Katherine E. Kelley

Medication Use During Pregnancy, With Particular Focus On Prescription Drugs: 1976-2008

OBJECTIVE The objective of the study was to provide information on overall medication use throughout pregnancy, with particular focus on the first trimester and specific prescription medications. STUDY DESIGN The study design included the Slone Epidemiology Center Birth Defects Study, 1976-2008, and the National Birth Defects Prevention Study, 1997-2003, which together interviewed more than 30,000 women about their antenatal medication use. RESULTS Over the last 3 decades, first-trimester use of prescription medication increased by more than 60%, and the use of 4 or more medications more than tripled. By 2008, approximately 50% of women reported taking at least 1 medication. Use of some specific medications markedly decreased or increased. Prescription medication use increased with maternal age and education, was highest for non-Hispanic whites, and varied by state. CONCLUSION These data reflect the widespread and growing use of medications by pregnant women and reinforce the need to study their respective fetal risks and safety.

Medications as a potential source of exposure to phthalates in the U.S. population.

Background Widespread human exposure to phthalates, some of which are developmental and reproductive toxicants in experimental animals, raises concerns about potential human health risks. Underappreciated sources of exposure include phthalates in the polymers coating some oral medications. Objective The objective of this study was to evaluate whether users of phthalate-containing medications have higher urinary concentrations of phthalate metabolites than do nonusers. Methods We used publically available files from the National Health and Nutrition Examination Survey for the years 1999–2004. For certain survey periods, participants were asked to recall use of prescription medication during the past 30 days, and for a subsample of individuals, the urinary concentrations of phthalate metabolites were measured. We a priori identified medications potentially containing phthalates as inactive ingredients and then compared the mean urinary concentration of phthalate metabolites between users and nonusers of those medications. Results: Of the 7,999 persons with information on urinary phthalate concentrations, 6 reported using mesalamine formulations, some of which may include dibutyl phthalate (DBP); the mean urinary concentration of monobutyl phthalate, the main DBP metabolite, among these mesalamine users was 50 times higher than the mean for nonusers (2,257 μg/L vs. 46 μg/L; p < 0.0001). Users of didanosine, omeprazole, and theophylline products, some of which may contain diethyl phthalate (DEP), had mean urinary concentrations of monoethyl phthalate, the main DEP metabolite, significantly higher than the mean for nonusers. Conclusion Select medications might be a source of high exposure to some phthalates, one of which, DBP, shows adverse developmental and reproductive effects in laboratory animals. These results raise concern about potential human health risks, specifically among vulnerable segments of the general population and particularly pregnant women and children.

Identification of Phthalates in Medications and Dietary Supplement Formulations in the United States and Canada

Background: In animal studies, some ortho-phthalates, including di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP), have been shown to be reproductive and developmental toxicants. Human studies show widespread population exposure to background levels of phthalates. Limited evidence suggests that particularly high exposure levels may result from orally ingested medicinal products containing phthalates as excipients (inactive ingredients). Objective: In this study we aimed to identify and describe the scope of prescription (RX) and nonprescription (over-the-counter; OTC) medicinal products and dietary supplements marketed in the United States and Canada since 1995 that include phthalates as excipients. Methods: We used lists of modified-release drug products to identify potential drug products. Inclusion of phthalates was verified using available electronic databases, print references, published package inserts, product packages, and direct communication from manufacturers. Additional products were identified using Internet searches utilizing keywords for phthalates. Results: Based on labeling information, 6 RX drug products included DBP as an excipient, and 45 specified the use of diethyl phthalate (DEP). Phthalate polymers with no known toxicity—hypromellose phthalate (HMP), cellulose acetate phthalate (CAP), and polyvinyl acetate phthalate (PVAP)—were included in 75 RX products. Three OTC drug and dietary supplement products listed DBP, 64 listed DEP, and > 90 indicated inclusion of polymers. Conclusions: Numerous RX and OTC drug products and supplements from a wide range of therapeutic categories may use DBP or DEP as excipients in oral dosage forms. The potential effects of human exposure to these phthalates through medications are unknown and warrant further investigation.

