Headache Diagnosis Management in Evaluation Pregnancy - - PowerPoint PPT Presentation

Headache Management in Pregnancy

Morris Levin, MD Professor of Neurology, UCSF Director, UCSF Headache Center

Headache Management in Pregnancy

 Diagnosis  Evaluation  Pharmacological options  Injections and neuromodulation  Alternative options

• 1. New 1st trimester

headaches

 29 year old G1 woman LMP 8 weeks ago

began having frequent severe HAs with nausea, photosensitivity and phonosensitivity about 1 month ago. She denies having migraines or other headaches in the past but her mother and aunt have migraine.

 Acetaminophen is not helpful – “I just

have to ride them out”

• 2. Preexisting headaches

worsening in pregnancy

 31 year old woman with migraines with aura

since late teens; had infrequent headaches until early in this 3rd pregnancy now in 2nd

• trimester. “My mother says that is because

this is a boy”.

 There is some baseline nausea but during

headaches this worsens, and she has had more pronounced visual auras

• 3. New late pregnancy HA

 22 year old pregnant woman at 38 weeks was

admitted last night with a severe holocranial

• headache. She had several milder headaches

earlier in this her first pregnancy.

 She has no history of migraine or other

headaches, but does recall several family members with headaches.

 Exam is remarkable only for intense

photophobia and unwillingness to move at all.

Women’s headaches

 Migraine is 3x more common in women (18%)

than men (6%), with the highest prevalence in peak reproductive years: ~30% of women

 85% of Chronic Migraine sufferers are women  Menses, pregnancy, menopause are all times of

significant change in migraine

 Most neurologists are not trained in hormonal

management of menstrual migraines or migraines during pregnancy; and most gynecologists are not trained in migraine treatment

Migraine Prevalence

Dating Married life Death of husbands “I used to have a headache. But he went away.”

Migraine course in pregnancy

 Migraine tends to improve during pregnancy [1],  BUT some women experience an increase in

frequency or intensity [2], particularly in the first trimester when human chorionic gonadotropin levels are falling.

 When improvement is not seen after this point,

migraine is likely to continue throughout the pregnancy and extend into the postpartum period [3].

• 1. Granella F, Sances G, Pucci E, Nappi RE, GhiottoN, et al.Migrainewith aura and reproductive life

events: a case control study.Cephalalgia. 2000;20:701–7.

• 2. Maggioni F, Alessi C, Maggino T, Zanchin G. Headache during pregnancy. Cephalalgia. 1997;17:765–9
• 3. Sances G, Granella F, Nappi RE, FignonA, Ghiotto N, et al. Courseof migraine during pregnancy and

postpartum: a prospective study.Cephalalgia. 2003;23:197–205.

Migraine-related pregnancy risks

 Retrospec review in Taiwan - 4911 preg women with migraine c/w

>24,000 controls - Migraine seems to be risk of preterm delivery and preechlampsia (OR’s 1.2, 1.4) [1]

 Prospective cohort study in Italy also demonstrated that preterm

birth occurred at a higher rate in those with a history of headache (OR: 2.74) [3]

 Co-morbid mood disorders double those risks [2]  Increased risk of overall hypertensive disorders including

gestational hypertension and preeclampsia compared to non- migraine sufferers - OR 2.85 [4]

 Increased risk of ischemic stroke in pregnancy (OR range 7.9 to

30.7), acute myocardial infarction and heart disease (OR 4.9), and thromboembolic events (deep venous thrombosis OR 2.4 [5]

• 1. Chen HM, et al. Increased risk of adverse pregnancy outcomes for women with migraines: a nationwide population-based study.
• Cephalalgia. 2010;30(4):433–8
• 2. Marozio L, et al. Headache and adverse pregnancy outcomes. Eur J Obstet Gynecol Reprod Biol. 2012;161(2):140–3
• 3. Cripe, S.M, et al 2011. Risk of preterm delivery and hypertensive disorders of pregnancy in relation to maternal co‐morbid mood and

migraine disorders during pregnancy. Paediatric and perinatal epidemiology, 25: 116-123.

• 4. Facchinetti F,, et al. Migraine is a risk factor for hypertensive disorders in pregnancy. Cephalalgia 2009;29:286–92.
• 5. Wabnitz A, Bushnell C. Migraine, cardiovascular disease, and stroke during pregnancy: systematic review of the literature.
• Cephalalgia. 2015;35(2):132–9.

