It is essential to have good information and guidelines regarding the proper treatment of migraine during pregnancy and breastfeeding . A review of articles published over the past year on the treatment of migraine during pregnancy and breastfeeding revealed little , which may seem discouraging. However, this article reviews information related to the risks and safety of treating migraine during pregnancy and breastfeeding , citing both recent and older publications.
Up to 40.9% of women of childbearing age suffer from migraines.
Little, if any, formal research is conducted on the pharmacotherapy of migraine occurring during pregnancy or lactation. This is likely due to two issues: (1) neurology offers little training in female sex hormones , whereas gynecology is a surgical field; (2) studies in pregnant women are legally very complicated; a possible accident would be very expensive.
Migraine is three times more common in women than in men , and its prevalence is highest during the period of peak fertility. Most headache centers report that approximately 85% of their migraine patients are female , and at least 70% of female migraine sufferers report a menstrual association of their attacks , as well as changes in their headaches. headaches related to hormonal contraception , pregnancy and menopause.
Often, most neurologists are not trained in the hormonal management of menstrual migraine or catamenial epilepsy, while most gynecology training does not address the diagnosis and treatment of migraine, epilepsy, or other neurological disorders. There is therefore an important need to remedy this.
A lack of information on migraine treatments to use during pregnancy
In a recent study, 401 Norwegian women with migraine were examined during pregnancy and lactation. Almost three-quarters of them said they had sought information about the safety of their medications for acute and preventative migraine during pregnancy. The most frequent sources were their doctors (88.5%), but 48.4% consulted the Internet and 42.9% on information leaflets. Overall, the average number of news sources consulted was 1.8. Of the women who consulted these different sources of information (n = 214), nearly half did so after receiving conflicting information, and more than a third said they had stopped the drug in question for good reason. These women clearly expressed a desire for more reliable, available and consistent information to guide them.
Although observational studies have shown that migraine tends to lessen during pregnancy , some women experience an increase in frequency or intensity , particularly towards the end of the first trimester , when gonadotropin levels fall. When no improvement is seen, migraine is likely to continue throughout pregnancy and even extend into the postpartum period. With the extremely high estrogen levels during pregnancy, the aura may also appear for the first time. And quite commonly, a severe migraine without aura follows childbirth, usually within 2-3 days postpartum, triggered by the abrupt drop in estrogen concentration .
In bottle-feeding women, the frequency of migraine attacks they had before pregnancy tends to reappear very quickly; breastfeeding women, on the other hand, tend to maintain the protective effect of anovulatory cycles for an extended period of time, usually until menstruation resumes.
Treatment of migraine during pregnancy
It is estimated that at least 10% of all birth defects result from maternal drug exposure , and more than 80% of pregnant women take over-the-counter or prescription drugs during pregnancy. Very few drugs are classified as category A (meaning they are safe for use in pregnancy), with the exception of some vitamins and thyroid hormone in replacement doses. At the other end of the spectrum, categories D and X list drugs that have been shown to cause harm in humans. However, in category D, the drug can still be used if its potential benefits outweigh the risks. Categories B and C, which fall between the two, have thus been defined as follows:
Category B: NO EVIDENCE OF RISK IN HUMANS
Animal reproduction studies have not shown any risk to the fetus , and there are no adequate and reliably controlled studies in pregnant women.
Category C: THE RISK CANNOT BE ELIMINATEDAnimal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and controlled studies in humans, but the potential benefits may justify the use of the drug in pregnant women despite the risks. Because adequate and well-controlled studies in pregnant women are rarely, if ever, done, the difference between categories B and C has simply been determined by the results of animal studies.
These results, in turn, often reflected the extent of the animal's exposure, ie how large the dose was, how and how often it was administered. For example, when acetaminophen hit the US market in 1955, FDA regulations were less stringent. This treatment is classified as category B and is therefore widely used during pregnancy, despite the lack of clinical data to confirm that there is no association with adverse effects on the fetus. Similarly, Fioricet is classified as Category C, with the following wording: "Animal reproduction studies have not been conducted with Fioricet". Two of its three components (butalbital and caffeine), on the other hand, are classified as category C, and the third (acetaminophen) has been the subject of inappropriate studies on animals.
