Migraine and pregnancy

Background. Migraine is a frequent neurological disorder affecting mostly women in the childbearing age. It is influenced by fluctuation of female hormones, especially estrogen levels. Objectives. This review aims to describe the expression of migraine during the reproductive ages summarizing the diag nosis and effective, available treatment options. Materials and Methods. We performed a literature review searching relevant information on the subject in PubMed and Medscape databases. Outcomes. It reveals that during the first trimester due to symptoms of hyperemesis gravidarum, migraine attacks can exacerbate, while, through second and third trimester when estrogen levels rise, women report relief of symptoms. Ther apy includes firstly behavioural approach and secondly pharmacological drugs along with non-invasive procedures, some still under investigation for pregnant state. For mild cases the first line is acetaminophen alone or together with antiemet ics and in more severe cases or in women with past history of migraine triptans can used as the mainstay therapy. Conclusions. Despite recent discoveries on therapy and drugs, our understanding of the way medications may affect the fetus or new-born is incomplete and further evidence is needed, bringing potential for improved management of mi graine during pregnancy.


INtRoDuctIoN
Migraine is a common neurovascular disorder with a sex ration prevalence of about 3:1, with a female preponderance and a peak prevalence in women of childbearing age [1].The increased burden of migraine relates to both developmental and variable action of women's hormones during life.Approximately 2% of women develop their first migraine during pregnancy, usually along the first trimester [2].Understanding its pathophysiology can help prevent, treat, and develop new treatment options, especially during pregnancy when its management can be challenging.
Migraine is the type of headache most affected by alterations of estrogen levels, resulting from biological processes as menstruation, pregnancy or menopause or exogenous mechanisms as contraceptive use or in-vitro fertilization.
Diagnosis is usually clinical, based on history and physical examination.It is typically unilateral, localised pain (frontotemporal and/or ocular area) that tends to have a throbbing or pulsatile characteristic and it can be associated or not with aura.Patients define pain as moderate to severe, augmenting with movement or physical activity, lasting for about 4 to 72h, associated with nausea and/or photophobia and phonophobia; this is migraine without aura (MO).Aura commonly occurs before headaches begin or sometimes accompany the headache and symptoms of it include visual, sensory, speech or language, motor or retinal manifestations, fully reversible; this is migraine with aura (MA) [3].

MAtERIAls AND MEthoDs
We performed a literature review searching relevant information regarding migraine and its management during pregnant state in PubMed and Medscape databases.We analysed articles and meta-analyses in English, from the last ten years, including only the ones offering data on the field of Obstetrics and Gynecology.

Pathophysiology
The pathophysiology of this disorder relates to the modifications in neural networks concerning pain.Arousal of central pain pathways from both cortex and brainstem stimulated the trigeminal vascular system with efferent fibres to dura mater and cranial blood vessels causing release of vascular inflammatory substances as calcitonin-gene related peptide (CGRP), cytokines and prostaglandins.The afferent fibres of these structures go to the trigeminocervical complex (TCC) explaining the area of action of migraine at the level of frontotemporal area and ocular area [4,5].Estrogens can modulate this pathway and proofs support the genetic influence of this hormone in women with menstrual migraine [3,6,7].It also has the capacity to augment the sensitivity to nociceptive responses to central and peripheral stimuli [8,9].

Effect of pregnancy on migraine
The occurrence and severity of migraine is influenced by the fluctuating levels of estrogens.About 60-70% of patients with past history of this headache (migraine with aura, menstrual migraine) report improvement over the course of pregnancy and only 5% describe worsening of the symptoms [10,11].
During the first trimester due to frequent symptoms of hyperemesis gravidarum, migraine attacks can exacerbate.While, during the second and third trimester when estrogen levels rise, women report relief of symptoms, except the ones with history of migraine with aura.Also, current literature describes the appearance for the first time during first trimester of migraine with aura [12].
Moreover, in the first 3 to 6 days after delivery women can encounter an exacerbation of symptoms due to both environmental factors as change of status (especially for primigravida), sleep disturbance, stress, irregular meals and decreasing of estrogen levels.In the postpartum, some data suggest that breast feeding delays occurrence or recurrence of migraine, related to the anovulation mechanism [13,14].
Effect of migraine on pregnancy Pregnant women with past history of migraine attacks are at increased risk for gestational hyper-tension, preeclampsia and preterm birth [15,16].Studies evaluating pregnancy outcome in people affected by this headache conclude that whether treated or not, it is linked to an increased prevalence for hypertensive disorders of pregnancy.
Migraine is a risk factor for a secondary headache, for pregnancy associated stroke and preeclampsia.A new headache together with fever, hypertension or any neurological signs should raise suspicion and be investigated by MRI without contrast as gadolinium should be avoided during pregnancy.
Pregnant women diagnosed with migraine are at increased risk for gestational diabetes and postpartum depression compared to the one non affected, suggesting the need for more careful follow-up and recommendations for neurological investigation after delivery [17].