Migraine pregnancy risks

 Sleep disturbances are inevitable during

pregnancy and are risks for both headaches and mood disorders

 Depression and anxiety are more likely in

pregnant women with migraine*

 In migraine, 50% of pregnancies are unplanned

*Orta, OR, et al. Depression, anxiety and stress among pregnant migraineurs in a pacific northwest cohort. J Affect Disord 2014, 172:390-6

• 1. Migraine without aura

Headache attacks lasting 4-72 h (untreated or unsuccessfully treated) Headache has 2 of the following

• 1. unilateral location
• 2. pulsating quality
• 3. moderate or severe pain intensity
• 4. aggravation by or causing avoidance of routine

physical activity (eg, walking, climbing stairs) During headache 1 of the following:

• 1. nausea and/or vomiting
• 2. photophobia and phonophobia

ICHD 3

1.2 Migraine with aura

1 of the following fully reversible aura symptoms:

• 1. visual; 2. sensory; 3. speech and/or language;
• 4. motor ; 5. brainstem; 6. retinal

2 of the following 4 characteristics:

• 1. 1 aura symptom spreads gradually over ≥5 min,

and/or 2 symptoms occur in succession

• 2. each aura symptom 5-60 min
• 3. 1 aura symptom is unilateral
• 4. aura accompanied or followed

in <60 min by headache

• 2. Tension type HA

2 of the following 4 characteristics:

• 1. bilateral location
• 2. pressing or tightening (non-pulsating) quality
• 3. mild or moderate intensity
• 4. not aggravated by routine physical activity

Both of the following:

• 1. no nausea or vomiting
• 2. no more than one of photophobia or

phonophobia

Diagnosing Primary Headaches – The essentials

Migraine - unilat, throbbing, female 3:1, nausea, +/- aura Tension-type HA – bilateral, milder, no nausea, no aura Cluster - Unilateral, male predom, brief, recurring in cycles

International Classification of Headache Disorders 2018

Primary HA

• 1. Migraine
• 2. Tension-type HA
• 3. Cluster headaches relatives (TAC)
• 4. Exertional and other headaches

Secondary HA

• 5. Posttraumatic
• 6. Vascular disease
• 7. Abnormal ICP, Neoplasm, Hydrocephalus
• 8. Substances
• 9. CNS infection
• 10. Metabolic
• 11. Cervicogenic, Eyes, Sinuses, Jaw
• 12. Psychiatric HA
• 13. Neuralgias

ICHD 3

 Unusual headache for patient  Change in personality, cognition, neuro exam  Sudden, Effort induced or Positional  Febrile or Systemic illness - AIDS, Cancer

Secondary Headaches - When to look for them in Pregnant pt

 Unusual headache for patient  Change in personality, cognition, neuro exam  Sudden, Effort induced or Positional  Febrile or Systemic illness - AIDS, Cancer

Secondary Headaches - When to look for them in Pregnant pt

Key headache ddx in pregnancy

New frequent long-lasting HAs 1st/2nd trimester

 Migraine  Intracranial hypertension  Cerebral venous thrombosis  Idiopathic Intracranial Hypertension

 Late emergence of HAs including postpartum

 Eclampsia (migraineurs seem to be at higher risk)  Intracranial hemorrhages  Reversible Cerebral Vasoconstriction Syndrome (RCVS)  Intracranial hypotension (CSF leak)

 5-year record review of 140 pregnant women seeking treatment

for acute headache via emergency department or labor/delivery/antepartum units revealed that:

 65 % had primary headache disorders (59 % were migraine)  35 % presented with secondary headache disorders  “Hence the importance of neuroimaging and close monitoring in

this population”.

Robbins MS, FarmakidisC, Dayal AK, Lipton RB. Acute headache diagnosis in pregnant women: a hospital- based study. Neurology. 2015;85(12):1024–30.

Evaluation of HA in Pregnancy

 CT poses minimal risk to fetus, but Iodinated

contrast should be avoided as it may suppress fetal thyroid

 MRI considered safer, and is more useful than

non-c CT

 Gadolinium does cross the BBB and animal

studies suggest potential adverse fetal effects, so avoid if possible

 Lumbar puncture (LP) safe and is necessary in

suspected meningitis, subarachnoid hemorrhage (SAH), or idiopathic intracranial hypertension (IIH).