Prenatal Nitrate Intake from Drinking Water and Selected Birth Defects in Offspring of Participants in the National Birth Defects Prevention Study

Background: Previous studies of prenatal exposure to drinking-water nitrate and birth defects in offspring have not accounted for water consumption patterns or potential interaction with nitrosatable drugs. Objectives: We examined the relation between prenatal exposure to drinking-water nitrate and selected birth defects, accounting for maternal water consumption patterns and nitrosatable drug exposure. Methods: With data from the National Birth Defects Prevention Study, we linked addresses of 3,300 case mothers and 1,121 control mothers from the Iowa and Texas sites to public water supplies and respective nitrate measurements. We assigned nitrate levels for bottled water from collection of representative samples and standard laboratory testing. Daily nitrate consumption was estimated from self-reported water consumption at home and work. Results: With the lowest tertile of nitrate intake around conception as the referent group, mothers of babies with spina bifida were 2.0 times more likely (95% CI: 1.3, 3.2) to ingest ≥ 5 mg nitrate daily from drinking water (vs. < 0.91 mg) than control mothers. During 1 month preconception through the first trimester, mothers of limb deficiency, cleft palate, and cleft lip cases were, respectively, 1.8 (95% CI: 1.1, 3.1), 1.9 (95% CI: 1.2, 3.1), and 1.8 (95% CI: 1.1, 3.1) times more likely than control mothers to ingest ≥ 5.42 mg of nitrate daily (vs. < 1.0 mg). Higher water nitrate intake did not increase associations between prenatal nitrosatable drug use and birth defects. Conclusions: Higher water nitrate intake was associated with several birth defects in offspring, but did not strengthen associations between nitrosatable drugs and birth defects. Citation: Brender JD, Weyer PJ, Romitti PA, Mohanty BP, Shinde MU, Vuong AM, Sharkey JR, Dwivedi D, Horel SA, Kantamneni J, Huber JC Jr., Zheng Q, Werler MM, Kelley KE, Griesenbeck JS, Zhan FB, Langlois PH, Suarez L, Canfield MA, and the National Birth Defects Prevention Study. 2013. Prenatal nitrate intake from drinking water and selected birth defects in offspring of participants in the National Birth Defects Prevention Study. Environ Health Perspect 121:1083–1089; http://dx.doi.org/10.1289/ehp.1206249

Medications as a potential source of exposure to phthalates among women of childbearing age

OBJECTIVE To evaluate the association between the use of medications potentially containing phthalates and urinary concentrations of specific phthalate metabolites around conception. METHODS Women enrolled in the Environment and Reproductive Health project from 2006 to 2009 completed questionnaires about the use of medications and provided multiple urine samples before and after conception. We compared the mean urinary concentration of phthalate metabolites between users of phthalate containing medications and a matched unexposed control group. RESULTS One woman used Asacol(®) (mesalamine), which utilizes dibutyl phthalate (DBP) as a delayed release coating material, and had a mean urinary concentration of the main DBP metabolite 200 times higher than the controls (8176μg/L vs. 37.5μg/L). The three users of stool softeners had a higher concentration of the main diethyl phthalate (DEP) metabolite (8636μg/L vs. 714.2μg/L). Neither the three additional Prilosec(®) (omeprazole) users nor one cyclobenzaprine user had higher urinary concentration than controls. CONCLUSION Selected medications may be important sources of DBP and DEP exposures around conception.

Nitrosatable drug exposure during the first trimester of pregnancy and selected congenital malformations

BACKGROUND Nitrosatable drugs can react with nitrite in the stomach to form N-nitroso compounds, and results from animal studies suggest that N-nitroso compounds are teratogens. With data from the National Birth Defects Prevention Study, the relation between prenatal exposure to nitrosatable drugs and limb deficiencies, oral cleft, and heart malformations in offspring was examined. METHODS Maternal reports of drugs taken during the first trimester of pregnancy were classified with respect to nitrosatability for mothers of 741 babies with limb deficiencies, 2774 with oral cleft malformations, 8091 with congenital heart malformations, and 6807 without major congenital malformations. Nitrite intake was estimated from maternal responses to a food frequency questionnaire. RESULTS Isolated transverse limb deficiencies and atrioventricular septal defects were associated with secondary amine drug exposures (adjusted odds ratios [aORs], 1.51; 95% confidence limit [CI], 1.11-2.06 and aOR, 1.97; 95% CI, 1.19-3.26, respectively). Tertiary amines were associated with hypoplastic left heart syndrome (aOR, 1.50; 95% CI, 1.10-2.04) and single ventricle (aOR, 1.61; 95% CI, 1.06-2.45). These two malformations were also significantly associated with amide drugs. For several malformations, the strongest associations with nitrosatable drug use occurred among mothers with the highest estimated dietary nitrite intake, especially for secondary amines and atrioventricular septal defects (highest tertile of nitrite, aOR, 3.30; 95% CI, 1.44-7.58). CONCLUSION Prenatal exposure to nitrosatable drugs may be associated with several congenital malformations, especially with higher nitrite intake. The possible interaction between nitrosatable drugs and dietary nitrite on risk of congenital malformations warrants further attention.

