Pregnancy-related issues of pre-existing conditions

Epilepsy

Epilepsy, with a prevalence of 0.8% and an incidence of 0.05%, is one of the most common chronic neurological conditions in women of childbearing age (1). The classification of epilepsy was revised in 2010 and includes the aetiology of epilepsy as genetic (previ­ously idiopathic), structural/metabolic (previously symptomatic), and of unknown cause (previously cryptogenic) (2).

(4). This results in about 20-25% of epilepsies being drug resistant

(5). A neurologist or epilepsy specialist should manage the diagnosis and treatment of epilepsy. All women and girls of childbearing age on AEDs should be offered 5 mg of folic acid before the possibility of pregnancy (6).

With respect to pregnancy, most women will develop epilepsy prior to pregnancy given that the prevalence peak is before the age of 25 and after the age of 65. However, a minority of women will develop epilepsy or seizures during pregnancy. In those cases, acute symptomatic seizures due to eclampsia, intracranial venous throm­bosis, reversible posterior leucoencephalopathy, or other acute con­ditions have to be excluded.

AED-associated risk to the fetus

Most women with epilepsy (WwE) are on AEDs. There are sev­eral issues to consider: pregnancies in WwE should be planned as AEDs may impact the major congenital malformation (MCM) risk. Several pregnancy in epilepsy registers have been established world­wide addressing this question.

Epilepsy, AEDs, seizures, and pregnancy

Approximately two out of three WwE will remain seizure free during pregnancy, which is more likely in idiopathic generalized epilepsies compared to localization-related epilepsies. Generalized tonic- clonic seizures occur in 15% of women in pregnancy and are associ­ated with a higher risk for preterm birth and low birth weight (21).

Pregnancy-related risks

WwE have a slightly increased risk of spontaneous miscarriage, ante- or postpartum haemorrhage, hypertensive disorder, caesarean

Table 24.1 Rates of major congenital malformations for the most commonly used anti-epileptic drugs in pregnancy registries for women with epilepsy.

* Dose dependent, ** women with epilepsy not on AEDs; § also part of EURAP

1.

2. Campbell E, Kennedy F, Russell A, Smithson WH, Parsons L, Morrison PJ, et al. Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers. J Neurol Neurosurg Psychiatry. 2014;85:1029-34.

3. Mawhinney E, Craig J, Morrow J, Russell A, Smithson WH, Parsons L, et al. Levetiracetam in pregnancy: results from the UK and Ireland epilepsy and pregnancy registers. Neurology. 2013;80:400-5.

4. Hernandez-Dfaz S, Smith CR, Shen A, Mittendorf R, Hauser WA, Yerby M, et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology. 2012;78:1692-9.

5. Vajda FJE, Graham J, Roten A, Lander CM, O'Brien TJ, Eadie M. Teratogenicity of the newer antiepileptic drugs--the Australian experience. J Clin Neurosci. 2012;19:57-9.

section, and fetal growth restriction with an odds ratio (OR) be­tween 1.3 and 1.5. Risk for induction of labour is slightly higher (OR 1.7) whereas preterm birth (treated with a 3- 5-day course of high-dose steroids. The majority of prednisone, prednisolone, and methylprednisolone is converted into inactive metabolites by the placenta. In contrast, betamethasone and dexa­methasone are only minimally metabolized and should therefore not be administered during pregnancy. Corticosteroid use during the first trimester may be associated with an increased risk of cleft lip and palate (39, 40).

With the emergence of a plethora of new disease-modifying drugs in recent years, the therapeutic management of women with MS planning to get pregnant has become more challenging and gen­erally needs to be based upon individualized counselling. This is complicated by the lack of adequate data on the safety of use during pregnancy and lactation for most of the disease-modifying drugs.

Clinicians tend to advise discontinuation of disease-modifying drugs prior to conception (41). This tendency is well founded for drugs with serious indications of embryo-fetal toxicity—s uch as mitoxantrone and teriflunomide—b ut more arguable for other agents. In particular, glatiramer acetate and interferon beta may be continued in patients with highly active disease after thorough coun­selling (42, 43); available data on currently used disease-modifying drugs are summarized in Table 24.2). Alternatively, intermittent application of high-dose corticosteroids or intravenous immuno­globulin may be considered for relapse prevention during pregnancy and postpartum (39, 40). The caveats applying to corticosteroid use during gestation were discussed previously.

As to the outcome of pregnancy in MS patients, some studies de­scribe an increased risk of intrauterine growth restriction and of the need for induction and instrumental delivery (44, 45). These findings could not be reproduced in other evaluations, in which mothers with MS were no more likely to experience significant preg­nancy complications or adverse fetal outcomes than healthy females (46-48).