• Pregnant women are at risk for cerebral

venous thrombosis and idiopathic intracranial hypertension.

• If there are any signs of increased intracranial pressure

MRI without gadolinium and MRV are indicated.

• If imaging is normal, but there are signs of intracranial

hypertension, lumbar puncture should be performed even though intracranial hypertension is very unlikely without papilledema or other symptoms such as visual

• bscurations, pulsatile tinnitus, double vision, or neck or

back pain

Increased intracranial pressure Headache attributed to IIH Pseudotumor Cerebri

• A. Any headache fulfilling criterion C
• B. Idiopathic intracranial hypertension (IIH)

diagnosed, with CSF pressure >250 mm CSF C.Evidence of causation demonstrated by ≥2 of the following:

• 1. headache has developed in temporal relation to IIH,
• r led to its discovery
• 2. headache is relieved by reducing intracranial

hypertension

• 3. headache is aggravated in temporal relation to

increase in intracranial pressure D.Not better accounted for by another ICHD-3 diagnosis

MRI findings include empty sella, tortuosity of the optic nerves with dilation of the perioptic nerve subarachnoid space, flattening of the posterior globe, and small ventricles

Idiopathic intracranial hypertension

IIH itself does not cause any fetal complications The main risk to mother is visual loss The risks for visual loss and pregnant women with IIH is the same as in the non-pregnant Neuroophth evaluation is essential including field testing Treatment of IOH includes high-volume lumbar punctures and acetazolamide One study of Acetzolamide in the second trimester was reassuring without any major congenital malformations* There is no contraindication to spinal anesthesia in IIH unless there is a lumbar shunt in place

Idiopathic intracranial hypertension

*Falardeaux, J et al. The use of Acetazolamide in pregnancy in intracranial hypertension patients Journal of Neuroophthalmology 2013. 33:9-12

• 7% of cases of CVT are assoc with preg in US, presumably

because of the prothrombotic risk in preg, coupled with any dehydration or forced bed rest

• Presentation = severe pain, signs of increased ICP – later,

encephalopathy, seizures, strokes

• Often missed on CT or MRI - MR venogram is best
• Treatment is debatable –

Heparin, despite hemorrhage risks (avoid if venous strokes seen),

• r intra-sinus thrombolysis

CVT – Cerebral venous thrombosis

No flow in left transverse sinus

RCVS presents often with thunderclap headache The process involves vasoconstriction segmentally seen

• n vascular imaging

Headaches are the most common presentation RCVS is monophasic and most women do well However seizures ,subarachnoid hemorrhage focally and even stroke can occur Treatment is similar to that of eclampsia which includes strict control of blood pressure and intravenous magnesium; calcium channel blockers seem to help

Reversible Cerebral Vasoconstriction Syndrome

Reversible Cerebral Vasoconstriction Syndrome

• Angiography with “strings

and beads”

• Focal subarachnoid

hemorrhage

• Pituitary hemorrhage is rare but life-threatening

potentially - it generally presents with a thunderclap headache

• Subarachnoid hemorrhage, ruptured AVM
• Cervical arterial dissection
• Intracerebral hemorrhage
• Eclampsia (week 2 through post partum period) –

more likely in migraine pts

Peripartum Headache

Marcoux, et al. History of migraine and risk of pregnancy induced

• hypertension. Epidemiology 1992 3:53-56
• Sheehan 1937 reported 11 cases of women who

died in puerperium, all had pituitary necrosis and most had hemorrhages

• Pituitary hypertrophy during pregnancy is thought to

lead to infarction, then necrosis, then hemorrhage

• Can be missed on CT since the hemorrhage can

initially be small; MRI better

• Presentation –
• HA,
• visual loss,
• ophthalmoplegia

Pituitary hemorrhage

Postpartum, migraines tend to increase, probably

• n a multi factorial basis including sleep

deprivation, stress, and hormonal fluctuations Nonsteroidals can be useful to control pain Intracranial hypotension can complicate pospartum - not infreq after epidural anesth

Postpartum Headaches Headache attributed to spontaneous low ICP

• A. Any headache fulfilling criterion C
• B. Low CSF pressure (<60 mm CSF) and/or evidence
• f CSF leakage on imaging
• C. Headache has developed in temporal relation to

the low CSF pressure or CSF leakage, or has led to its discovery

• D. Not better accounted for by another ICHD-III

diagnosis.

