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Show The Use of Acetazolamide During Pregnancy in Intracranial Hypertension Patients Julie Falardeau, MD, Brenna M. Lobb, MS, MPH, Sara Golden, MPH, Steven D. Maxfield, BS, Emanuel Tanne, MD Background: Acetazolamide is the mainstay of medical therapy for idiopathic intracranial hypertension (IIH). Its use in pregnant women has not been recommended because of reported teratogenic effects in rodents and rabbits. How-ever, the safety of acetazolamide use during human pregnancy remains unclear. We report the pregnancy and offspring outcomes in women with intracranial hypertension (IH) treated with acetazolamide during pregnancy. Methods: Data were collected through questionnaires sent to patients with IH and their physicians. The questionnaires focused on IH diagnosis, obstetric history and outcomes, and pediatric outcomes. Results: A total of 101 women with IH were consented (total of 158 pregnancies) and acetazolamide usage before 13 weeks of gestation was reported in 50 pregnancies. The risk of spontaneous abortion was similar to the control group and no major complication was identified in the offspring of women treated with acetazolamide. Conclusion: There is no convincing evidence for an adverse effect for acetazolamide use in human pregnancy, even when prescribed prior to the 13th week of gestation. While the liberal use of acetazolamide should be avoided during pregnancy, this medication should remain a treatment option in pregnant women when clinically indicated. Journal of Neuro-Ophthalmology 2013;33:9-12 doi: 10.1097/WNO.0b013e3182594001 © 2012 by North American Neuro-Ophthalmology Society Idiopathic intracranial hypertension (IIH) is characterized by papilledema, headache, pulse synchronous tinnitus, and increased intracranial pressure without focal neurolog-ical deficits. IIH is typically seen in overweight women of reproductive age and is reported occasionally during preg-nancy. Previous studies have shown that pregnancy occurs in IIH at about the same rate as in the general population, and IIH can occur in any trimester, although it usually appears in the first half of pregnancy (1,2). While acetazolamide, a car-bonic anhydrase inhibitor, is the mainstay of medical ther-apy for IIH, its use during pregnancy remains controversial. A number of reports recommend against the use of acet-azolamide during pregnancy because of the teratogenic potential of this drug (3-9). A recent survey addressing different issues related to the management of IIH, including medical treatment of this condition, was emailed to 530 physician members of the North American Neuro-Ophthalmology Society and was completed by 83 (7 ophthalmologists and 76 neuro-ophthalmologists, response rate = 16%). Results of the survey showed that 65% of treating physicians would dis-continue acetazolamide for a stable IIH patient who becomes pregnant, while 10% would reduce the dosage, and 25% would maintain the patient at the same dosage. Eighty-seven percent of treating physicians considered the maximum acceptable daily dose of acetazolamide to be $2,000 mg for nonpregnant patients, while only 32% of these physicians considered $2,000 mg an appropriate maximum daily dosage for pregnant IIH patients (S. Max-field, personal communication, February 2011). The re-luctance to prescribe acetazolamide during pregnancy is not surprising given that the safety of acetazolamide in human pregnancy has not been established, and currently there are limited data discussing pregnancy and offspring outcomes among acetazolamide users. We retrospectively collected data on pregnancy and offspring outcomes in patients treated with acetazolamide for IIH. Department of Ophthalmology (JF); Intracranial Hypertension Registry (BML, SR, ET); and Intracranial Hypertension Research Foundation (ET), Oregon Health and Science University, Portland, Oregon; and Dartmouth Medical School (SDM), Hanover, New Hampshire. The Intracranial Hypertension Registry is a joint project of the Intracranial Hypertension Research Foundation and the Casey Eye Institute at Oregon Health and Science University. The authors have no conflict to disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www.jneuro-ophthalmology.com). Address correspondence to Julie Falardeau, MD, Casey Eye Institute, Oregon Health and Science University, 3303 SW Bond Avenue, 11th floor, Portland, OR 97239; E-mail: falardea@ohsu.edu Falardeau et al: J Neuro-Ophthalmol 2013; 33: 9-12 9 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. METHODS Participants received a consent form, questionnaire, and authorization to disclose their health history by mail. Potential participants included self-identifying individuals from the Intracranial Hypertension Research Foundation's (IHRF) website (www.ihrfoundation.org), patients already enrolled in the Intracranial Hypertension Registry (IHR), and direct physician referral to the study. An announcement was posted on the IHRF website and sent to all enrolled patients in the IHR requesting their participation in the study if their pregnancy occurred during or after their in-tracranial hypertension (IH) diagnosis date. Patients were primarily from North America (95%), with 3% from Europe, and 2% from Oceania. After the signed consent and patient questionnaire were received by study staff, additional questionnaires were