Myasthenia gravis

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease affecting the nicotinic acetylcholine receptors (AChRs) blocking the initiation of muscle contraction. It is more common in women then man (male:female ratio of 2:3) and its peak incidence is in the third decade of life. MG can be exacerbated with certain medications or conditions such as pregnancy (for a list, see http:// www.myaware.org). Clinically, patients present with muscular weakness which might affect the ocular muscles only, or appear more generalized. Dysphagia and dyspnoea can occur and in severe cases or myasthenic crisis, ventilation might be required. Typically, there is a fatigability and circadian rhythm with more prominent symptoms in the evening hours. In case of appropriate clinical fea­tures, diagnosis is confirmed by neurophysiological studies, and AChR antibodies.

Pregnancy in woman with MG should be carefully planned. If possible, pregnancy should be avoided within the first 2 years of the disease as disease activity is particularly high during this period. If indicated, thymectomy should be performed prior to concep­tion. Treatment of MG usually includes pyridostigmine as first-line therapy and if progressive, with steroids (e.g. prednisolone). When long-term immunosuppression is required, azathioprine is added to reduce the steroid dose. In severe cases, methotrexate, ciclosporin, mycophenolate mofetil, or rituximab might be indicated. In some severe, unstable cases of MG, pregnancy might be contraindicated. Where appropriate, medication should be optimized well before conception.

The course of MG during pregnancy is highly variable. Whereas 80% of patients experience a stable condition or improvement, 20% will worsen within pregnancy including relapses of asymptomatic patients (52). The course of MG in further pregnancies is also vari­able. Additionally, exacerbation of newly presenting MG in preg­nancy occurs. Deterioration during pregnancy usually occurs in the first trimester or in the last 4 weeks. Up to 20% experience respira­tory crisis during pregnancy with the need for ventilation. Woman with MG should be closely monitored during pregnancy. Treatment options are similar to the prepregnancy period with the exception of immunosuppressants other than steroids. There are limited safety data on most drugs used but pyridostigmine, neostigmine, intra­venous immunoglobulins, azathioprine, and ciclosporin appear to be safe in pregnancy (53). Prednisone and prednisolone show a 3.4- fold increased risk of cleft palate (54). Women with MG who are stable on prednisolone and azathioprine should continue this medi­cation. Plasmapheresis and immunoadsorption are well tolerated during pregnancy if necessary.

Magnesium sulphate which is a standard treatment for eclampsia should be avoided in pregnant women with MG as magnesium in­hibits acetylcholine release. In case magnesium sulphate has to be used, worsening of MG should be expected and intensive care unit treatment including ventilation should be available. Alternatively, other AEDs, narcotics, or sedatives can be used (55). MG mim­icking eclampsia can be treated with pyridostigmine or intravenous neostigmine (56).

Caesarean section should be discussed for the delivery mode as muscular fatigue can occur during spontaneous delivery. Caution is again advised for those anaesthetic drugs and antibiotics which worsen myasthenia. A list of drugs with a risk of worsening myas­thenia can be found online (e.g. http://www.myaware.org). If spon­taneous delivery is decided upon, regular doses of pyridostigmine should be continued.

Caution is advised for postnatal care of the newborn as neonatal myasthenia might occur with a frequency of 1:12. Immunoglobulin G(IgG) autoantibodies cross the placenta and are secreted in the breast milk causing a transient myasthenic condition in the new­born. Pyridostigmine is the treatment of choice for the newborn. Symptoms will disappear within a few weeks.

Migraine and other types of headache

Headache is a common complaint in the neurological patient. Primary and secondary headaches are distinguished, with each category comprising a multitude of different entities (see the International Headache Society classification (57)). The most fre­quent types of headache in a primary care setting are migraine, tension-type headache, and headache related to systemic disorders (e.g. infectious diseases) (58).

Migraine typically presents with attacks of a unilateral throb­bing headache, which is accompanied by nausea and vomiting, phonophobia, and/or photophobia, and aggravated by physical ac­tivity. Atypical bilateral presentations exist. In migraine with aura,

Table 24.2 Summary of available data on embryofetal safety of currently used MS therapeutics (disease-modifying drugs, DMDs) during pregnancy and lactation. The wash-out period denotes the time span that should be allowed to pass between last application of the DMD and conception.

LITERATURE

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2. Coyle PK. Multiple sclerosis and pregnancy prescriptions. Expert Opin Drug Saf. December 2014;13(12):1565-8.

3. Amato MP, Portaccio E. Fertility, pregnancy and childbirth in patients with multiple sclerosis: impact of disease-modifying drugs. CNS Drugs. March 2015;29(3):207-20.

4. Prescribing information Dimethyl fumarate [Internet]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204063s014lbl.pdf (accessed April 24 2016)

5. Prescribing information Fingolimod [Internet]. Verfugbar unter: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022527s008lbl.pdf (accessed July 18 2019)

6. Karlsson G, Francis G, Koren G, Heining P, Zhang X, Cohen JA, u. a. Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis. Neurology, 25. February2014;82(8):674-80.