Key diagnostic clue = worsening on standing

Migraine pathophysiology

 Step 1 – Cortical

spreading depression

Aristides Azevedo Pacheco Leão

https://www.youtube.com/watch?v=yZr9Joe85wg

Migraine pathophysiology

 Step 2 – Trigeminal nerve activation with release of

inflammatory substances in the vicinity of meningeal arteries

Migraine pathophysiology

 Step 3 activation of

central trigeminal system and autonomic centers with central sensitization and reactive vasodilation

Migraine pathophysiology a unified hypothesis

 Targeting any of these steps might help to prevent

• r relieve HA in migraine, e.g.:

 Antiepileptics – Cortical spreading depression  Triptans – Trigeminovascular activation

Persistent Headache Central sensitiz. Trigemino- vascular activation and inflamm Cortical spreading depression Genetics and triggers

Managing Migraine in Pregnancy

 Common misconception about paucity of

treatment options

 Widespread fear of blame if bad outcome of

pregnancy

 OBGYN often refer  Most neurologists reluctant to prescribe

Migraine in Preg -Tx barriers

 Very little evidence for safety in treatments

for migraine during Pregnancy

 no designation of “legally safe” that can be

applied to a drug’s use in pregnancy and lactation.

 1st principle – discuss options prior to

pregnancy

 Discontinue potentially risky meds prior to

pregnancy planning

Acute Migraine Tx in Pregnancy

At home

 Acetaminophen, possibly NSAID’s  Metoclopramide 10 mg po  Tripans - probably safe; sumatriptan 100 mg po

ED

 IV fluids  IV magnesium 1-2 g  Methylprednisolone 1 g IV  Metoclopramide 10 mg IV or prochlorperazine 5 to

10 mg IV

Acute Migraine Tx in Pregnancy

 Ice  Massage  Relaxation  Acupressure  Acupuncture  TENS

Acute Migraine - Tx options

Triptans

Sumatriptan Imitrex 6mg IM, 20 NS, 50-100 po Naratriptan Amerge 2.5 po Rizatriptan Maxalt 10 mg po Zolmitriptan Zomig 2.5-5 mg po Almotriptan Axert 12.5 mg po Frovatriptan Frova 2.5 mg po Eletriptan Relpax 40-80 mg po

Safety categories in pregnancy

Category A: Safety studies in pregnant women show no harm. Category B: There are no controlled studies in pregnant women, but in animal studies, no harm has been found. Category C: There are no controlled studies in pregnant women, but in animal studies harm has been found. Category D: Risk has been found to humans following use in pregnant women. Category X: absolutely contraindicated in pregnancy

FDA risk classification

 As of June 2015, FDA discontinued

ABCDX system and replaced with PLLR*

 Phased in gradually – New PLLR officially

mandatory in June 2018

 Describe data including numbers of

congen malformations

 “Now doctors will have up-to-date and well-organized

information on pregnancy and lactation. They will be in a better position to help their patients make critical decisions.”

*Pregnancy Lactation Labeling Rule

Acute Migraine tx in pregnancy

Medication FDA category TERIS risk rating Acetaminophen B No risk Ibuprofen B (D in 3rd Trimester) Minimal Naproxen B (D in 3rd Trimester) Undetermined Oxycodone, Morphine B (D near term) Magnesium B Unlikely Metoclopramide B Unlikely Prednisone C in 1st trimester; ? 2nd/3rd trimesters Minimal Promethazine C None

Acute Migraine tx in pregnancy

Notes:

 Acetaminophen linked to child developing ADHD [1,2]  Magnesium can cause low calcium and bone

abnormalities in the fetus [3,4]

 Butalbital and opioids can lead to neonatal withdrawal  Butalbital has been assoc with congenital heart defects  NSAIDs not to be used in 3rd tri – cleft palate/lip

• 1. Brandlistuin, RE. Prenatal paracetamol exposure and child neurodevelopment. Int J Epidemiology,

2013, 42:1702-13

• 2. Liew, Z, et al. Acetaminophen use during pregnancy, behavioral problems and hyperkinetic disorders.

