Safe Administration of Botulinum Toxin Type A Injections During Pregnancy: A Report of Two Cases

Abstract

Local injections of botulinum toxin type A (BoNT/A) are safe and efficacious to treat focal and segmental dystonia. However, there are no adequate studies in humans regarding the safety of BoNT/A during pregnancy. Despite the fact that 25 case reports have been published on patients who received BoNT/A injections during a total of 31 pregnancies, in only 3 patients were the injections continued beyond the first trimester. We report on 2 females with cervical and segmental dystonia who received BoNT/A injections during pregnancy beyond the first trimester and gave birth to 2 healthy children.

The efficiency and safety of botulinum toxin type A (BoNT/A) for the treatment of cervical dystonia (CD) has been demonstrated in several randomized and controlled trials.1, 2, 3, 4 However, owing to the unknown risks for the unborn child and the lack of any controlled human studies about the application of BoNT/A during pregnancy, it is considered by the U.S. Food and Drug Administration a class C medication during pregnancy. Although data about the systemic spread of BoNT after intramuscular injections in cases of pregnant women are missing, there is evidence from studies with nonpregnant humans about subclinical effects on distant muscles and, in experimental conditions, on remote central nervous system (CNS) effects.5, 6 These facts support concerns about possible effects on maternal myometrial or fetal muscular activity as well as on CNS neurotransmitter release and brain plasticity. Regarding the increase in administration of BoNT/A for medical as well as cosmetic reasons, it is important to gather more information of BoNT/A during pregnancy. Since the first report in 2004, a total of 31 pregnancies in 25 females have been published (Table 1).7, 8, 9, 10, 11, 12, 13, 14 Thereof, in most cases, the injections were done accidentally during the first weeks of gestation, and BoNT/A treatment was discontinued after discovery of the pregnancy.8, 9, 10, 11, 13 In only 3 patients was BoNT/A treatment continued beyond the first trimester.7, 10, 14

Table 1.

Injections of botulinum toxin during pregnancy

n	Age	Indication	Botulinum Toxin	Gestational Age			Outcome of Pregnancy	Author and Reference
				1. TM	2. TM	3. TM
1	41	CD	OT/A	—	250 IU	250 IU	Healthy baby	Aranda et al.14
1	17	Strabismus	OT/A	2.5 IU	—	—	Healthy baby	Li Yim and Weir13
1	39	Esophageal achalasia	OT/A	—	80 IU	—	Growth‐restricted baby, but already before injection	Wataganara et al.12
1	46	Cosmetic reasons	OT/A	Dose n.c.	—	—	n.a.	Kuczkowski11
1	34	Cosmetic reasons	OT/A	54 IU	—	—	Healthy baby	De Oliveira Monteiro9
1	37		OT/A	65 IU	—	—	Healthy baby
9	n.a.	CD	n.c.	n = 12	n = 1	n = 1	17 healthy babies 1 therapeutic abortion 1 miscarriage	Morgan et al.10
2	n.a.	Strabismus		Dose range: 1.25 to 300 IU n = 1 gestational age unknown n = 1 woman was treated during three separate pregnancies with 1 to 3 injections over all three TMs with a dose of approximately 300 IU per treatment
2	n.a.	Blepharospasm
1	n.a.	Limb dystonia
1	n.a.	Oromandibular dystonia
1	n.a.	Spasmodic dysphonia
16a
1	38	CD	OT/A	200 IU	—	—	Healthy baby	Bodkin et al.8
1	39	CD	OT/A	500 IU	—	—	Miscarriage
1	26	CD	OT/A	300 IU	200 IU 100 IU booster	300 IU	Healthy baby	Newman et al.7
				300 IU	—	300 IU	Healthy baby
				—	300 IU	—	Healthy baby
				0	300 IU	300 IU	Healthy baby

^an = 16; 1 female was pregnant with twins and 1 female was injected during 3 pregnancies; in summary, 18 pregnancies and 19 fetuses.

IU, International Units; n.a. ‐ not applicable; OT/A, onabotulinum toxin A; TM, trimester.

Here, we report on 2 further cases of continuous BoNT/A injections during the entire pregnancy.

Case Report 1

A 38‐year‐old patient diagnosed with moderate‐to‐severe CD was referred to the movement disorder outpatient clinic of our center in 2009 when she was 8 weeks pregnant. She had a disease history of 10 years, no family history of dystonia, and normal brain MRI. Segawa dystonia, Wilson's disease (WD), and neuroacanthocytosis were excluded as well as previous exposure to neuroleptics. She had been regularly treated with injections of BoNT/A every 3 months with a total dose of 200 IU of incobotulinumtoxinA each time. The patient presented with a laterocollis to the left of approximately 30 degrees, a torticollis to the left of approximately 25 degrees, an elevation of her left shoulder, and an irregular dystonic head tremor that was partially responsive to a geste maneuver. Additionally, the patient suffered from concomitant tension headache with an intensity of 6/10 on the pain visual analog scale. The Tsui score was 14 of 25 points. Previous injections of incobotulinumtoxinA reduced dystonic symptoms by approximately 70% with complete remission of her headache.

