH Professor, Dept. of Epidemiology, Harvard Chan School of Public Health Krista F. Huybrechts, PhD Associate Professor of Medicine, Brigham and Women's Hospital and Harvard Medical School Brian T. Bateman, MD, MSc Associate Professor of Anesthesia, Brigham and Women's Hospital and Harvard Medical School 13-Jun-23 Hernandez-Diaz
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89 Funding: NIMH, NICHD, NIDA AHRQ FDA Eli Lilly, GlaxoSmithKline, Pfizer, Shire (Takeda) Research Activity: >50 Publications Book Chapters Courses Presentations Students/Fellows/Trainees http://www.harvardpreg.org/ Methods Pediatrics Vaccines Auto-immune disorders (MS, RA, IBD) Pain (opioids) HIV Diabetes Asthma Cardiovascular/Metabolic Psychiatry / Neurology Areas of interest 13-Jun-23 Hernandez-Diaz
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90 Funding: NIMH, NICHD, NIDA AHRQ FDA Eli Lilly, GlaxoSmithKline, Pfizer, Shire (Takeda) Research Activity: >50 Publications Book Chapters Courses Presentations Students/Fellows/Trainees http://www.harvardpreg.org/ Validations Neurodevelopment Infections Maternal mortality NAS Birth defects Gestational diabetes Prematurity Preeclampsia Fetal death Outcomes 13-Jun-23 Hernandez-Diaz
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Future Next level for less commonly used drugs: Big Data Pooling We had a dream… Identify Exposed Pregnancy Cohorts Nested in a multi-national collaboration of health care databases with demonstrated ability to study the safety of medications in pregnancy 13-Jun-23 Hernandez-Diaz 91
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92 13-Jun-23 Hernandez-Diaz
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93 Advantages Prospective drug exposure information. No recall bias. Concentrating on selected drugs can increase efficiency, particularly to study uncommon drugs in relation to common events. Longitudinal. Can estimate risk and risk differences. Assess real use through maternal interview. Can study multiple exposures and multiple outcomes Registries 13-Jun-23 Hernandez-Diaz
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94 Limitations Non-representative (self-referral bias, volunteers). Often lack control group (non-comparable external comparison groups). Inefficient (cost and time). Limited power. Short follow up (cannot assess late development). Left truncation. Enrollment late in pregnancy Right truncation. Losses to follow-up (selective under-ascertainment) Registries 13-Jun-23 Hernandez-Diaz
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95 Advantages Information on non-prescription drugs. Assess real use. Information on wide range of covariates. Statistical power to study the risk of specific (uncommon) birth defects in relation to relatively common medications. Case-Control Studies 13-Jun-23 Hernandez-Diaz
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96 Limitations May be relatively slow to complete. Cost and time. Rely on volunteer participation (under-represent minorities). Need to identify a valid control group (e.g. malformed controls). Need to obtain complete and unbiased drug exposure information Case-Control Studies 13-Jun-23 Hernandez-Diaz
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97 Advantages Population based. No control selection bias Prospective drug exposure information. No recall bias Information on a wide range of confounders Efficient (cost and time) Real clinical practice, not limited to volunteers Longitudinal. Can estimate risk and risk differences Can study multiple exposures and multiple outcomes May have large sample size Healthcare Databases 13-Jun-23 Hernandez-Diaz
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98 Limitations Limited to prescription drugs Assess prescription or dispensing ≠ real use (need sensitivity analyses) Incomplete ascertainment of terminations (need sensitivity analyses) Limited information on specific potential confounders, e.g. BMI (need sensitivity analyses) Limited power when exposure & outcome are infrequent (need collaborations) Relatively short follow up (explore feasibility of studying long-term consequences) Healthcare Databases 13-Jun-23 Hernandez-Diaz