sent to the physicians listed by the patient, and the patient's pertinent medical records were requested. Either medical records and/or a physician questionnaire were returned. All medical records were abstracted by Registry staff. The main focus of the questionnaires sent to physicians concen-trated on obstetric history and outcomes, IH diagnosis, and pediatric outcomes per pregnancy. For confirmation of IH, each patient's medical history was reviewed by a staff phy-sician and either confirmed to be idiopathic or secondary to a specific cause. The review was based on the modified Dandy criteria (2) for idiopathic cases. Questionnaires Patient (pregnancy). The questionnaires were completed by IH patients who experienced one or more pregnancies during their lifetime. This questionnaire asked basic demographic questions and the date of IH diagnosis. All other questions pertained to pregnancy and the IH patient's experience during pregnancy (see Supplemental Digital Content 1, http://links.lww.com/WNO/A35). Obstetric. Questions included pregnancy course, pre-scription medications (names, dosage, duration), and complications during pregnancy/delivery (live birth, abor-tion, other). The questionnaire was either completed by the patient's obstetric physician or nurse for that pregnancy, or the information was abstracted by Registry staff from obstetric medical records (see Supplemental Digital Con-tent 2, http://links.lww.com/WNO/A36). Pediatric. This questionnaire was sent to all pediatricians involved in the evaluation and/or treatment of the child of each pregnancy. Information obtained was Apgar score at birth, physical findings at birth and up to the present, learning disabilities, neurodevelopmental delays, mental disorders, and mental retardation. The questionnaire was completed by the child's pediatrician or nurse, or the information was abstracted by the Registry staff from pedi-atric medical records (see Supplemental Digital Content 3, http://links.lww.com/WNO/A37). IH Diagnosis. The Intracranial Hypertension Diagnosis Questionnaire was mailed to all physicians listed by the IH participant on the pregnancy questionnaire. Questions included signs and symptoms of IH, the results of any neuroimaging study, and the results of lumbar puncture. The completed questionnaire and/or additional medical records were reviewed by a staff physician. Due to the retrospective nature of the record review, some information was incom-plete or missing. Every effort was made to resolve the issue either by obtaining further medical records, or by re-contacting the patient for more information (see Supplemental Digital Content 4, http://links.lww.com/WNO/A38). RESULTS A total of 101 patients with IH were consented (total of 158 pregnancies) and acetazolamide was used in 63 pregnan-cies. Use of this medication before 13 weeks of gestation was reported in 50 pregnancies and all had a confirmed diagnosis of IH (Table 1). We chose 13 weeks as our cutoff since it represents the teratogenic period. Four patients had secondary IH: 2 cases of venous sinus thrombosis and 2 cases of med-ication- related IH. These 4 individuals represented 5 pregnan-cies, 4 of which were in the acetazolamide user group. Those with IIH who did not receive acetazolamide during their first trimester (108 pregnancies) served as the control group. The total abortion rate was not statistically increased among acetazolamide users (acetazolamide users 28%, nonusers 21.3%, P = 0.36; Table 2). There was no statis-tical difference in the rate of spontaneous abortion when comparing the untreated group, acetazolamide users ,1,000 mg/day, and acetazolamide users .1,000 mg/day (13.9%, 22.2%, and 17.4%, respectively). The pregnancy and delivery characteristics of IH patients are presented in Table 3. None of the differences among the various groups were statistically significant. The age of the offspring of all acetazolamide users at their last examination ranged from 5 weeks to 12 years (mean: 3.5 years). Abnormalities following birth of children of patients treated with acetazolamide before 13 weeks were noted in 5 cases: 1 child with asthma and reactive airway disease, 1 with cerebral palsy, 1 with hydronephrosis, 1 with TABLE 1. Number of pregnancies in intracranial hypertension patients with maximum daily dosage of acetazolamide Dose (mg) Before 13 Weeks Acetazolamide Taken at Any Time 250 10 10 500 11 18 750 6 8 1,000 16 16 1,500 6 6 2,000 1 5 Total 50 63 10 Falardeau et al: J Neuro-Ophthalmol 2013; 33: 9-12 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. craniosynostosis, and one with juvenile rheumatoid arthritis, heart murmur and esotropia. One child with mild external ear malformation was born to a mother treated with acetazolamide after the 13th week of gestation (,1,000 mg/day, initiated at 16 weeks of gestation). No case of fore-limb or other axial skeletal malformations was identified. Offspring of subjects treated with acetazolamide did not ap-pear to have an increased risk of abnormalities compared with the nonuser group. Abnormalities of similar severity were reported in 16 children in the nonuser group, including seizure disorder, heart murmur, asthma, hydronephrosis, Henoch-Schonlein purpura, attention deficit hyperactivity disorder, Tourette syndrome, and speech delay. DISCUSSION The teratogenic potential of acetazolamide has been