Prevalence and Patterns of Nitrosatable Drug Use among U.S. Women during Early Pregnancy

BACKROUND Experimental evidence indicates that certain drugs, that are secondary or tertiary amines or amides, form N-nitroso compounds in the presence of nitrite in an acidic environment. Nitrosatable drugs have been associated with birth defects in a few epidemiologic studies. This study describes the prevalence and patterns of nitrosatable drug use among U.S. women during early pregnancy and examines maternal factors associated with such use. METHODS Data were analyzed from the National Birth Defects Prevention Study and included 6807 mothers who gave birth to babies without major congenital malformations during 1997 to 2005. Information was collected by telephone interview about medication use, demographic factors, and maternal health. Drugs taken during the first trimester were classified according to nitrosatability, amine and amide functional groups, and primary indication of use. RESULTS Approximately 24% of the women took one or more nitrosatable drugs during the first trimester, including 12.4%, 12.2%, and 7.6% who respectively took secondary amines, tertiary amines, or amides. Five of the ten most commonly taken drugs were available over the counter. Women who were non-Hispanic white (29.5%), with 1 year or more college education (27.3%) or 40 years or older (28.8%) had the highest prevalence of use. Supplemental vitamin C, an inhibitor of nitrosation, was not taken by 41.6% and 19.3% of nitrosatable drug users during the first and second months of pregnancy, respectively. CONCLUSIONS In this U.S. population, ingestion of drugs classified as nitrosatable was common during the first trimester of pregnancy, especially among non-Hispanic white, more educated, and older mothers. Birth Defects Research (Part A) 2011.