Over-the-counter medications also carry these indications. Aspirin is grade D throughout pregnancy, and it's important to remember that it's also mixed with brand name migraine treatments like Excedrin. Although NSAIDs were classified as category B during the first two trimesters, they become category D after the 30th week because they cause premature closure of the ductus arteriosus. Sudafed is Grade C, as are Tums and Caffeine .
Smoking is category D. Ergotamine and dihydroergotamine (DHE) were originally classified as category X by the FDA due to fetal growth retardation , but a recent large study has shown that although the DHE significantly increases the rate of prematurity (odds ratio 4.18), it does not reveal an increase in major congenital malformations, low birth weight or spontaneous abortions.
A failing system, poorly informed patientsThe FDA has acknowledged that the current system often leaves patients misinformed and with false assumptions about what these letters actually mean. This is why in December 2014, the FDA removed these categories of letters with the intention of replacing them with statements that would convey more meaningful information to both patients and their physicians .
She acknowledged that many women need drug treatment during pregnancy due to chronic conditions, and that refusing this treatment would be dangerous for both mother and baby.
Although the labeling of new drugs coming to market is an improvement over the old format, it rarely provides a definitive "yes" or "no" answer, and clinical interpretation is still needed on a case-by-case basis. case.
Treatment of migraine during pregnancy
Acetaminophen has always been considered safe at all stages of pregnancy. However, three recent studies have presented data that have raised concerns about adverse effects on neurodevelopment in children who have experienced greater exposure to acetaminophen (more than 28 days) in utero. The European Medicines Agency assessed two of these studies and found insufficient evidence to support the link between prenatal exposure and later neurodevelopmental outcomes.
Nonsteroidal anti-inflammatory NSAIDs
With NSAIDs , adverse effects differ by trimester of exposure. They are generally considered category B during the first two trimesters. However, use in the first trimester has been possibly or inconclusively associated with miscarriages and birth defects. Other studies have not found an increased risk of miscarriage; nevertheless, the risk after NSAID use in the first trimester could not be satisfactorily ruled out. Similarly, links between exposure to NSAIDs during pregnancy and birth defects have been assessed in studies involving over 20,000 pregnancies. Some have found associations with birth defects, others have not. NSAIDs remain contraindicated after the 30th week because of the risk of premature closure of the arterial duct.
Triptans during pregnancy
Nearly two decades ago, a literary journal incorrectly claimed that triptans were "contraindicated" in pregnancy . This has never been the case; they were simply classified as category C. If one looks more closely at this classification, it was assigned because when extreme doses were given to pregnant rats, there was a decrease in the survival of the pups to days 2, 4, and 20. The dose that produced these results was 1000 mg/kg/day (equivalent dose for a 70 kg woman would be 70,000 mg sumatriptan/day). But the researchers also calculated the safest (or no-effect) dose for this finding: A dose of 100 mg/kg/day was safe for the rat fetus . This would correspond to the equivalent of seventy tablets of 100 mg of sumatriptan/day for a 70 kg woman.
Similarly, when sumatriptan was administered to pregnant rats during the period of organogenesis, an increased incidence of fetal blood vessel abnormalities was observed. The highest no-effect level for this observation was 60 mg/kg/day or 4200 mg/day for a 70 kg human.
Sumatriptan, the least risky treatment for migraines during pregnancy
With respect to retrospective studies in humans, two recent studies of sumatriptan administration during pregnancy found no evidence of teratogenicity . These data included a prospective pregnancy registry conducted in the United States and Canada as well as the large mother-infant cohort in Norway, in which 2.2% of the 69,929 pregnant women in the study used triptan during pregnancy. pregnancy (mainly sumatriptan). No association between triptan use during pregnancy and birth defects compared to controls has been found; the adjusted odds ratios were 0.9 (0.7-1.2) for any malformation and 1.0 (0.7-1.3) for major congenital malformations.
