Dihydroergotamine (DHE) Use During Gestation and the Risk of Adverse Pregnancy Outcomeshead_ Anick Bérard, PhD; Shashidhar Kori, MD

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1 Headache 2012 American Headache Society ISSN doi: /j x Published by Wiley Periodicals, Inc. Research Submission Dihydroergotamine (DHE) Use During Gestation and the Risk of Adverse Pregnancy Outcomeshead_ Anick Bérard, PhD; Shashidhar Kori, MD Background. Dihydroergotamine (DHE) is perceived to be associated with a higher risk of adverse pregnancy events, but it has significantly less vasoconstrictive and uterotonic effects compared with ergotamine, and has demonstrated no teratogenic effect in animals. The objectives of this study were to quantify the risk of major congenital malformations (MCMs), prematurity, low birth weight (LBW), and spontaneous abortions (SAs) associated with gestational use of DHE, triptans, and nonsteroidal anti-inflammatory drugs (NSAIDs). Methods. Four independent case control analyses were conducted within the Quebec Pregnancy Registry: (1) MCM; (2) prematurity (<37 weeks of gestation); (3) LBW (birth weight <2500 g); (4) clinically detected SA. Exposure was defined dichotomously as use of DHE, triptan, and NSAIDs during pregnancy. Results. Overall, 59,707 pregnant women met the eligibility criteria and were considered (53 [0.08%] used DHE, 139 [0.23%] triptans, and 2990 [5.01%] NSAIDs). Adjusting for potential confounders, gestational use of DHE was not significantly associated with the risk of MCM (odds ratio [OR]: 0.97; 95% confidence interval [CI]: ), LBW (OR: 1.41; 95%CI: ), or SA (OR: 1.97; 95% CI: ). DHE use was, however, increasing the risk of prematurity (OR: 4.18; 95% CI: ). In users of triptans, the OR for MCM was 1.49 (95% CI: ), prematurity 0.76 (95% CI: ), LBW 0.83 (95% CI: ), and SA 2.65 (95% CI: ). In users of NSAIDs, the OR for MCM was 1.20 (95% CI: ), prematurity 1.10 (95% CI: ), LBW 1.29 (95% CI: ), and SA 2.97 (95% CI: ). Conclusions. This study showed that other than for prematurity, DHE use during pregnancy was similar to that of triptan use and was smaller than the risk associated with NSAID use. Key words: DHE, spontaneous abortion, major congenital malformations, prematurity, low birth weight, Quebec Pregnancy Registry (Headache 2012;52: ) From the Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada (A. Bérard); Research Center, CHU Ste-Justine, Montreal, QC, Canada (A. Bérard); MAP Pharmaceuticals Inc., Mountain View, CA, USA (S. Kori). Address all correspondence to A. Bérard, Sainte-Justine Hospital, Research Center, 3175, chemin de la Côte-Ste-Catherine, Montreal, QC, H3T 1C5, Canada, anick.berard@umontreal.ca Accepted for publication April 5, Conflicts of Interest: A. Bérard has no conflicts of interest to disclose. S. Kori is a full-time employee of MAP Pharmaceuticals. Funding Source: This study was funded by MAP Pharmaceuticals Inc. Anick Bérard is the recipient of a career award from the Fonds de la recherche en santé du Québec and is on the endowment research chair on Medications, Pregnancy, and Lactation at the Faculty of Pharmacy of the University of Montreal. The results of this article were presented in part at the American Headache Society Conference in Washington, DC, in June 2011, and at the Annual Teratology Society Conference in San Diego, CA, in June

2 1086 July/August 2012 Migraine headaches are greatly influenced by hormone variations and generally improve during pregnancy. 1-4 Minimal changes in frequency or increase in attacks, usually during the first trimester, are experienced by 25% of women with a history of migraine. 2 Many women with migraine will require pharmacological treatment during the first trimester of pregnancy, which corresponds to the most vulnerable period of fetal development. 5-8 Antimigraine therapies include ergotamine, dihydroergotamine (DHE), and selective serotonin 5-HT receptor agonists (triptans), as well as nonspecific drugs such as nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs). However, ergotamine use during pregnancy increases sympathetic activity and vasoconstriction, leading to multiple adverse effects such as decreased uterine blood flow and increased uterine muscle contractility DHE, an ergot alkaloid, is also perceived to be associated with a high risk of adverse pregnancy events. However, DHE has significantly less vasoconstrictive and uterotonic effects compared with ergotamine Furthermore, DHE has demonstrated no teratogenic effect in animals. 