Preventive treatment
Migraine can be a deciding factor in pregnancy, thus its management should reunite preconceptional counselling and history of migraine attacks, preventive treatment options and most recent, effective medications to use both during pregnancy and postpartum.
The first-line actions for the management of migraine during pregnancy are the behavioural approaches, which are non-pharmacological options.It consists of improvement of sleep quality and duration, relaxation therapy and biofeedback, stress cessation, balanced and regular meals, good hydration and physical exercise [18].The actual recommendations are for women to start these actions prior to conceive in order to reduce the frequency of attacks.
Vitamins and minerals can be an option for mild cases that do not want pharmacological agents.However, an important mention at this level is regarding the use of magnesium, because prolonged high doses administered intravenous can result into bone abnormalities and decreased fetal calcium, thereby it can be administered oral.Another vitamin recommended is riboflavin to reduce the risk for anemia and some studies show efficacy of coenzyme Q10 in migraine and preeclampsia prevention, but still extensive studies need to be performed [19,20].

Acute treatment during pregnancy
The management of acute migraine during pregnancy is different due to drug's adverse effects on fetus.Current literature indicates a start with a firstline drug-acetaminophen 1000mg, because of the maternal fetal safety during all trimesters.If migraine does not respond to it, a combined therapy can be indicated: acetaminophen 650 mg to 1000 mg and metoclopramide 10 mg or acetaminophen and codeine 30 mg, with attention that codeine should not be used more than nine days per month [21].Acetaminophen was associated with some neurodevelopmental outcomes for fetuses exposed more than 28 days, but further studies developed by the European Medicine Agency found insufficient evidence [22,23].
Non-steroidal anti-inflammatory drugs (ibuprofen, naproxen, diclofenac) are also used as first-line drugs, considered safe during the second trimester, but raising concerns during the first one regarding the risk of miscarriage and the third one for the risk of premature closure of ductus arteriosus [1,24].From all, ibuprofen offers the best data concerning safety of use.
Antiemetics are second-line drugs used in the management of migraine attacks, alone or along with acetaminophen.Metoclopramide is the preferred antiemetic, while data regarding ondansetron and fetal effects are still conflicting, some show risks for palate and heart defects [25].
Triptans are a mainstay therapy for migraine, with sumatriptan being the most studies and used.It is the most hydrophilic triptan with very difficult passage of the placental membrane, preferably administered as nasal spray than the 25 mg tablet, but with same efficacy [22,26].

Novel treatments
There are several non-invasive neurostimulation devices available for the treatment of migraine like transcranial magnetic stimulation, vagal or transcutaneous supraorbital nerve stimulators, but their safety has not been determined during pregnant state [12].The same goes for occipital and trigeminal peripheral nerve blocks (PNBs).They could be-come a suitable alternative in the future, but further data is required.
A revolution in the management of migraine attacks was the discovery of calcitonin gene-related peptide (CGRP Atb) monoclonal antibodies blocking a protein that cause inflammation and pain, but its use is still restricted during pregnancy and lactation because of the toxicity, risks for spontaneous abortion and unknown fetal effects.The US Food and Drug Administration has approved a calcitonin gene-related peptide receptor antagonist CGRP-atogepant (Qulipta), a novel calcitonin gene-related peptide (CGRP) for the prevention of episodic migraine, lacking the vasoconstrictor effect of triptans.The once-daily medication will be available in doses of 10 mg, 30 mg, and 60 mg [27,28].Its safety during pregnancy and lactation is still not determined.

coNclusIoN
The expression of migraine in women is common and varies with the hormonal phases through their lives.The fluctuations of hormones during the reproductive years explain its higher prevalence compared to man.In order to optimize treatment in the prenatal period, preconception counselling and regular visits to specialists should be encouraged.Although recent discoveries on therapy and drugs have been made, our understanding of the way drugs may affect the fetus or new-born is incomplete and further evidence is needed, bringing potential for improved management of migraine.

Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship and/ or publication of this article.