Increasing use of ADHD medications in pregnancy

To the Editor: Attention-deficit hyperactivity disorder (ADHD) is one of the most common conditions of childhood1, 2 and is typically treated with medication. Once initiated, medication often becomes chronic therapy and approximately 30% of patients are estimated to continue pharmacologic treatment into adulthood3. As a result, these drugs are likely to be used by pregnant women, raising concerns about possible fetal exposure. A recent publication noted that premarket studies focused only on the short-term safety and efficacy of these medications in children4; further, no premarketing studies have focused on pregnant women and their offspring. To identify the prevalence of use of ADHD medications among pregnant women, we reviewed data from the Slone Epidemiology Center’s Birth Defects Study (BDS), an ongoing case-control surveillance effort focused on birth defects in relation to antenatal medication use. BDS methods have been described previously5–7. Infants with any of a wide range of malformations (cases) are identified at hospital-based study centers and state-based birth defects registries; during the years of the present analysis, these include the areas surrounding Philadelphia, Toronto (through 2003), San Diego (initiated 2000), and Nashville (initiated 2012), as well as a portion of New York State and the state of Massachusetts. A sample of nonmalformed infants (controls) is identified at study hospitals in all centers; in 1998, enrollment in Massachusetts was expanded to include a population-based random sample of newborns. The current analysis was restricted to interviews conducted between 1998 (corresponding to women whose last menstrual period [LMP] was in 1997), and July, 2014 (LMPs in 2013). To identify medication exposure, BDS uses a series of questions designed to maximize recall. We first inquire about specific illnesses and conditions that may have occurred during pregnancy, followed by questions about use of medications for specific indications; we then inquire about certain specifically-named medications. In July, 2013, we added a specific indication for ADD/ADHD (“attention disorder, [ex, ADD or ADHD”). Prior to that, these medications were typically reported in response to the indication “Other psychological condition” or “Medication for any other reason.” Because of this change in the specificity of the question, we examined trends separately for the interviews conducted before and after its introduction. We defined medications used to treat ADHD to be any of the following: amphetamine mixed salts (Adderall®/Adderall XR® and generics), methylphenidate HCl (Ritalin®, Concerta® and generics), lisdexamfetamine dimesylate (Vyvanse®), dextroamphetamine (Dexedrine® and generics), and atomoxetine (Strattera®). We included all exposures at any time from the LMP through the pregnancy. This study has been approved by the institutional review boards of Boston University Medical Center and all participating institutions as appropriate. There were 29,540 women who were interviewed between 1998 and 2014; 87 reported exposure to an ADHD medication. While the overall prevalence of use of any ADHD medication was 0.3%, there was a marked increase in the prevalence of use over the period of the study, from 0.2% for women with LMP dates in 1997–98 to 1.3% for women with LMP dates in 2013 (2-sided Cochran-Armitage test for trend: p<.0001), Figure 1). Because of the addition of a specific ADHD indication prompt in mid-2013, affecting women with LMP dates in 2012, we examined the prevalence of use for LMP year 2012 according to whether the interviews were conducted before or after the change. For subjects with LMPs in 2012, 902 were interviewed prior to the introduction of the new prompt and use was 0.9%; among the 1,352 interviewed with the new prompt, the prevalence was 1.0%. We therefore combined the pre- and post-modification data. Figure 1 Trends in the use of ADHD medications during pregnancy according to LMP year The most commonly-reported ADHD medication was amphetamine mixed salts (Adderall®/Adderall XR® and generics), which accounted for 57.5% of total exposures. Use of this product was not reported for LMP years 1997–98, while for LMP year 2013 the prevalence was 1.0% (2-sided Cochran-Armitage test for trend: p<.0001, Figure 1); this increase entirely accounts for the overall increase in ADHD medications. Other medications included methylphenidate (Ritalin®, Concerta® and generics), lisdexamfetamine dimesylate (Vyvanse®), and atomoxetine HCl (Strattera®), accounting for 29.9. 5.7, and 3.4% of total exposures, respectively. Of the 87 women who were exposed to an ADHD medication, all but one used it during the first trimester; 18 (20.7%) continued use into the second trimester and 11 (12.6%) continued into the third trimester. We examined trends separately for cases (19,811) and controls (9,729) and for each center (Boston, 9,476; Philadelphia, 7,970; Toronto, 3,323; San Diego, 4,969; New York, 3,531; Tennessee, 271). The secular trends were not explained by either factor; the trends were most striking in the centers with the largest sample sizes. We observed a markedly increasing trend in the use of ADHD medications in pregnancy from 1998 through 2013. Given other reports documenting that use of these drugs is increasing in the adult population, this is not surprising2, 8. To our knowledge, only one other study, conducted in Denmark, has examined trends in the use of ADHD medications specifically among pregnant women9. Our observation, together with similar findings from Denmark through 20109, raise particular concern because pregnant women constitute a special population for whom exposure carries a potential risk not only to the woman herself, but also to the fetus she is carrying. In animal studies, methylphenidate has not produced teratogenic effects in mice or rats; in rabbits, only doses that were about 40 times the maximum recommended human dose resulted in an increased risk of spina bifida10. Amphetamines given orally in doses approximately 1.5 and 8 times the normal human dose to both pregnant mice and rabbits had no apparent effects on fetal development, although parenteral doses at approximately 6 times the human dose resulted in fetal malformations in mice.11 However, it is important to note that animal studies are not predictive of human effects12; teratogenicity in animals does not imply the same effect in humans, and lack of teratogenicity in animals does not ensure no effect in humans13. The few human studies that have explored possible effects of these drugs on the fetus included only small numbers of subjects 14, 15 or were primarily focused on methylphenidate15–17, while our experience indicates that amphetamine mixed salts is by far the most common (and most rapidly increasing) ADHD medication used by pregnant women in the United States. With exposure prevalence now approximately 1%, these drugs rank among the most commonly used prescription medications in pregnancy,18, 19 and it is also possible that use will increase further as more women whose exposure began in childhood enter childbearing age. Additional exposures could occur from expanded indications as at least one medication is currently under review for a possible new indication to treat binge eating20, 21. This study relies on self-report, which represents both a potential limitation and a strength. The limitation relates to possible underreporting; however, our interview is designed to maximize recall22. A strength of our approach is that analyses based on exposures identified through other sources, e.g., medical records or claims data, may include prescriptions that are unfilled or unused and fail to capture medications that are borrowed23, all of which can have a major impact on results. The increase in use of ADHD medications in pregnancy, and particularly Adderall®/Adderall XR®, amphetamine mixed salts), together with the troubling lack of information regarding potential fetal risks in humans, indicate that this is an area where postmarketing studies are urgently needed.