7. Prescribing information Glatiramer acetate [Internet]. Verfugbar unter: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020622s057lbl.pdf (accessed April 24 2016)

8. Lu E, Wang BW, Guimond C, Synnes A, Sadovnick AD, Dahlgren L, u. a. Safety of disease-modifying drugs for multiple sclerosis in pregnancy: current challenges and future considerations for effective pharmacovigilance. Expert Rev Neurother. March 2013;13(3):251-260; quiz 261.

9. Lu E, Wang BW, Guimond C, Synnes A, Sadovnick D, Tremlett H. Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review. Neurology, 11. September 2012;79(11):1130-5.

10. Prescribing information Interferon beta [Internet]. Verfugbar unter: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103780s5172lbl.pdf (accessed April 24 2016)

11. Prescribing information Mitoxantrone [Internet]. Verfugbar unter: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019297s030s031lbl.pdf (accessed April 24 2016)

12. Hellwig K, Schimrigk S, Chan A, Epplen J, Gold R. A newborn with Pierre Robin sequence after preconceptional mitoxantrone exposure of a female with multiple sclerosis. J Neurol Sci. 15. August 2011;307(1-2):164-5.

13. Prescribing information Natalizumab [Internet]. Verfugbar unter: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125104s950lbl.pdf (accessed April 24 2016)

14. Prescribing information Teriflunomide [Internet]. Verfugbar unter: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202992s001lbl.pdf (accessed April 24 2016)

15 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103948s5158lbl.pdf (accessed July 18 2019)

the aura is visual in greater than 90% of patients. It characteristically occurs within 60 minutes before onset of cephalalgia (note that aura symptoms may be present without subsequent headaches) (57).

Tension-type headaches manifest as episodic or chronic bilateral, mild-to-moderate-intensity headaches of a pressing or tightening quality, which are not exacerbated by routine physical activities. Chronic tension-type headaches often concur with medication­overuse headache (57).

The diagnostic approach to headaches rests on a detailed history and physical examination. If these reveal red flags—such as a new- onset headache, altered characteristics of a pre-existing headache, or concomitant neurological signs—further diagnostic evaluation is warranted. Depending on the suspected pathology, this may include neuroimaging (during gestation preferably by MRI), a spinal tap, and specific laboratory studies. Blood pressure should be taken in gravid women presenting with headache to screen for pre-eclampsia (the incidence of which may be higher in women with a previous history of migraine) (59). Further important causes of secondary headaches that need to be excluded in the pregnant or lactating patient include venous sinus thrombosis, reversible cerebral vasoconstriction syn­drome, posterior reversible encephalopathy syndrome, idiopathic intracranial hypertension, pituitary apoplexy, and intracerebral/ subarachnoid haemorrhage (60).

Many migraine sufferers will experience an abatement of symptoms during pregnancy (61, 62). In those who do not, non-pharmacological measures—such as maintaining a regular lifestyle, avoiding known triggers, and application of behavioural treatment strategies—may suffice (60). If medication is deemed necessary, care should be taken to select those drugs with the best maternal-fetal safety profile. Regarding the drugs commonly used in acute migraine attacks, there are no controlled safety studies in pregnant women showing no harm. Acetaminophen is frequently used for this indication, alone or in combination with metoclopramide or caffeine. Study data connecting its use with an increased incidence of childhood asthma are so far not entirely conclusive (63). For non-steroidal anti-inflammatory drugs (NSAIDs), first-trimester use has been associated with a potentially increased risk of miscarriage, and third-trimester use with premature ductal closure and an adverse effect on fetal renal function. There is conflicting evidence on the safety of aspirin during the first trimester, when its use may be associated with an increased risk of gastroschisis (64, 65). In the third trimester, analgesic doses of aspirin ought to be avoided due to its effect on the ductus arteriosus and platelet inhibition (66). Current evidence is reassuring as to the fetal safety of triptans with most trials failing to demonstrate associated teratogenicity (67­69). The most solid data are available for sumatriptan. Ergotamine is contraindicated during pregnancy for its potential to cause vasocon­striction and uterine contractions (60, 61). In patients with frequent migraine attacks, prophylactic treatment may be considered. Beta­blockers such as propranolol and metoprolol are first-line agents, although they have been linked to mild fetal growth restriction and re­spiratory depression (70). According to limited data, calcium channel blockers such as verapamil seem to be safe (71). Acupuncture has been shown to be effective for migraine prophylaxis, although sham acu­puncture was not superior to ‘true’ intervention (72).

There are no adequate data on the use of CGRP-antagonists in pregnancy. Acute treatment of tension-type headaches is based on NSAIDs and aspirin. During pregnancy, the caveats previously dis­cussed apply. Care should be taken to avoid medication overuse.