14 Hence, to investigate the association between the use of DHE during pregnancy and the risk of adverse pregnancy outcomes, and to compare the risk with that of triptan and NSAID use, we performed a study within the Quebec Pregnancy Registry. METHODS Source of Data. This study was conducted within the Quebec Pregnancy Registry, built with the linkage of three databases: the Régie de l assurance maladie du Québec (RAMQ), MED-ECHO, and the Institut de la statistique du Québec (ISQ) databases. The RAMQ database provides prospectively collected data on filled prescriptions, physician-based diagnoses, physician and emergency department visits, hospitalizations, and health care provider and patient characteristics. 15,16 RAMQ covers all 7.3 million residents of Quebec for medical services and 53% of the population for pharmaceutical services. The MED- ECHO database, which is a hospital database put in place for patient follow-ups, records acute care hospitalization data for all Quebec residents, including gestational age (defined from the first day of the last menstrual period to the end of pregnancy, confirmed by ultrasound) for planned and spontaneous abortions, and deliveries. 17 The Fichier des événements démographiques, administered by the ISQ, provides data on all births and stillbirths including birth weight and gestational age at deliveries. Pregnancy-related variables such as birth weight, gestational age, and date of delivery, as well as physician-based ICD-9 codes of MCM, have been compared and validated against patient charts. 18,19 Women are followed from the date of entry in the registry, defined as the first day of the last menstrual period confirmed by ultrasound, until the end of pregnancy (planned or spontaneous abortion, or delivery). Study Population: Cohort Definition. Women in the Quebec Pregnancy Registry with pregnancies that occurred between January 1, 1998 and December 31, 2007 were included in the study population if they were between 15 and 45 years of age on the date of entry, and continuously insured by the RAMQ drug plan for at least 12 months prior to and during pregnancy. If a woman had more than 1 pregnancy during the study period, only the first pregnancy meeting the eligibility criteria was considered. For each pregnant woman, we obtained data on all filled prescriptions in the year preceding and during pregnancy including date of filling, name, dosage, form, quantity, and duration. From the RAMQ, we also obtained data on all inpatient and ambulatory medical services, including physician-based diagnoses provided before and during pregnancy, and in the 12 months postpartum. MED-ECHO provided data on all maternal acute care hospitalizations in the year prior and during pregnancy, and in the year after pregnancy for the mother and the baby. The ISQ provided data relevant to the pregnancy (parity, gestational age), maternal education level, marital status, and baby characteristics (gender, birth weight, gestational age at delivery). Study Design. Four independent nested case control analyses were performed within the study cohort to estimate the association between DHE, triptan, and NSAID exposure during pregnancy and the risk of: (1) major congenital malformations (MCMs), (2) prematurity (<37 weeks of gestation),

3 Headache 1087 (3) low birth weight (LBW) (<2500 g), and (4) spontaneous abortions (SAs). Pregnancy Outcomes. For the case control analyses on MCM, prematurity, and LBW, only pregnancies ending in a live birth were considered. For these 3 outcomes, index date was the date of delivery. MCMs. All cases of MCMs were identified during the first year of life using validated ICD-9 physician-based diagnostic codes (ICD-9: , , , , , , , , , , and ) recorded in the RAMQ and MED-ECHO databases. Our list of MCM was compared with the list provided by the US Collaborative Perinatal Group 20 and validated by a geneticist. Women having delivered babies with no major or minor congenital malformations (ICD-9 codes for minor malformations: 7436, , 744.8, 744.9, 747.0, 747.5, 750.0, 752.4, 752.5, 754.6, 755.0, 755.1, , and 758.4) were defined as controls. Prematurity. Cases were defined as women who delivered a preterm infant (<37 weeks gestation). Controls were defined as women who gave birth at 37 weeks of gestation. LBW. Cases of LBW were defined as women giving birth to an infant weighing <2500 g. Controls were women that gave birth to a newborn weighing 2500 g. SA. For this outcome, women with planned abortions were excluded from analyses. Within our study cohort of pregnant women, cases were defined as women with a diagnosis or procedure for SA that occurred anytime between the first day and the 20th week of gestation. Only women with clinically detected SAs were considered and included, as has been done in previous studies on this research question. 