Similarly in Sweden, where for more than 95% of all drug exposures during the first trimester through a midwifery interview, the risk of malformation (major or minor) in the general population was 3.6%. For sumatriptan exposure in the first trimester (n=2027), it was 3.6%, showing that its use does not increase risk. Finally, a recent meta-analysis reviewed published data from 1991 to 2013 regarding the outcomes of exposure to triptans during pregnancy .
A total of one case-control study and five cohort studies met the inclusion criteria and provided data on 4,208 children of women who used triptans (mainly sumatriptan) and 1,466,994 children of women with migraine who did not use triptans. have not used triptans during pregnancy. No increase in increased risk of major birth defects , prematurity , or spontaneous abortions was observed when comparing the triptan exposed group to the control group.
Not all triptans should be considered equally safe during pregnancy. Sumatriptan is the most hydrophilic triptan, making it more difficult to cross the placental membrane (only about 15% of a dose of sumatriptan passes into the fetal compartment in 4 hours), whereas other triptans are lipophilic.
What is the safest treatment for treating migraines during pregnancy?In the current state of our knowledge, the ideal choice for the acute treatment of migraine during pregnancy would be the sumatriptan nasal delivery system or the nasal spray for two reasons: they deliver maternal serum concentrations equivalent to or lower than those of sumatriptan 25 mg tablet, and nasal administration maintains efficacy in the presence of gastric stasis or nausea, symptoms commonly observed when migraines tend to peak in the late first trimester. Subcutaneous parenteral injections, on the other hand, result in surprisingly higher maternal blood levels in maternal blood.
In the United States, the overall incidence of birth defects is 3-5%. Multiple reports have not identified an increased risk of teratogenesis with the use of sumatriptan compared to the general population. It would therefore seem appropriate for the FDA to admit that adequate meta-analyses and database reviews have not demonstrated an increased risk of human fetal abnormalities with exposure to sumatriptan and to change its pregnancy category. in B - but unfortunately these categories no longer exist.
Preventive treatments for migraine during pregnancy
According to the author of the referenced study, the best preventive treatment against migraine is good sleep hygiene , and there should certainly be no contraindications to the use of this preventive treatment during pregnancy. A study on the relationship between chronic migraine , non-restorative sleep, and poor sleep habits found that chronic migraine sufferers report shorter sleep episodes than episodic migraine sufferers and are more likely to complain of difficulty falling asleep and maintain their sleep.
There is also a strong association between sleep problems and chronic morning headaches . Restless legs syndrome was prevalent in this population. Particularly in people who met the criteria for medication overuse headaches or who were taking medications to induce sleep. The effectiveness of behavioral treatment in converting these chronic migraines to episodic migraines was demonstrated in a placebo-controlled trial involving 43 women with more than 11 years of chronic migraine history.
Treatment of migraine while breastfeedingAlmost all medications pass into breast milk to some degree . Exceptions are particularly large molecules like heparin and insulin , whose physical size prohibits crossing these biological membranes. The amount of drug transferred into breast milk is usually described quantitatively using the milk/plasma (L/P) concentration ratio, in which the infant dose (mg/kg) is expressed as a percentage of the maternal dose (mg/kg). One of the highly reputable and comprehensive reference books on drug safety during pregnancy and breastfeeding is Drugs in Pregnancy and Lactation by Briggs, Freeman and Yaffe. The authors provide recommendations for breastfeeding, basing their judgment on data such as milk and maternal plasma concentrations , post-exposure infant drug concentrations, and reported adverse effects.
All triptans are considered compatible or probably compatible ; ergotamine and dihydroergotamine are contraindicated.
Among NSAIDs , ibuprofen is the preferred choice due to its low relative infant dose and the fact that it has been well studied in children. NSAIDs with long half-lives, such as naproxen, sulindac, and piroxicam, can accumulate in infants with prolonged use.
The toxicity of the drug when breastfeeding
When a drug is compatible with breastfeeding, the first concern is the concentration of that drug that will be present in breast milk . Virtually all medications taken by the mother will be present in some degree in breast milk. The relative dose for the infant can be determined and expressed as a percentage of the maternal dose. The arbitrary threshold of 10% has been accepted as a guide for the safe use of most medications during lactation. For drugs with greater inherent toxicity, this threshold does not apply and breastfeeding would be contraindicated.
Sumatriptan showed a low RID (relative infant dose) (3.5%) even when measured after the much higher plasma concentrations achieved with subcutaneous injections. This suggests that its use during lactation - even with the high levels achieved with injections - should not pose a substantial risk to the infant . Eletriptan, although not on the AAP lists, demonstrated a low DIR of 0.2%. However, the concentration of the active metabolite (which has a longer plasma half-life) was not measured. Because rizatriptan is concentrated in the breast milk of female rats, with a DIR at least five times higher than maternal plasma concentrations, it would not be a good choice for use during lactation until more information becomes available.
ConclusionMigraine is a common problem in pregnant or breastfeeding women. Indeed, there is no clear and sufficient information for these patients on appropriate and safe treatment. Women are urgently seeking closer follow-up and more knowledgeable advice from their healthcare providers. The best way to achieve this would probably be to proceed in two steps:
- A new field of medicine should be created: non-surgical gynecology. This discipline could then study and prevent menstrual migraine, catamenial epilepsy, menstrual asthma and hormonal mood disorders. It could further research and promulgate the best treatments for medical conditions that occur during pregnancy and lactation.
- Due to litigation concerns over birth defects (which affect 3-5% of all pregnancies), an official list of drugs considered "legally safe" in pregnancy should be developed and kept up-to-date, in accordance with best practices. current medical information. A similar "legally safe" list should be developed for treatment while breastfeeding to avoid any concerns healthcare providers may have about potential lawsuits for problems that may develop years later.
- • Amundsen S, Øvrebø TG, Amble NM, Poole AC, Nordeng H. Use of antimigraine medications and information needs during pregnancy and breastfeeding: a cross-sectional study among 401 Norwegian women. Eur J Clin Pharmacol. 2016;72(12):1525–35. This article highlights the problem of inadequate authoritative guidance for treatment of migraine inpregnancy and lactation .
- Granella F, Sances G, Pucci E, Nappi RE, Ghiotto N, et al. Migraine with aura and reproductive life events: a case control study. 2000;20:701–7.
- Maggioni F, Alessi C, Maggino T, Zanchin G. Headache during pregnancy. 1997;17:765–9.
- Sances G, Granella F, Nappi RE, Fignon A, Ghiotto N, et al. Course of migraine during pregnancy and postpartum: a prospective study. 2003;23:197–205.
- Kvisvik EV, Stovner LJ, Helde G, Bovim G, Linde M. Headache and migraine during pregnancy and puerperium: the MIGRA-study. J Headache Pain. 2011;12:443–51.
- Goldszmidt E, Kern R, Chaput A, Macarthur A. The incidence and etiology of postpartum headaches: a prospective cohort study. Can J Anaesth. 2005;52:971–
- Wilson JG. Current status of teratology. In: Wilson JG, Fraser FC, editors. Handbook of teratology. New York: Plenum; 1977. p. 47.
- Jacobs LR. Prescription to over-the-counter drug reclassification. Am Fam Physician. 1998;57:2209–14.
- Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In: Witorsch RJ, editor. Reproductive toxicology. 2d ed. New York: Raven; 1995. p. 175–93.
- Collins E. Maternal and fetal effects of acetaminophen and salicylates in pregnancy. Obstet Gynecol. 1981;585(Suppl):57S–62S.
- Bérard A, Kori S. Dihydroergotamine (DHE) use during gestation and the risk of adverse pregnancy outcomes. 2012;52(7): 1085–93.
- Thompson JM, Waldie KE, Wall CR, Murphy R, Mitchell EA. Associations between acetaminophen use during pregnancy and ADHD symptoms measured at ages 7 and 11 years. PLoS One. 2014;9:e108210.
- Brandlistuen RE, Ystrøm E, Nulman I, Koren G, Nordeng H. Prenatal paracetamol exposure and child neurodevelopment: a siblingcontrolled cohort study. Int J Epidemiol. 2013;42:1702–13.
- Lie Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr. 2014;168:313–20.
- European Medicines Agency. Pharmacovigilance Risk Assessment Committee (PRAC): minutes of the meeting on 5–8 May 2014. PRAC: Agendas, minutes and highlights
, http://www. ema.europa.eu/docs/en_GB/document_library/Minutes/2014/06/WC500169468.pdf (2014).
- Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. 2003;327:368.
- Hernandez RK, Werler MM, Romitti P, Sun L, Anderka M. Nonsteroidal antiinflammatory drug use among women and the risk of birth defects. Am J Obstet Gynecol. 2012;206:228.e1–8.
- Edwards DR, Aldridge T, Baird DD, Funk MJ, Savitz DA, Hartmann KE. Periconceptional over-the-counter nonsteroidal anti-inflammatory drug exposure and risk for spontaneous abortion. Obstet Gynecol. 2012;120:113–22.
- Nezvalová-Henriksen K, Spigset O, Nordeng H. Effects of ibuprofen, diclofenac, naproxen, and piroxicam on the course of pregnancy and pregnancy outcome: a prospective cohort study. BJOG. 2013;120:948–59.
- Ofori B, Oraichi D, Blais L, Rey E, Berard A. Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: a nested case-control study. Birth Defects Res B Dev Reprod Toxicol. 2006;77:268–79.
- van Gelder MM, Roeleveld N, Nordeng H. Exposure to nonsteroidal anti-inflammatory drugs during pregnancy and the risk of selected birth defects: a prospective cohort study. PLoS One. 2011;6:e22174.
- Pfaffenrath V, Rehm M. Migraine in pregnancy. What are the safest treatment options? Drug Safe. 1998;19:383–8.
GlaxoSmithKline, Inc. 2013 ; Available from: https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Imitrex_Nasal_Spray/pdf/IMITREX-NASAL-SPRAY-PI-PIL.PDF .
- FoxAW. Revised estimate for probability of successful outcome of pregnancy after sumatriptan exposure
- Cunnington M, Ephross S, Churchill P. The safety of sumatriptan and naratriptan in pregnancy: What have we learned? 2009;49:1414–22.
- Nezvalová-Henriksen K, Spigset O, Nordeng H. Triptan exposure during pregnancy and the risk of major congenital malformations and adverse pregnancy outcomes: results from the Norwegian Mother and Child Cohort Study. 2010;50(4):563–75.
- Marchenko A, Etwel F, Olutunfese O, Nickel C, Koren G, Nulman I. Pregnancy outcome following prenatal exposure to triptan medications: a meta-analysis. Headache J Head Face Pain. 2015;55:490–501.
- Calhoun AH, Ford S. Behavioral sleep modification may revert transformed migraine to episodic migraine. Headache. 2007;47:1178–83.
- Calhoun AH, Ford S, Finkel A, Kahn D, Mann JD. The prevalence and spectrum of sleep problems in women with transformed migraine. 2006;46(4):604-10.
- American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. 2001;108(3):776–89.
- Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 9th ed. Philadelphia: Lippincott Wilkins and Williams; 2011.
- Hale TW. Medications and mothers' milk. 16th ed. Amarillo: Hale Publishing; 2014.
- Wojnar-Horton RE, Hackett LP, Yapp P, Dusci LJ, Paech M, Ilett KF. Distribution and excretion of sumatriptan in human milk. Br J Clin Pharmacol. 1996;41(3):217–21.
- David PS, Kling JM, Starling AJ. Migraine in pregnancy and lactation. Curr Neurol Neurosci Rep. 2014 Apr;14(4):439.
- Relpax (eletriptan hydrobromide)
. Kirkland, QC: Pfizer; 2004.