The patient was informed about the lack of data and resulting uncertainty about possible risks of BoNT/A injections during pregnancy. Pointing to her high degree of physical as well as psychological distress resulting from the CD as well as obstructions in activities of daily living (ADLs), the patient decided to continue the treatment. After giving informed consent, the patient was treated with 200 IU of BoNT/A. At the next appointment 12 weeks later, the patient reported a miscarriage in the 10th week of pregnancy (2 weeks after BoNT/A therapy). The miscarriage was a result of an inherent anembryonic pregnancy, most likely without any relation to the BoNT/A injection, according to her obstetrician. The patient had experienced a treatment response as usual, with approximately 80% symptom relief and received a further injection. At the following appointment 15 weeks later, the patient was pregnant at 16 weeks. Again, she decided to proceed with the treatment. She received 2 further BoNT/A injections, at 16 and 29 weeks of pregnancy with the same dose of 200 IU of incobotulinumtoxinA (70 IU in the left splenius muscle, 50 IU in the right splenius muscle, 30 IU in the right sternocleidomastoid muscle, and 50 IU in the left trapezius muscle) without adverse effects and similar known efficacy. The child was delivered at 38 weeks' gestation by Cesarean section owing to its large size. The obstetrician assumed a possible miscalculation of gestation age resulting from late discovery of pregnancy caused by an irregular cycle, suggesting that the patient received incobotulinumtoxinA injections during all three trimesters. Apgar scores were 10/10/10, birth weight was 4,570 g, and size at birth was 55 cm. The boy was followed by a pediatrician for regular screening and routine reviews for infants. Motor and cognitive development have been normal during the observation period of 3 years. After delivery, the patient did not nurse her child, and BoNT/A treatment with incobotulinumtoxinA was continued the same as before pregnancy.

Case Report 2

The second patient, 34 years of age at initial consultation, was diagnosed with segmental dystonia in 2004. She presented with involuntary painful torsion of the head, resulting in a torticollis to the right of approximately 45 degrees, a laterocollis to the right of approximately 35 degrees, and a slight retrocollis including right‐sided shoulder elevation and pulling of the back, which was partially responsive to a geste maneuver. The initial Tsui score was 14 of 25 points. During the course of the disease, the patient also developed blepharospasm and oromandibular dyskinesia. Segawa dystonia, WD, neuroacanthocytosis, as well as a VPS13‐A‐, DYT1‐, and DYT6‐mutation were excluded as well as previous exposure to neuroleptics. The patient received 25 mg of trihexiphenidyl and a total dose of 170 IU of onabotulinumtoxinA injections every 3 months with a clinical response of approximately 50% for the time period of approximately 5 years.

In late 2009, the patient, meanwhile 39 years old, contacted the department to report that she was 5 weeks pregnant, having received her last onabotulinumtoxinA injections 3 weeks earlier. After consultation, the patient decided to pause with BoNT/A injections and withdrew oral trihexiphenidyl to minimize any risks for the unborn child. Approximately 3 months later, at 16 weeks of pregnancy, she presented in the emergency room because of severe dystonia with painful spasms, leading to significantly compromised ADLs. Again, she was informed in detail about the lack of data and the resulting uncertainty about possible risks of BoNT/A injections during pregnancy. Nevertheless, the patient decided to resume the onabotulinumtoxinA treatment. After giving her informed consent, she was treated with a reduced total dosage of 100 IU of onabotulinumtoxinA (20 IU in the left Musculus. sternocleidomastoideus, 30 IU in the right M. splenius, 30 IU in the right M. trapezius, and 20 IU in the right M. levator scapulae) that led to a 50% improvement of the cervical dystonia for approximately 6 weeks. Thus, she was injected with onabotulinumtoxinA twice during her pregnancy, once in the first trimester as well as in the second trimester. The child was delivered by Cesarean section at 37 weeks' gestation owing to severe aggravation of pre‐existing dystonic symptoms during pregnancy. Apgar scores were 6/7/8. The patient decided against breastfeeding and resumed medication with trihexiphenidyl and onabotulinumtoxinA therapy (120 IU) shortly after delivery. Motor and cognitive development of the child has been reported to be normal during the regular pediatric screening and routine reviews for infants during the observation period of 3 years. Because of limited response to BoNT/A and B after delivery, the patient meanwhile underwent pallidal DBS with excellent effect.

Discussion

Here, we present 2 females who deliberately received injections of BoNT/A during their pregnancy. We performed a risk/benefit analysis evaluating the following aspects: There was a possible risk to the child's welfare owing to fetal damage or unknown time‐dependent effects on the one side. On the other side, the benefit to relieve the patients' physical distress, the local action of BoNT/A that is restricted to the injected muscles, as well as the data published to date, which do not point to any risks to the child's well‐being.7, 8, 9, 10, 11, 12, 13, 14 The latter aspects as well as the patients' severe and painful condition with considerable physical and psychological distress were the main arguments for continuing and resuming the BoNT/A treatment during pregnancy, respectively.

In line with previous reports, our patients experienced high treatment efficacy during pregnancy, and no adverse events were reported. The first miscarriage was most likely a result of other medical conditions not related to the BoNT/A injection. The second pregnancy in case 1 and the pregnancy of case 2 were unremarkable with the birth of a healthy, normally developing child.

Our observation, together with the data published thus far, suggest that BoNT/A injections are efficacious and may be safely continued throughout the entire pregnancy. However, BoNT/A treatment should be continued during pregnancy only in selected cases after carefully considering the potential risks and benefits as well as after detailed education and informed consent of the patients.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

H.K.: 1A, 1C, 3A

P.K.: 1C, 3B

A.K.: 3B

A.A.K.: 1A, 1B, 3B

Disclosures

Funding Sources and Conflicts of Interest: This work was supported by a grant from the German Research Foundation (DFG, KFO 247). The authors report no conflicts of interest.

Financial Disclosures for previous 12 months: Dr. Andrea Kühn has received financial support from DTG, Germany, Grant KTO247. Andreas Kupsch: Consultancies: none; Advisory Boards: Medtronic USA; Honoraria for speaking from Allergan, Boehringer Ingelheim, Ipsen Pharma, Lundbeck, Medtronic, Merck, Merz Pharmaceuticals, Orion, St. Jude UCB; Grants: German Research Council, German Ministry of Education and Research.