19 Index date was defined as the calendar date of the SA. Ten controls were randomly selected for each case, and matched on index date and gestational age. Using a nested case control design, controls were selected among subjects at risk of having an SA conditional on their gestational age. 17 Maternal Exposure to DHE. For each analysis, exposure to DHE (Drug Identification Numbers [DINs]: , , and ) during pregnancy was assessed dichotomously (yes/no) as having filled at least 1 prescription between the 30-day time window before gestation until index date. Maternal Exposure to Triptans and NSAIDs. Similarly, for each case control analysis, we assessed exposure to triptans (American Hospital Formulary [AHF] class 28:31.28: naratriptan, rizatriptan, sumatriptan, zolmitriptan) and nonaspirin NSAIDs (AHF class 28:08.04: naproxen, ibuprofen, diclofenac, celecoxib, rofecoxib, flurbiprofen, nabumetone, etodolac, ketoprofen, piroxicam, diflunisal, meloxicam, tiaprofenic acid, sulindac) during pregnancy dichotomously (yes/no) and independently as having filled at least 1 prescription between the 30-day time window before gestation until index date. Potential Confounding Variables. The following risk factors for our outcomes of interest were considered potential confounding variables: (1) maternal sociodemographic characteristics on the first day of gestation (maternal age, welfare status, area of residence [rural/urban]); (2) pregnancy-related variables (gestational age at index date); and (3) maternal chronic conditions (chronic or gestational hypertension and diabetes assessed using physician-based diagnoses or filled prescriptions of related medications in the year before pregnancy until index date). The presence of migraine before pregnancy was considered a potential confounder (given that it is associated with antimigraine drug use and adverse perinatal outcomes), and was identified from physician-based diagnoses of migraine or filled prescriptions for DHE or triptans in the year prior to gestation. This was done to specifically take into account indication bias, and thus sort out the effect of the drugs from the effect of the underlying indication or disease. Although it is true that migraine patients qualify for antimigraine drugs, not all of them will receive pharmacological treatment; nonaspirin NSAIDs have other indications. Statistical Analyses. For each study outcome, descriptive statistics were calculated with P values obtained from independent t-tests for continuous variables and chi-square tests for categorical variables. Crude and adjusted odds ratios (OR) with 95% confidence intervals (CI) were obtained using conditional logistic regression models for all 4 case control

4 1088 July/August 2012 analyses separately. To adjust for confounding by indication, we considered variables that were associated with the use of DHE such as history of migraine. Other potential confounders were kept in the models if they were modifying risk estimates by more than 10% in the univariate analyses. Ethics Approval. This study was approved by CHU Ste-Justine s Ethics Committee. The Commission d accès à l information du Québec has authorized the linkage between databases. RESULTS Overall, 59,707 pregnant women met the eligibility criteria and were considered for analyses (53 [0.08%] used DHE, 139 [0.23%] triptans, and 2990 [5.01%] NSAIDs) (Table 1). Overall mean maternal age was 27.3 years (standard deviation [SD]: 5.7), and mean gestational age for pregnancies resulting in live Table 1. Study Population Quebec Pregnancy Registry N = 59,707 n (%) DHE 53 (0.08) Triptans 139 (0.23) NSAIDs 2990 (5.01) Maternal age (year) on the first day of gestation (mean SD) Gestational age (weeks) (mean SD) Region of residence (urban vs rural [ref]) 13,971 (23.4) Welfare recipient 18,292 (30.6) Diabetes (chronic and/or gestational) 4151 (6.95) Hypertension (chronic and/or 3917 (6.56) gestational) Migraine prior to gestation 1649 (2.76) Diagnosis of chronic or gestational hypertension defined as having a diagnosis of hypertension or a filling for an