Prenatal exposure to nitrosatable drugs, vitamin C, and risk of selected birth defects.

UNLABELLED Nitrosatable drugs, such as secondary or tertiary amines and amides react with nitrite in an acidic environment to form N-nitroso compounds, teratogens in animal models. Vitamin C is a known nitrosation inhibitor. METHODS Using data from the National Birth Defects Prevention Study, we assessed nitrosatable drug exposure and vitamin C intake during the first trimester among 11,606 case-mothers of infants with oral clefts, limb deficiencies (LDs), or congenital heart defects and 6807 control-mothers of infants without major birth defects during 1997-2005. Daily intake of vitamin C was estimated from maternal interviews that elicited information about supplement use and dietary intake. RESULTS With no reported use of nitrosatable drugs as the referent group, a lower odds ratio (OR) was observed for transverse LDs among births to mothers exposed to secondary amine drugs and daily vitamin C supplementation (adjusted odds ratio [aOR] 1.2, 95% confidence interval [CI] 0.83-1.8) compared with women taking these drugs and no supplementation (aOR 2.7, 95% CI 1.5-4.6). The OR for longitudinal LDs associated with secondary amine exposure was lower with daily dietary vitamin C intake ≥85 mg (aOR 1.2, 95% CI 0.68-2.0) compared with <85 mg (aOR 1.9, 95% CI 1.2-3.1). Daily vitamin C supplementation in combination with higher dietary vitamin C intake reduced associations between nitrosatable drug exposures and limb deficiencies and atrial septal defects not otherwise specified. CONCLUSION Prenatal dietary and vitamin C supplement intake may diminish the association between nitrosatable drug exposure during pregnancy and selected birth defects.

Medications as a potential source of exposure to parabens in the U.S. population

Introduction: Use of paraben‐containing medications has been shown to be associated with urinary paraben concentrations among couples undergoing fertility treatment, but it is unknown whether this association is also present among the general population. Methods: A list of prescription medications of interest was developed based on their likelihood of containing parabens and the ability to identify users in the National Health and Nutrition Examination Survey (NHANES); alendronate, escitalopram oxalate, fluoxetine, and olanzapine were chosen. Participants reported whether they had used each medication in the past month. Linear regression models were used to compare model‐based mean urinary concentrations of each paraben among users and non‐users of these four medications. Results: A total of 10,302 respondents were included in the analysis, 265 (2.6%) of whom had reported using a paraben‐containing prescription medication in the previous month. Users of alendronate had mean concentrations of ethyl paraben that were approximately three‐fold higher than non‐users (p ≥ 0.001 in unadjusted and adjusted models), which was likely due to three participants with very high concentrations. No other differences in paraben concentrations were found for any of the medications of interest (all p ≥ 0.13). Compared to non‐users, a significantly greater proportion of alendronate users had butyl and ethyl paraben concentrations above the 95th percentile (17.8% and 12.3%, respectively) compared to non‐users (5.0% and 5.0%, respectively; both p ≤ 0.01), despite ethyl paraben not being an expected ingredient in the brand name formulation of alendronate. Conclusion: Despite previous work showing that medications can be an important source of paraben exposure, there was no clear overall evidence of associations between the use of paraben‐containing medications and increases in urinary paraben concentrations among participants in NHANES 2005–2012. These results highlight the difficulties inherent in proper assessment of exposures with short half‐lives based on a single cross‐sectional biologic sample. HighlightsParaben‐containing medications may an important source of paraben exposure.No clear evidence of paraben exposure from medications in a national dataset.Assessment of exposures with short half‐lives difficult in cross‐sectional samples.Assessing paraben exposure within the correct pharmacokinetic window is crucial.