Migraine in Pregnancy

Transcription

1 Migraine in Pregnancy Dr. Ana Bradi June 16, 2019 Affiliations: Ottawa Headache Centre and Queensway Carleton Hospital

2 Learning Objectives To explore cases of migraine in various stages of pregnancy and review the management implications.

3 Disclosures Nothing to disclose

4 Case 1 33 year old female with chronic migraine headaches taking Topiramate and Ibuprofen as needed. Prior to preventative therapy was having 10 migraines a month and 20 total headache days per month. Otherwise well. Her headache frequency is now 4 per month, responds well to PRN medication. She returns for follow up and tells you she and her partner are trying to conceive.

5 Questions: What is the natural history of migraine in pregnancy? Can she continue on her current medications?

6 1) Migraines of all kinds tend to improve in pregnancy What is the natural history of migraine in pregnancy? 2) Migraine with aura improves but migraine without aura may not 3) Migraine without aura improves but migraine with aura may not 4) Menstrual migraines improve but not other forms of migraine

7 Natural history of migraine in pregnancy First trimester generally worst Migraine with aura is less likely to improve than without aura Migraine with aura may occur for the first time in pregnancy Higher levels of estrogen with less fluctuation generally cause improvement in migraines in the pregnancy Higher levels of endogenous opioids may also help Wells et al. Curr Neurol Neurosci Rep 2016 Allais et al. Neurological sciences 2019

8 Pregnancy complications Migraine sufferers have an increased risk of pregnancy complications: Gestational hypertension and eclampsia OR 2.85 Stroke OR DVT, PE ~ OR 3 Preterm OR 1.24 Low birthweight OR 1.16 Wells et al. Curr Neurol Neurosci Rep 2016

9 Vascular risk in pregnancy with migraine Systematic review in 2015 showed higher risk of vascular events (ischemic + hemorrhagic stroke, gestational hypertension, preeclampsia, and cardiac ischemia) in migraine patients Reason not clear, but also noted higher incidence of obesity, smoking, hypertension and hyperlipidemia in women with migraine In pregnancy, estrogen levels are higher which stimulates hepatic synthesis of clotting factors (increased procoagulants) In third trimester, progesterone increases as well and this increases venous distensability, allowing for venous stasis Wabnitz A, Bushnell, C Migraine, cardiovascular disease and stroke during pregnancy: Systematic review of the literature. Cephalalgia (2) 132

10 Allais et al. Neurological sciences 2019

11 Vascular risk in pregnancy with migraine Ultimately recommended: patients with migraine and additional vascular risk factors be followed as a high risk pregnancy Patient education is critical to recognize warning signs

12 Ideally, when should medications be discontinued when trying to conceive? When birth control is no longer being used At positive pregnancy test Depends on which drug and patient specific factors

13 Challenges in studying teratogenicity Most spontaneous abortions occur weeks 0-18 Organogenesis occurs between weeks 2-9, often before diagnosis of pregnancy Diagnosis of malformations can take up to 4 years (baseline risk 3-5%) This has made studying drug effects difficult as early spontaneous abortions may not be detected/reported, and long follow up is needed to fully account for all malformations

14 FDA classification drugs in pregnancy Category A B C D X Description Controlled human studies showed no risk No evidence of risk in studies (no risk in animal studies and human studies don t exist, or evidence of risk in animal studies but not in human studies) Risk cannot be ruled out (animal studies show risk to fetus and human studies are not available, OR no studies available) Positive evidence of risk (from human studies) but benefits may outweigh the risks Contraindicated in pregnancy and women who may become pregnant (use of drug in pregnancy outweighs possible benefit)

15 Medication FDA Risks Propranolol (First line) Candesartan Lisinopril Amitriptyline (Second line) C D C IUGR, Preterm birth, respiratory distress In the third trimester, neonatal bradycardia, hypotension and hypoglycemia can occur so should be tapered off before labour Significant fetal risk possible cardiovascular or limb abnormalities but not a clear causal relationship. Watch for withdrawal symptoms if used late in pregnancy like constipation or dry mouth Venlfaxine C Avoid in pregnancy increased spontaneous abortions and noenatal seizures and withdrawal VPA X Neural tube defects, cleft palate, cardiac and urinary tract defects Topiramate D Increased risk low birth wt, cleft lip/palate especially in first trimester Gabapentin C Association with bone deformities not clear if causational but not recommended Lamotrigine C Less than 1% increase in oral cleft in one study, otherwise no increased risk found Flunarazine Fetal risk cannot be ruled out

16 When to discontinue medications Depends on the level of risk in pregnancy and patient s baseline migraine frequency. Drugs which are not recommended in pregnancy should ideally be discontinued when trying to conceive, and may need a washout period depending on their halflife

17 Return to case Our patient was taking Topamax as a preventative agent and is planning to conceive Half life elimination is hrs (renal) so she can stop around one week before trying to conceive, but should taper down before this to reduce risk of seizure, so likely would take a few weeks to a month to stop. You advise her that her migraines may improve during pregnancy, and also about non pharmacologic and lifestyle factors that can help reduce migraine frequency