antihypertensive drug in the year before or during pregnancy; diagnosis of chronic or gestational diabetes defined as having a diagnosis of diabetes or a filling for an antidiabetic drug including insulin in the year before or during pregnancy. Diagnosis of migraine or fillings of at least 1 prescription of DHE or triptan. DHE = dihydroergotamine; NSAID = nonaspirin nonsteroidal anti-inflammatory drug; SD = standard deviation. births was 39.0 weeks (SD: 1.9) (Table 1). Clinically detected SAs were diagnosed at 12 weeks of gestation on average (SD: 1.5) (data not shown). Among live births, 4716 (7.9%) pregnancies resulted in a newborn with at least 1 MCM (5 [9%] DHE users, 18 [13%] triptan users, 286 [10%] NSAID users) (Table 2), which is in line with the population average within the Quebec Pregnancy Registry. 21 Adjusting for potential confounders including history of migraine and/or antimigraine drug use, DHE and triptan use during pregnancy were not statistically significantly associated with the risk of MCMs (OR: 0.97 [95% CI: ] and 1.49 [95% CI: ) for DHE and triptan use, respectively). However, NSAID use during pregnancy was significantly associated with the risk of MCMs (OR: 1.20; 95% CI: ) (Table 2). Overall, among live births, 3941 (6.6%) pregnant women had a preterm delivery (9 [17%] DHE users, 7 [5%] triptan users, 225 [8%] NSAID users) (Table 3). Irrespective of medication use, cases delivered on average at 34.1 weeks of gestation (SD: 2.8), and controls at 39.3 weeks of gestation (SD: 1.1) (Table 3). Adjusting for potential confounders, DHE use during pregnancy was statistically significantly increasing the risk of prematurity (OR: 4.18; 95% CI: ) (Table 3). Triptan and NSAID use during pregnancy were not statistically significantly associated with the risk of prematurity (OR: 0.76 [95% CI: ] and 1.10 [95% CI: ] for triptan and NSAID use, respectively) (Table 3). Among live births, 3389 (5.7%) pregnant women delivered an LBW infant (8 [15%] DHE users, 6 [4%] triptan users, 227 [8%] NSAID users) (Table 4). The mean birth weight for cases and controls were 2038 g (SD: 478) and 3420 g (SD: 453), respectively (data not shown). Adjusting for potential confounders including indication for use, DHE and triptan use during pregnancy were not statistically significantly associated with the risk of LBW infants (OR: 1.41 [95% CI: ] and 0.83 [95% CI: ] for DHE and triptan use, respectively). However, NSAID use during pregnancy was significantly associated with the risk of LBW (OR: 1.29; 95% CI: ) (Table 4).

5 Headache 1089 Table 2. Use of DHE, Triptans, and NSAIDs During Pregnancy and the Risk of Major Congenital Malformations Cases Controls N = 4716 N = 54,991 n (%) n (%) Crude Odds Adjusted Odds DHE 5 (0.10) 48 (0.08) 1.27 ( ) 0.97 ( ) Triptans 18 (0.38) 121 (0.22) 1.74 ( ) 1.49 ( ) NSAIDs 286 (6.06) 2704 (4.92) 1.25 ( ) 1.20 ( ) Maternal age (year) on the first day of gestation ( ) 1.00 ( ) (mean SD) Gestational age (weeks) (mean SD) ( ) 0.88 ( ) Region of residence (urban vs rural [ref]) 937 (19.9) 13,034 (23.7) 1.25 ( ) 1.25 ( ) Welfare recipient 1471 (31.2) 16,821 (30.6) 1.03 ( ) 0.97 ( ) Diabetes (chronic and/or gestational) 388 (8.23) 3763 (6.84) 1.22 ( ) 1.11 ( ) Hypertension (chronic and/or gestational) 411 (10.49) 3506 (6.38) 1.40 ( ) 1.24 ( ) Migraine prior to gestation 157 (3.33) 1492 (2.71) 1.23 ( ) 1.16 ( ) Diagnosis of chronic or gestational hypertension defined as having a diagnosis of hypertension or a filling for an antihypertensive drug in the year before or during pregnancy; diagnosis of chronic or gestational diabetes defined as having a diagnosis of diabetes or a filling for an antidiabetic drug including insulin in the year before or during pregnancy. Diagnosis of migraine or fillings of at least 1 prescription of DHE or triptan. CI = confidence interval; DHE = dihydroergotamine; NSAID = nonaspirin nonsteroidal anti-inflammatory drug; SD = standard deviation. Table 3. Use of DHE, Triptans, and NSAIDs During Pregnancy and the Risk of Prematurity Cases Controls N = 3941 N = 55,766 n (%) n (%) Crude Odds Adjusted Odds DHE 9 (0.22) 44 (0.07) 3.14 ( ) 4.18 ( ) Triptans 7 (0.18) 132 (0.24) 0.75 ( ) 0.76 ( ) NSAIDs 225 (5.7) 2765 (4.96) 1.16 ( ) 1.10 ( ) Maternal age on the first day of gestation (mean SD) ( ) 1.00 ( ) Region of residence (rural vs urban [ref]) 891 (22.6) 13,080 (23.5) 1.05 ( ) 1.01 ( ) Welfare recipient 1451 (36.8) 16,841 (30.2) 1.35 ( ) 1.35 ( ) Diabetes (chronic and/or gestational) 384 (9.74) 3767 (6.76) 1.49 ( ) 1.34 ( ) Hypertension (chronic and/or gestational) 574 (14.56) 3343 (5.99) 2.67 ( ) 2.62 ( ) Migraine prior first day of gestation 103 (2.61) 1546 (2.77) 0.94 ( ) 0.90 ( ) Diagnosis of chronic or gestational hypertension defined as having a diagnosis of hypertension or a filling for an antihypertensive drug in the year before or during pregnancy; diagnosis of chronic or gestational diabetes defined as having a diagnosis of diabetes or a filling for an antidiabetic drug including insulin in the year before or during pregnancy. Diagnosis of migraine or fillings of at least 1 prescription of DHE or triptan. CI = confidence interval; DHE = dihydroergotamine; NSAID = nonaspirin nonsteroidal anti-inflammatory drug; SD = standard deviation.

6 1090 July/August 2012 Table 4. Use of DHE, Triptans, and NSAIDs During Pregnancy and the Risk of Low Birth Weight Infants Cases Controls N = 3389 N = 56,318 n (%) n (%) Crude Odds Adjusted Odds DHE 8 (0.23) 45 (0.07) 3.28 ( ) 1.41 ( ) Triptans 6 (0.18) 133 (0.24) 0.75 ( ) 0.83 ( ) NSAIDs 227 (6.70) 2763 (4.91) 1.39 ( ) 1.29 ( ) Maternal age on the first day of gestation (mean SD) ( ) 1.01 ( ) Gestational age (weeks) at birth (mean SD) ( ) 0.44 ( ) Region of residence (rural vs urban [ref]) 774 (22.8) 13,197 (23.4) 1.03 ( ) 0.96 ( ) Welfare recipient 1337 (39.5) 16,955 (30.1) 1.51 ( ) 1.35 ( ) Diabetes (chronic and/or gestational) 290 (8.56) 3861 (6.86) 1.27 ( ) 0.78 ( ) Hypertension (chronic and/or gestational) 573 (16.91) 3344 (5.94) 3.22 ( ) 2.12 ( ) Migraine prior first day of gestation 101 (2.98) 1548 (2.75) 1.09 ( ) 1.08 ( ) Diagnosis of chronic or gestational hypertension defined as having a diagnosis of hypertension or a filling for an antihypertensive drug in the year before or during pregnancy; diagnosis of chronic or gestational diabetes defined as having a diagnosis of diabetes or a filling for an antidiabetic drug including insulin in the year before or during pregnancy. Diagnosis of migraine or fillings of at least 1 prescription of DHE or triptan. CI = confidence interval; DHE = dihydroergotamine; NSAID = nonaspirin nonsteroidal anti-inflammatory drug; SD = standard deviation. Among all pregnant women meeting the eligibility criteria, regardless of having a live birth delivery or not but excluding planned abortions, 4769 cases of SAs were identified (Table 5). Adjusting for potential confounders including history of migraines, DHE use during pregnancy was not statistically significantly associated with the risk of SAs (OR: 1.97; 95% CI: ). However, triptan and NSAID use during pregnancy were significantly associated with the risk of SAs (OR: 2.65 [95% CI: ] and OR: 2.97 [95% CI: ] for triptan and NSAID use, respectively) (Table 5). DISCUSSION DHE was not statistically significantly associated with the risk of SA, MCMs, or LBW. In contrast, gestational exposure to triptans was associated with an increased risk of SAs, and gestational use of NSAIDs was associated with an increased risk of SA, MCMs, and LBW. However, we found that DHE use during pregnancy was associated with a 4-fold increased risk of prematurity. Other than for prematurity, the risk of other adverse pregnancy outcomes in DHE users was similar to that found for triptan users, and was smaller than that of NSAIDs users. At present, much remains unclear with regard to the exact mechanism of actions that would explain the differences found between exposure groups. However, migraine has been associated with hypertensive disorders during pregnancy, 22 which is a risk factor for prematurity and LBW. 23 To date, no one specifically studied the effect of DHE use during early pregnancy on the risk of adverse pregnancy outcomes. Even ergotamine (which is known to cause significant arterial vasoconstriction and hence is different from DHE) use during pregnancy has not been associated with the risk of congenital malformations in the Hungarian population-based cohort of pregnant women 10 but has been found to increase the risk of prematurity and LBW. 9 Ergotamine can cause significant and severe vasoconstriction throughout the body, in particular affecting the arterioles. 7,8,24 In contrast, DHE is an agonist at 5-HT 1B receptors, has little agonistic activity at 5-HT 2A receptors, and has a potent antagonistic activity at the a2 receptors. 25 As a result, DHE is believed to be more of a venoconstrictor, with only a mild arteriolar vasoconstrictive effect in the peripheral and coronary vessels.

