Falardeau, Julie MD; Lobb, Brenna M. MS, MPH; Golden, Sara MPH; Maxfield, Steven D. BS; Tanne, Emanuel MD
Idiopathic intracranial hypertension (IIH) is characterized by papilledema, headache, pulse synchronous tinnitus, and increased intracranial pressure without focal neurological deficits. IIH is typically seen in overweight women of reproductive age and is reported occasionally during pregnancy. 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 carbonic anhydrase inhibitor, is the mainstay of medical therapy for IIH, its use during pregnancy remains controversial. A number of reports recommend against the use of acetazolamide 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 discontinue 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. Maxfield, personal communication, February 2011). The reluctance 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.
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 intracranial 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 concentrated 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 physician 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.
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, prescription medications (names, dosage, duration), and complications during pregnancy/delivery (live birth, abortion, 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 Content 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 pediatric 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 incomplete 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).
A total of 101 patients with IH were consented (total of 158 pregnancies) and acetazolamide was used in 63 pregnancies. 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 medication-related IH. These 4 individuals represented 5 pregnancies, 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 statistical 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 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 forelimb or other axial skeletal malformations was identified. Offspring of subjects treated with acetazolamide did not appear 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.
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 monkeys (23). This teratogenic effect was produced when acetazolamide 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 during 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 acetazolamide 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 throughout pregnancy. One neonate had metabolic acidosis, hypocalcemia, and hypomagnesemia that resolved with treatment. 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 teratogenic 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 pediatric outcomes, we recognize that learning and mental disorders 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, misunderstanding of questions, and the subjective nature of questionnaires in general, some information may not be accurate. This was mitigated somewhat by searching and corroborating 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. We agree with Lee et al (25) that the avoidance of acetazolamide during the first trimester has very little medical justification and is mainly guided by medical–legal rationale. We do believe, however, as in the case with all medication usage during pregnancy, that acetazolamide should be administered with caution and justification. Negative data do not exclude the teratogenic possibility, and appropriate counseling should take place regarding the risk–benefit ratio of treatment with acetazolamide versus observation or alternative management.
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