established in rats, mice, hamsters, and rabbits, producing postaxial limb malformations, such as polydactyly or limb deficiency (10-22). No such effect has been found in mon-keys (23). This teratogenic effect was produced when acet-azolamide was administered during early gestation using dosages that were several times more than that administered to humans (human equivalent dose of 60-80 mg/kg using the body surface area formula) (11,12). Prescription of acetazolamide during pregnancy is often a source of anxiety among health care providers, and because of a unique case of sacrococcygeal teratoma (8), the medical community adopted the recommendation to avoid the use of acetazolamide within the first 20 weeks of gestation. Acetazolamide is a category C medication in the Food and Drug Administration (FDA) classification of pregnancy risk. This indicates that animal reproduction studies have shown an adverse effect on the fetus, but there are no adequate and well-controlled studies in humans. As a class C drug, acetazolamide should be given only if the potential benefit justifies the potential risk to the fetus, per FDA recommendations. However, there is little evidence for an adverse effect of acetazolamide used in human pregnancy. Heinonen et al (24) did not find any congenital malformations among offspring of their 12 patients using carbonic anhydrase inhibitors dur-ing pregnancy. Lee et al (25) reported 12 patients treated with acetazolamide during pregnancy. No minor or major congenital malformations were identified, and all pregnancy outcomes were classified as normal. There is a single case of a sacrococcygeal teratoma in an infant born to a mother treated with acetazolamide until the 19th week of pregnancy (8). However, the authors state "We do not propose a cause-and- effect relationship between the maternal use of acetazol-amide and the development of an uncommon tumor.." Over a 14-year period, Merlob et al (26) encountered only 3 infants born to mothers treated with acetazolamide thro-ughout pregnancy. One neonate had metabolic acidosis, TABLE 2. Frequency of abortion in intracranial hypertension patients when treated before the 13th week of gestation None Spontaneous Abortion Medical Abortion Induced Abortion Total Abortions Spontaneous Abortion (%) Total Abortions (%) Total Number of Pregnancies No acetazolamide 85 15 3 5 23 13.9 21.3 108 All acetazolamide users 36 10 1 4 14* 20 28 50 Total 121 25 4 9 37* 15.8 23.4 158 *Includes 1 case of twins, 1 twin spontaneous abortion, and 1 twin induced abortion (so 1 pregnancy is included in 2 categories; thus, total abortions will not add up). TABLE 3. Pregnancy and delivery characteristics of intracranial hypertension patients No Acetazolamide ,1 g Used ,13 Weeks $1 g Used ,13 Weeks Total Birthweight* (lbs) 7.5 (n = 38/108) 6.3 (n = 12/27) 7.3 (n = 11/23) 7.1 (n = 61/158) Gestation age* (weeks) 37.5 (n = 84/108) 37.6 (n = 19/27) 38.4 (n = 17/23) 37.8 (n = 120/158) Gestational diabetes, n (%) 6 (5.6) 0 (0) 0 (0) 6 (3.8) Preeclampsia, n (%) 6 (5.6) 3 (11.1) 1 (4.3) 6 (3.8) Cesarean section, n (%) 46 (42.6) 9 (33.3) 12 (52.2) 67 (42.4) Vaginal, n (%) 39 (36.1) 10 (37.0) 5 (21.7) 54 (34.2) Abortions, n (%) 23 (21.3) 8 (29.6) 6 (26.1)† 37 (23.4) Total number of pregnancies 108 27 23 158 *Average (n = number of pregnancies in which data are available/total number of pregnancies). †Includes 1 case of twins, 1 twin spontaneous abortion, and 1 twin induced abortion. Falardeau et al: J Neuro-Ophthalmol 2013; 33: 9-12 11 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. hypocalcemia, and hypomagnesemia that resolved with treat-ment. With the exception of a single infant born to a mother treated for 3 weeks with acetazolamide before delivery who had signs of dehydration at 48 hours, no other neonatal metabolic effects of this medication have been reported (26,27). There is clearly a lack of convincing evidence for a teratogenic effect associated with this use of acetazolamide during pregnancy. In all reported cases, there is no common morphological abnormality that one would expect with a ter-atogenic agent, and specifically, there are no cases of postaxial limb malformations in human offspring as found in animal models. Although our study is the largest observational case series looking at pregnancy and offspring outcome among patients taking acetazolamide, it has several limitations. First, the sample size was too small to evaluate the risk of suspected rare teratogenic conditions, such as sacrococcygeal teratoma. Second, we were unable to address the possible effects of acetazolamide dosage .2 g/day. Third, in examining pedi-atric outcomes, we recognize that learning and mental dis-orders are often not apparent until at least 2 years of age, and some of our children were younger than 2 years. A final limitation of our study involves the self-reporting method of gathering information. Due to poor recollection, misunder-standing of questions, and the subjective nature of question-naires in general, some information may not be accurate. This was mitigated somewhat by searching and corroborat-ing information from the medical record. In summary, our study confirms the lack of convincing evidence for adverse effects of acetazolamide use in human pregnancy, even when prescribed prior to the 13th week of gestation. 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