18 What about the rest of the treatment toolkit? Vitamins? Blocks? Botox? Monoclonal antibodies?

19 Vitamins Medication FDA Risks Magnesium (up to 350mg / d) Coenzyme Q10 Riboflavin D (from Cat A in 2013) Safe in pregnancy, reports of transient neurologic sx and hypotonia in newborns Long term IV Mg can induce bone abnormalities, making use in pregnancy controversial No reports of severe adverse effects, but not studied well in pregnancy. One study showed reduced incidence of pre-eclampsia with supplementation in pregnancy (200mg) No severe adverse effects but not yet studied in pregnancy

20 Occipital nerve blocks Lidocaine is FDA category B in pregnancy Bupivicaine is FDA C Both widely used in anesthesia, dentistry and obstetrics for pain relief in pregnancy Data from randomized controlled studies on chronic daily headache and retrospective uncontrolled studies on migraine show efficacy Case series in pregnant women suggest efficacy as well without adverse events Govindappagari, S. et al Obstetrics and Gynecology 2014

21 Injectables Erenumab crosses placenta, half life 28 days so discontinuation around 5 months would be safest (women in trials were required to use birth control) Botox case reports of doses up to 300 U, no fetal abnormalities reported but one miscarriage in a woman with previous history of miscarriage.

22 Counselling and education Remember that up to half of pregnancies are unplanned and therefore good counselling has to happen at first prescribing the medication and ongoing in follow up If accidental pregnancy occurs, discussion of risks/benefits of remaining on medication or discontinuing is important

23 Case 1 continued You have stopped Topamax and plan to watch migraine frequency for now, expecting it may improve on its own in pregnancy You have a backup plan to use Propranolol or nerve blocks as a preventative agent if needed What about Ibuprofen use in pregnancy?

24 Which is true of Ibuprofen use in pregnancy? It is contraindicated in the first trimester It is contraindicated in the second trimester It is contraindicated in the third trimester It is contraindicated in the first and third trimester It is contraindicated in all stages of pregnancy

25 Which are the safest abortive medications in pregnancy?

26 What are the risks? Medication FDA Risks Tylenol Level B Maternal overdose can cause fetal liver toxicity Metoclopramide Level B No evidence of fetal malformations but no adequate studies Sumatriptan Level C Extensive registry data reassuring. Possible increase in risk of postpartum hemorrhage and spontaneous abortion. Preterm delivery (OR 2.3)Animal studies showed fetal risks at very high doses. Opioids Level C Fetal dependence and withdrawal, IUGR, neonatal respiratory depression. Evidence for malformations with 1 st trimester codeine use and neonatal seizures, stillbirth with tramadol use NSAIDs Level D after 30 wks Increased risk of miscarriage in first trimester. 3 rd trimester cleft palate, cardiovascular (premature closure of ductus arteriosus) Ergots Level X Premature uterine contractions, decreased fetal blood supply Steroids Avoid in 1 st trimester associated with cleft lip/pallate, but useful for status migrainosus

27 Sumatriptan registry data 2001 Swedish delivery registry n = 905 women no change in rate of malformations 2002 study n = 289 women no increase in spontaneous abortions (small numbers) and 4% risk of malformations (most in first trimester) which is baseline risk 2001 Obstetric complications study n = 905 higher risk of preterm delivery (<37 weeks) and low birthweight but not statistically significant (worse in untreated migraine), no increase in malformation rate 2009 sumatriptan / naratriptan registry reported 4.6% rate of malformations (n=599, 479 first-trimester exposures to suma)

28 Case 1 conclusion You have stopped Topamax and plan to watch migraine frequency for now, expecting it may improve on its own in pregnancy You have a backup plan to use Propranolol as a preventative agent if needed Tylenol is to be used first line for migraines and Sumatriptan is also prescribed for severe migraines

29 Case 2 28 year old female with menstrual migraine, postpartum day 7 after uncomplicated pregnancy. Presents to hospital with severe headache and vomiting for 4 hours.

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31 Rule out other causes of headache CVST Pre-eclampsia, Eclampsia RCVS (postpartum angiopathy), SAH Post dural puncture headache In a 5 yr study of pregnant and postpartum women seeking ER treatment for acute headache, 65% had migraine and 35% had secondary headache disorders

32 A word on pre-eclampsia postpartum pre-eclampsia occurs even in women with normal BP during pregnancy 50% had normal BP No longer required to have proteinuria for a diagnosis of pre-eclampsia Hypertension (>140/90) + ONE of Proteinuria Low platelets Kidney dysfunction Pulmonary edema New headaches or visual change

33 A word on other secondary headaches CVST, RCVS, PRES, SAH can be assessed with neuroimaging This often brings up concerns about safety of imaging while pregnant or breastfeeding

34 Neuroimaging in pregnancy and postpartum CT Imaging risk highest risk between conception and implantation (0-15 days) Increased risk miscarriage up to 4 weeks. Also very vulnerable between 8-15 weeks (increased risk of mutations and MR) Contrast risk Class B - avoid if possible in pregnancy. Experimentally there was an increase in fetal hypothyroidism, but only when administered directly into cavity. Lactation: 24H pump and dump can be recommended but no evidence of harm in low concentrations MRI No evidence of harm but most non-urgent imaging can be delayed to 2-3 rd trimester or postpartum crosses placenta - in high concentration in animal studies: abortion and developmental abnormalities Lactation: 24 hour pump and dump but probably safe

35 Case 2: course in ER She has a negative urgent MRI and MRA/ MRV and her headache resolves completely 2 hours after treatment with IV maxeran, toradol and rehydration What advice would you give her regarding recurrence of migraine while she is breastfeeding? What can she use for treatment?