7 Headache 1091 Table 5. Use of DHE, Triptans, and NSAIDs During Pregnancy and the Risk of Spontaneous Abortions QPR Cases Controls N = 52,459 N = 4769 N = 47,690 n (%) n (%) n (%) Crude Odds Adjusted Odds DHE 5 (0.01) 1 (0.02) 4 (0.01) 2.50 ( ) 1.97 ( ) Triptans 82 (0.16) 21 (0.44) 61 (0.13) 3.45 ( ) 2.65 ( ) NSAIDs 1603 (3.06) 365 (7.65) 1238 (2.60) 3.09 ( ) 2.97 ( ) Maternal age on the first day of gestation ( ) 1.04 ( ) (mean SD) Region of residence (rural vs urban) 11,964 (22.8) 1045 (21.9) 10,919 (22.9) 1.06 ( ) 1.00 ( ) Welfare recipient 16,713 (31.9) 1707 (35.8) 15,006 (31.5) 1.21 ( ) 1.23 ( ) Diabetes (chronic and/or gestational) 623 (1.19) 93 (1.95) 530 (1.11) 1.77 ( ) 1.64 ( ) Hypertension (chronic and/or gestational) 3149 (6.00) 108 (2.26) 3041 (6.38) 0.34 ( ) 0.32 ( ) Migraine prior first day of gestation 1409 (2.69) 137 (2.87) 1272 (2.67) 1.08 ( ) 0.97 ( ) Diagnosis of chronic or gestational hypertension defined as having a diagnosis of hypertension or a filling for an antihypertensive drug in the year before or during pregnancy; diagnosis of chronic or gestational diabetes defined as having a diagnosis of diabetes or a filling for an antidiabetic drug including insulin in the year before or during pregnancy. Diagnosis of migraine or fillings of at least 1 prescription of DHE or triptan. CI = confidence interval; DHE = dihydroergotamine; NSAID = nonaspirin nonsteroidal anti-inflammatory drug; QPR = Quebec Pregnancy Registry; SD = standard deviation. This receptor activity has been confirmed in experimental models in humans both in vitro and in vivo. 11 Aellig and colleagues have demonstrated the predominantly venoconstructive effects and minimal arterial constriction in several human studies using different formulations of DHE. 13,26 Like us, other large population-based cohort studies 27,28 showed no increased risk of MCMs, prematurity, or LBW associated with gestational exposure to triptans as well as an increased risk of SAs, 29 and MCMs 30 associated with NSAID use during pregnancy. Källén et al have shown that migraine drug use (combining triptans and ergots) after the first trimester increased the risk of prematurity but did not significantly increase the risk of MCMs. 31 Our study is the first one comparing the risk of adverse pregnancy outcomes among DHE, triptan, and NSAID users. Strengths and Limitations. Our large populationbased study enabled us to evaluate the effect of DHE use during pregnancy and compare it with the risk associated with triptan and NSAID use.we used accurate information on filled prescriptions without having to rely on maternal recall, as well as prospectively and routinely collected physician-based validated diagnoses or procedures related to SAs, MCMs, prematurity, and LBW, limiting the potential for detection bias. Gestational age was validated and obtained in hospital charts at index date, which enabled us to calculate exact timing of DHE, triptan, and NSAID exposure during pregnancy. 18 Only clinically detected SAs were considered, without relying on maternal recall. SAs that were never detected by the woman themselves were excluded, as was done in all other similar studies to date. 10,15,19,29 If DHE increases the risk of SAs that are not clinically detected, our findings are conservative and thus would underestimate the true risk. However, if DHE is not associated with nonclinically detected SAs, there is no reason to believe that misclassification would be different between cases and controls, resulting in nondifferential misclassification. The same rationale holds for triptan and NSAID use. We adjusted our findings for the indication for DHE and triptan use. Therefore, we are confident that residual confounding by indication, if present, would not completely explain our findings. The evaluation of exposure was based on filled prescriptions and might not necessarily reflect actual intake. However, we hypothesize that women who filled a prescription for a