JAMA Pediatr 2014, 168:313-20

• 3. Holcom, WL, et al. Magnesium tocolysis and neonatal bone abnormalities. Obstet Gynecol. 1991,

78:611-14

• 4. Yokoyama, K, et al. Prolonged maternal magnesium administration and bone metabolism in neonates.

Early Human Dev. 2010, 86:187-91

Pregnancy outcome after anti- migraine treatment with triptans

Spielman, K, et al. Pregnancy outcome after anti- migraine triptan use: A prospective observational cohort

• study. Cephalalgia, Jan 2017

Prospective observational cohort study of 432 pregnant women exposed to triptans

 Primary objectives were major birth defects and spontaneous

abortion; secondary endpoints were preterm delivery, preclampsia, pregnancy complications.

 Compared to a non-migraine cohort no increase in:

– major birth defects (ORadj 0.84; 95% CI 0.4–1.9) – Spontaneous abortions (ORadj 1.20; 95% CI 0.9–1.7) – preterm delivery (ORadj 1.01; 95% CI 0.7–1.5), – preeclampsia (ORadj 1.33; 95% CI 0.7–2.5)

• Triptans do not pose major risk
• Sumatriptan - best studied triptan

Pregnancy outcome after anti- migraine treatment with triptans

Marchenko, A, et al. Pregnancy Outcome Following Prenatal Exposure to Triptan Medications: A Meta-Analysis. Headache 2015, 55:490-501



6 studies reviewed; 4208 infants of women who used sumatriptan or

• ther triptan medications, and 1,466,994 children of women who did

not use triptans during pregnancy. No significant increases in rates for major congenital malformations (MCMs), prematurity, or spontaneous abortions were found when comparing the triptan-exposed group to the migraine – no triptans control group (



however, there was a significant increase in the rates of spontaneous abortions (OR = 3.54 [2.24-5.59]). When the migraine no-triptan group was compared with healthy controls, a significant increase in the rates of MCMs was found (OR = 1.41 [1.11-1.80]).



Conclusion - the use of triptans during pregnancy does not appear to increase the rates for MCMs or prematurity. The increased rates of spontaneous abortions in the triptan-exposed group and the increased rates of MCM in the migraine no-triptan group require further research

Pregnancy outcome after anti- migraine treatment with triptans

Nezvalova-Henriksen, K et al. Triptan exposure during pregnancy and the risk of major congenital malformations and adverse pregnancy outcomes. Headache 2010. 50:563-575

69,929 pregnant women and their newborn children from Norwegian Mother and Child Cohort Study. Information on congenital malformations and other adverse pregnancy outcomes was obtained from the Norwegian Medical Birth Registry. Results—No significant associations between triptan therapy during the first trimester and major congenital malformations (unadjusted OR: 1.0; 95% CI 0.8-1.3, adjusted OR: 1.0; 95% CI 0.7-1.2) or other adverse pregnancy

• utcomes were found.

Triptan therapy during the second and/or third trimesters was significantly associated with atonic uterus (adjusted OR: 1.4; 95% CI and blood loss >500 mL during labor (adjusted OR: 1.3; 95% CI 1.1-1.5). Conclusions.—Triptan therapy during pregnancy was not associated with an

• verall increased risk of congenital malformations. A slight increase in the

risk of atonic uterus and hemorrhage was associated with triptan use during the second and/or third trimesters.

Choices in Migraine Prophylaxis

 Anticonvulsants – topiramate, valproate  Beta blockers – propranolol, atenolol  Cyclic antidepressants – amitriptyline, nortrip  Calcium channel blockers – verapamil, flunarizine  Angiotensin receptor blockers - candesartan  ACE inhibitors - lisinopril  Antispasmodics – baclofen, tizanidine

Choices in Migraine Prophylaxis All category C or D

 Anticonvulsants – topiramate, valproate  Beta blockers – propranolol, atenolol  Cyclic antidepressants – amitriptyline, nortrip  Calcium channel blockers – verapamil, flunarizine  Angiotensin receptor blockers - candesartan  ACE inhibitors - lisinopril  Antispasmodics – baclofen, tizanidine

Migraine Prophylaxis in pregnancy

 First – stop prev meds as quickly as safe  Lifestyle measures  Herbal and supplement therapy  Pharmacotherapy only if absolutely necessary

Choices in Migraine Prophylaxis in pregnancy

Memantine – category B, 5-10 mg bid;

• Minimal adverse effects, some GI possible

Cyproheptadine – category B, 4-8 mg daily

• may cause wt gain and/or fatigue

Beta blockers - pindolol category B

– beta blockers, if used, must be tapered off prior to delivery to prevent fetal bradycardia and decreased uterine contraction

‘Nutraceuticals’ for Migraine Prophylaxis in pregnancy

 Vitamin B2 riboflavin 400 mg/d  Magnesium – some possible

effects on fetal calcium absorption

 Co Q 10 300 mg daily

Lifestyle adjustment

Avoidance of triggers Exercise Sleep regulation

Relaxation techniques

Biofeedback, yoga, meditation, hypnotherapy

Manual therapies Acupuncture

Non medicinal Tx

John PJ, et al. Effectiveness of yoga therapy in the treatment of migraine without aura: a randomized controlled

• trial. Headache. 2007;47(5):654–61.

Posadzki P, Ernst E, Terry R, LeeMS. Is yoga effective for pain? A systematic review of randomized clinical trials. Complement Ther Med. 2011;19(5):281–7. Wells RE, Burch R, Paulsen RH,Wayne PM, Houle TT, Loder E. Meditation for migraines: a pilot randomized controlled trial. Headache. 2014;54(9):1484–95.

Treating migraine-assoc nausea in pregnancy

 Metaclopramide 10mg prn – category B  Ondansetron – category B  Ginger  Prochlorperazine, Chlorpromazine,

promethazine – judiciously

 Doxylamine+B6  Weigh potential benefits (reverse dangerous

fluid and electrolyte derangement, esophageal trauma0, v. risks

Safety categories in breastfeeding - Hale

L1 - Compatible L2 - Probably Compatible L3 - Probably Compatible L4 - Possibly Hazardous L5 - Hazardous

Managing Migraine during lactation

Proph meds which seem to be compatible

 Riboflavin  Magnesium  Probably compatible – gabapentin, candesartan,

verapamil, cyproheptadine, Botox

Botulinum toxin for Chronic Migraine

31 injections 5U each in forehead, temples, occiput, neck, trapezius Repeated every 3 mo AE’s – facial asymmetry, neck pain CATEGORY C in pregnancy

Interventional treatment of migraine and other headaches

 Nerve blockade with local anesthetic

Lidocaine B/C; Ropivicaine B; Bupivicaine C Occipital Supraorbital Auriculotemporal

Interventional treatment of Migraine and other headaches

 Non-invasive neural stimulation

• 1. New 1st trimester migraines

 29 year old G1 woman LMP 8 weeks ago began

having frequent severe HAs with nausea, photosensitivity and phonosensitivity about 1 month

• ago. She denies having migraines or other

headaches in the past but her mother and aunt have migraine.

 Acetaminophen is not helpful – “I just have to ride

them out”

 Probably no need for MRI or LP if exam is normal  Non-pharm approaches, perhaps triptan, control

nausea with ginger and doxylamine+B6

 Ramp up treatment if HAs persist

• 2. Preexisting migraines

worsening in pregnancy

 31 year old woman with migraines with aura since

late teens; had infrequent headaches until early in this 3rd pregnancy now in 2nd trimester with almost daily HAs.

 Baseline nausea worsens during headaches, and

she has had more pronounced visual auras

 Again, probably no need for work-up if exam is

normal including funduscopic exam

 Nerve blocks, non-pharm proph measures  Consider B2, memantine, cyproheptadine

• 3. New late-pregnancy HA

 22 year old at 38 weeks was admitted last night

with a severe holocranial headache. Infreq, mild headaches earlier in this first pregnancy.

 She has no history of migraine but + family hx  Exam is remarkable only for intense photophobia

and unwillingness to move at all.

 May be primary HA, but hemorrhage, CVT, RCVS

all need to be r/o with MRI and MRV, and if possible MRA

 LP might be necessary  Hydration, reassurance, prepare for OR

Headache Management in Pregnancy - conclusions

 Diagnosis is crucial, particularly if HA is

thunderclap or accompanied by ANY neuro/psych symptoms

 If doubt – MRI, MRV, ophth eval  Best approach to migraine during pregnancy

is to await 2nd trimester, using primarily acute intervention and non-pharm approaches

 If preventive measures are essential, non-

pharmacological measures can help; several pharmaceutical options seem safe.