36 Postpartum migraines Postpartum period lasts for 6 weeks Migraines often recur after first days to first month after giving birth Combined effect of drop in estrogen, sleep deprivation Unclear if breastfeeding is protective Inhibits ovulation, fluctuation of estrogen levels and menses Generally menses return by 27 weeks Wells et al. Curr Neurol Neurosci Rep 2016 Allais et al. Neurological sciences 2019

37 Treatment of postpartum migraines

38 Hale lactation rating Safety L1 Safest No adverse effects in infant, controlled studies do not show a risk or the drug is no orally bioavailable to the infant L2 Safer No controlled studies but studies in a limited cohort show no risk L3 Moderately safe No controlled studies but risk is possible, or controlled studies show a minimal non threatening adverse event L4 Possibly hazardous Positive evidence of risk to infant but may be outweighted by benefits L5 Contraindicated Often drugs with under 10% bioavailability to infant are considered compatible with breastfeeding

39 Abortive treatment of postpartum migraine Consider safety while breastfeeding: Safest: Tylenol, Ibuprofen Safe: Diclofenac, Ketorolac (avoid immediately postpartum), Metoclopramide Moderately safe: Triptans (sumatriptan), Naproxen Hazardous or contraindicated: Valproate Wells et al. Curr Neurol Neurosci Rep 2016

40 Preventative treatment of postpartum migraine Consider safety while breastfeeding: Safest: Safe: Carbamazepine, Amitriptyline, Venlafaxine, Propranolol Moderately safe: Topiramate, Candesartan, Hazardous or contraindicated: Valproic Acid Wells et al. Curr Neurol Neurosci Rep 2016

41 What about other treatment options Vitamins Blocks Botox? Erenumab?

42 Case two wrap up Your ER patient is treated with IV Ketorolac and Metoclopramide and IV fluids and improves enough for discharge. She decides to pump and dump for 24 h due to contrast received (though no clear evidence of harm) You advise she treat further headaches with Tylenol/Advil and if needed she can also use Sumatriptan for moderate/severe headaches You plan to trial Propranolol or Amitriptyline if her headaches worsen in frequency

43 Summary Migraines affect women of childbearing age and appropriate counselling about pregnancy risk should be done when prescribing medications In pregnancy, most women with migraine improve but some will still need preventative and abortive treatments Untreated migraine can have further risks to pregnancy

44 Summary Safest options for treatment in pregnancy are Tylenol, Sumatriptan, Nerve blocks and Propranolol Safest options for treatment while breastfeeding are Tylenol, NSAIDs, Sumatriptan, Amitriptyline, Venlafaxine and Propranolol

45 References Allais G, Chiarle G et al. Migraine during pregnancy and in the puerperium. Neurological sciences :Suppl1:581 Maassen Van den Brink, A., MacGregor, E.A., Gender and Migraine, Springer Nature Switzerland AG, 2019, print Marsh, M.S., Nashef, L.A., Brex, P.A. Neurology and Pregnancy: Clinical Management, Informa Healthcare, London, 2012, print Fox, AW, Chambers CD, et al. Evidence-Based Assessment of Pregnancy outcome after Sumatriptan Exposure. Headache 2002; 42: 8-15 Cassina, M, Di Gianatonio, E, et al. Migraine therapy during pregnancy and lactation. Expert Opin. Drug Saf (2010) 9(6) Kallen, B, Lygner, PE., Delivery outcomes in women who used drugs for migraine during pregnancy with Special Reference to Sumatriptan. Headache 2001; 41: Contag, SA, Mertz HL, Bushnell CD. Migraine during pregnancy: is it more than a headache? Nature reviews Neurology :449 Macgregor, EA. Migraine in pregnancy and Lactation: a clinical review. J Fam Plann Reprod Health Care :2: 83 Yusuf, A, Chia, V et al. Use of existing health care databases to evaluate medication safety in pregnancy: Triptan exposure in pregnancy as a case study. Pharmacoepidemiol Drug Saf :1309 Sader, E, Rayhill, M. Headache in Pregnancy, the puerperium and menopause. Semin Neurol :627 Wells RE, Turner DP et al. Managing migraine during pregnancy and lactation. Curr Neurol Neurosci Rep :40 Wabnitz A, Bushnell, C Migraine, cardiovascular disease and stroke during pregnancy: Systematic review of the literature. Cephalalgia (2) 132 Govindappagari, S. et al Peripheral Nerve blocks in the treatment of migraine in pregnancy Obstetrics and Gynecology 2014 (124)1169

46 Questions?