8 1092 July/August 2012 DHE, triptan, or NSAID took at least 1 dose, as within the Quebec drug plan,they need to pay in part for their medications. Finally, the 4 nested case control analyses permitted us to select control subjects originating from the same source population as cases, limiting the potential for selection bias. Within the Quebec Pregnancy Registry, information on potential confounding variables such as smoking, maternal obesity, and folic acid use are not exhaustively available. However, we have previously shown that smoking, maternal weight, and preconceptual folic acid intake are not strong enough confounders to reverse findings of associations between drug use during gestation and adverse pregnancy outcomes when adjusting for indication and health care utilization use as was done here. 32 Although Nezvalova-Henriksen et al 27 have shown that maternal weight was associated with the risk of MCMs, we doubt that women using DHE, triptan, or NSAIDs would differ significantly in terms of their weight, and thus this would not explain the differences in our risk estimates. Finally, Einarson and colleagues observed that smoking was not associated with the risk of SA. 33 Although migraine was not statistically significantly increasing the risk of adverse pregnancy outcomes in our study, and we have adjusted for history of migraines, gestational use of other antimigraine drugs (triptans and NSAIDs), and use of health services, we cannot completely exclude the possibility of residual confounding by underlying disease in the risk estimates for DHE (the same holds for triptans and NSAIDs). Also, we cannot rule out the possibility of chance findings in 5% of our statistically significant associations. Finally, analyses of specific adverse pregnancy outcomes might have missed significant associations due to lack of statistical power, and estimates for DHE exposure could be unstable given the small number of pregnant women taking DHE. CONCLUSION This study showed that, other than for prematurity, the risk of DHE use during pregnancy was similar to that of triptan use and was smaller than the risk associated with NSAID use. However, because of the small number of DHE exposures studied, further confirmation in a larger cohort is warranted. CONTRIBUTORS A. Bérard had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses. Study concept and design: A. Bérard, S. Kori. Acquisition of data: A. Bérard. Analysis of data: A. Bérard. Interpretation of data: A. Bérard, S, Kori. Drafting of the manuscript: A. Bérard, S. Kori. Critical revision of the manuscript for important intellectual content: A. Bérard, S. Kori. Statistical analysis: A. Bérard. Obtained funding: A. Bérard. Administrative, technical, or material support: A. Bérard. Study supervision: A. Bérard. REFERENCES 1. Airola G, Allais G, Castagnoli GI, Rolando S, Mana O, Benedetto C. Non-pharmacological management of migraine during pregnancy. Neurol Sci. 2010; 31(Suppl. 1):S63-S Pfaffenrath V, Rehm M. Migraine in pregnancy: What are the safest treatment options? Drug Saf. 1998;19: Alcantara J, Cossette M. Intractable migraine headaches during pregnancy under chiropractic care. Complement Ther Clin Pract. 2009;15: Duong S, Bozzo P, Nordeng H, Einarson A. Safety of triptans for migraine headaches during pregnancy and breastfeeding. Can Fam Physician. 2010;56: Nezvalova-Henriksen K, Spigset O, Nordeng H. Maternal characteristics and migraine pharmacotherapy during pregnancy: Cross-sectional analysis of data from a large cohort study. Cephalalgia. 2009; 29: Lucas S. Medication use in the treatment of migraine during pregnancy and lactation. Curr Pain Headache Rep. 2009;13: Contag SA, Mertz HL, Bushnell CD. Migraine during pregnancy: Is it more than a headache? Nat Rev Neurol. 2009;5: Silberstein SD. Headaches in pregnancy. J Headache Pain. 2005;6: Banhidy F, Acs N, Puho E, Czeizel AE. Ergotamine treatment during pregnancy and a higher rate of low birthweight and preterm birth. Br J Clin Pharmacol. 2007;64:

9 Headache Acs N, Banhidy F, Puho E, Czeizel AE. A possible dose-dependent teratogenic effect of ergotamine. Reprod Toxicol. 2006;22: Mellander S, Nordenfelt I. Comparative effects of dihydroergotamine and noradrenaline on resistance, exchange and capacitance functions in the peripheral circulation. Clin Sci. 1970;39: Aellig WH. Direct effects of vasoactive substances on superficial human veins in vivo. Int Angiol. 1985;4: Aellig WH, Rosenthaler J. Venoconstrictor effects of dihydroergotamine after intranasal and intramuscular administration. Eur J Clin Pharmacol. 1986;30: Torres A, Ena Regidor P. Pharmacological response of the association of chlorpromazine and dihydroergotamine on the guinea pig uterus and the pregnant uterus in women. Clin Lab (Zaragoza). 1955;60: World Health Organization. International Statistical Classification of Diseases and Related Health Problems (ICD-9). 9th revision. Geneva: World Health Organization; Bérard A, Lacasse A. Validity of perinatal pharmacoepidemiologic studies using data from the RAMQ administrative database. Can J Clin Pharmacol. 2009;16: Essebag V, Genest J Jr, Suissa S, Pilote L. The nested case-control study in cardiology. Am Heart J. 2003;146: Vilain A, Otis S, Forget A, Blais L. Agreement between administrative databases and medical charts for pregnancy-related variables among asthmatic women. Pharmacoepidemiol Drug Saf. 2008;17: Nakhai-Pour HR, Broy P, Bérard A. Use of antidepressants during pregnancy and the risk of spontaneous abortion. CMAJ. 2010;182: Heinonen O, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, CO: Publishing Sciences Group; Kulaga S, Zargarzadeh AH, Bérard A. Prescriptions filled during pregnancy for drugs with the potential of fetal harm. BJOG. 2009;116: Facchinetti F, Allais G, Nappi RE, et al. Migraine is a risk factor for hypertensive disorders in pregnancy: A prospective cohort study. Cephalalgia. 2009;29: Nakhai-Pour HR, Rey E, Bérard A. Antihypertensive medication use during pregnancy and the risk of major congenital malformations or small-forgestational-age newborns. Birth Defects Res B Dev Reprod Toxicol. 2010;89: Bradley PB, Humphrey PP, Williams RH. Evidence for the existence of 5-hydroxytryptamine receptors, which are not of the 5-HT2 type, mediating contraction of rabbit isolated basilar artery. Br J Pharmacol. 1986;87: Hool-Zulauf B, Stürmer E. Oxytocic activity of two dihydrogenated ergot peptide alkaloids on the rabbit uterus in situ. Arzneimittelforschung. 1977;27: Aellig WH. Venoconstrictor effect of dihydroergotamine in superficial hand veins. Eur J Clin Pharmacol. 1974;7: Nezvalová-Henriksen K, Spigset O, Nordeng H. Triptan exposure during pregnancy and the risk of major congenital malformations and adverse pregnancy outcomes: Results from the Norwegian Mother and Child Cohort Study. Headache. 2010;50: Bánhidy F, Acs N, Horváth-Puhó E, Czeizel AE. Pregnancy complications and delivery outcomes in pregnant women with severe migraine. Eur J Obstet Gynecol Reprod Biol. 2007;134: Nakhai-Pour HR, Broy P, Sheehy O, Bérard A. Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ. 2011;183: Ofori B, Oraichi D, Blais L, Rey E, Bérard A. Risk of congenital anomalies in pregnant users of nonsteroidal anti-inflammatory drugs: A nested casecontrol study. Birth Defects Res B Dev Reprod Toxicol. 2006;77: Källén B, Nilsson E, Otterblad Olausson P. Delivery outcome after maternal use of drugs for migraine: A register study in Sweden. Drug Saf. 2011;34: Bérard A, Kulaga S, Nakhai-Pour HR. Magnitude of confounding caused by missing information in the studies on adverse pregnancy outcomes. Pharmacoepidemiol Drug Saf. 2009;18(Suppl.): Einarson A, Choi J, Einarson TR, Koren G. Rates of spontaneous and therapeutic abortions following use of antidepressants in pregnancy: Results from a large prospective database. J Obstet Gynaecol Can. 2009;31: