Treating migraine attacks during pregnancy

overview

Non-pharmacological approaches should always be tried as initial treatment for migraines during pregnancy. Mild migraine attacks can be treated non-medication during pregnancy through stimulus isolation, rest, relaxation and ice packs. For nausea and vomiting, metoclopramide can be used throughout pregnancy. The selection of drug treatment for attacks requires an individual assessment of the expected benefits and the possible risks for the pregnant woman and the unborn child. A basic rule should be to aim for the lowest effective dose and the shortest possible treatment duration. Self-medication should be avoided during pregnancy and medical progress and success should be monitored. Careful and comprehensive periconceptional counseling is essential to promote a safe and healthy pregnancy and postpartum period for mother and child. The following table provides an overview of the different treatment situations and the benefit/risk assessment of drug attack therapy. To justify the classification, reference is made to the following statements.

Assessment :
A: Benefits high – risks low
B: Benefits medium – risks moderate
C: Benefits low – risks controversial
k: contraindicated

Migraines and pregnancy

Up to one in four women of childbearing age suffer from migraines, although up to 80% of them improve spontaneously during pregnancy [5, 82, 89, 104]. Approximately 25% of migraine patients will continue to have attacks during pregnancy, with hyperemesis, pathological pregnancy and menstruation-associated migraine before pregnancy being associated with a lack of improvement [89]. It is still unclear why some patients do not experience clinical improvement during pregnancy [89].

Pregnant women with a history of migraine have a higher risk of complicated pregnancy outcomes. They should be carefully informed, monitored and treated accordingly [7]. A recent comprehensive umbrella review [96] shows that women with migraines are generally more likely to develop preeclampsia, low birth weight of the child, premature birth, placental abruption and mental illness during pregnancy. The risk is increased by >50% with severe migraines. Severe migraine causes a high-risk pregnancy [7, 97, 108]. Pregnancy and migraine have hypercoagulability in common: During pregnancy, hypercoagulability is a significant risk factor for major cardiovascular events, including venous thromboembolism and cerebrovascular accidents. There is a 13-fold higher risk of a hypertensive disorder [67, 97]. Severe migraines may require an individual ban on employment. Preventative drug treatments during pregnancy are limited; they should only be considered in the most severe cases [5].

Non-pharmacological approaches should always be tried as initial treatment for migraine during pregnancy [89]. Mild migraine attacks can be treated non-medication during pregnancy through stimulus isolation, rest, relaxation and ice packs. Acute medications for migraines should only be used in pregnant women if the expected benefit for the mother outweighs any possible risk for the child. A basic rule should be to aim for the lowest effective dose and the shortest duration of treatment. Self-medication should be avoided during pregnancy and medical progress and success should be monitored. Careful and comprehensive periconceptional counseling is essential to promote a safe and healthy pregnancy and postpartum period for mother and child [5]. Given the widespread use of analgesics, it is important that there is clarity about the potential benefits and potential risks and harms of taking analgesics during pregnancy [66]. The explanation that the use of some over-the-counter analgesics is considered safe in most stages of pregnancy based on historical reputation is often based on an incomplete review of the current literature [129].

Treatment of nausea and vomiting

Women who experience severe nausea and vomiting during pregnancy have a poor quality of life and an increased risk of maternal and fetal complications. For nausea and vomiting, metoclopramide can be used throughout pregnancy. A high dose of metoclopramide at the end of pregnancy can cause extrapyramidal syndrome to occur in the newborn. Metoclopramide should therefore be avoided at the end of pregnancy. If metoclopramide is used necessarily, neonatal monitoring must be carried out.

If nausea is severe and metoclopramide is ineffective, ondansetron can be used under strict indications during the 2nd and 3rd trimester of pregnancy[38].

Comparison of benefits in attack therapy

The selection of drug treatment for attacks requires an individual assessment of the expected benefits and the possible risks for the pregnant woman and the unborn child. A standardized general first-line therapy is not effective due to the very different clinical symptoms of migraine and the required differential therapy. Drug therapy for attacks should only be carried out if the desired benefit outweighs the intended benefits. The initial basis for weighing up the individual benefits is knowledge and comparison of the expected effectiveness. The expected effectiveness is listed below based on the number needed to treat (NNT) compared to placebo treatment [5, 30, 31, 85, 98, 128]. The amount of NNT indicates the number of treatments necessary to achieve a positive effect compared to placebo. In the optimal case, the NNT has the amount 1, which would mean that every patient would benefit from the treatment method with the verum compared to placebo.

It is clear from the numbers that sumatriptan 6 mg sc has the highest benefit with an NNT of 2.3. If sumatriptan 100 mg is used orally for mild pain intensity at the beginning of an attack, the NNT is 3.0. If sumatriptan 100 mg orally is used for moderate or severe pain later in the attack, the NNT is 4.7. When using ibuprofen 400 mg or ASA 900-100 mg, the NNT is 7.2 and 8.2, respectively. Paracetamol has by far the lowest benefit with an NNT of 12. 12 pregnant women have to be treated with paracetamol 1000 mg so that one patient can benefit from pain relief after two hours. The majority of patients would not achieve any expected benefit from paracetamol 1000 mg.

The summary shows that sumatriptan is to be preferred in terms of the expected benefit in treating acute migraine attacks during pregnancy. It should be used as early as possible in the attack. If there is severe nausea and vomiting with impaired absorption in the stomach, subcutaneous use of sumatriptan 6 mg can be considered. Lower subcutaneous doses of 3 mg or pharmacy formulations of 2 and 4 mg are also available. There is less extensive data for the other triptans, which is why the list is limited to sumatriptan. The current product information for sumatriptan does not indicate a contraindication of sumatriptan in pregnancy; With the wording “The drug should only be used in pregnant women if the expected benefit for the mother outweighs any possible risk for the child,” it refers to the individual weighing of benefits. Similar formulations can also be found for the other triptans; Frovatriptan is not recommended during pregnancy. The following table lists the specifications of the specialist information for use during pregnancy and breastfeeding:

Alternatives in the first two trimesters of pregnancy with moderate benefit for mild and moderate migraine attacks include ibuprofen and ASA. However, these medications should not be used from the 20th week of pregnancy.

The least benefit is expected for paracetamol. Paracetamol, acetylsalicylic acid and ibuprofen are not approved for severe pain; their use would be off-label for severe and very severe migraine attacks.

In a large US longitudinal study of medication use during pregnancy, 859,501 pregnancies were examined, of which 8,168 women had migraines. Discontinuation of triptans during pregnancy results in more non-specific medications being used during pregnancy to treat attacks, primarily opioids and paracetamol [49]. The results suggest that recommendations to discontinue migraine-specific medications could lead to an increase in other perceived safer medications. Switching from migraine-specific treatment to non-specific off-label treatment such as acetaminophen or opioids for severe migraine attacks is associated with increased self-reported pain [49, 124]. This further reduces the benefits of such changes. Inadequately treated headaches can lead to stress, lack of sleep, inadequate nutritional intake, depression, medication overuse, progression and chronicity, which in turn can have negative consequences for mother and child [89].

Comparison of risks in attack therapy

Triptans

Sumatriptan was the first triptan to be approved in Germany in 1993. Effects of in utero exposure were examined in a companion global pregnancy registry. The final results of the 16-year sumatriptan, naratriptan and treximet (combination of sumatriptan and naproxen) pregnancy registry were finally published [37]. The pregnancy register was closed because no further findings were expected. The primary objective was to screen for evidence of teratogenicity by determining the risk of all major birth defects following in utero exposure to sumatriptan, naratriptan, and the combination drug sumatriptan/naproxen sodium (marketed in the United States as Treximet). We also looked for unusual patterns of defects that could indicate teratogenicity. In the prospective observational study, women who had taken sumatriptan, naratriptan or the combination drug sumatriptan/naproxen sodium during their pregnancy were surveyed on a voluntary basis by health professionals worldwide. Only pregnancies whose outcome was unknown at the time of study enrollment were analyzed. 680 evaluable pregnant women were included in the registry, resulting in 689 infants and fetuses. The estimated risk of major birth defects following first trimester exposure to sumatriptan was 4.2% (20/478 [95% confidence interval 2.6%-6.5%]). After first trimester exposure to naratriptan, a major birth defect was reported in an infant exposed to both sumatriptan and naratriptan (risk of birth defects: 2.2% (1/46 [95% CI 0.1%-13, 0%]). Effect of sumatriptan found to cause serious birth defects. This finding is consistent with the results of other observational studies that included different control groups [34, 35, 85, 96, 123, 128]. can be taken [33]. The risk rates for serious birth defects are similarly high as in the general population (3-5%) [89]. Accordingly, there are now no formal contraindications for taking it during pregnancy and it is based on an individual basis Benefit assessment referred to.

Regarding pregnancy outcomes in women treated with migraine medications, triptans were the only medications examined in a meta-analysis [96]. Marchenko et al. [85] showed that the odds of miscarriage were more than three times higher in migraine patients treated with triptans compared to healthy controls (pooled OR = 3.54 (2.24-5.59), two studies, n = 51,043). However, there was no significant association between triptans and migraine during pregnancy compared to women with migraine who were not treated with triptans during pregnancy (pooled OR = 1.27 (0.58-2.79), two studies, n = 260). Dudman et al. [34] compared only women treated with triptans with the general population in their meta-analysis. However, they reported pooled prevalences of pregnancy outcomes in women with migraine, comparing those who received treatment in pregnancy and those who did not receive treatment. In agreement with Marchenko et al. [85], this review found no significant difference in the prevalence of miscarriages associated with the use of triptans (8.2% (95% CI = 6.1-10.6%) in women who did not receive medication, versus 10.2% (95% CI = 5.3-16.1%) in women receiving triptans). However, the prevalence of miscarriage was higher in patients receiving NSAIDs (22.6% (95% CI = 20.7-24.9%)).

In a Norwegian mother-child cohort study, 41,173 live births without major malformations underwent 36-month postnatal follow-up. 396 took a triptan during pregnancy. This study found an increased risk of clinically relevant externalizing behaviors in children with prenatal exposure to triptans, and this risk was highest for exposure in the first trimester. The absolute risks were low and the results may have been confounded by the underlying migraine severity [125].

In a prospective cohort study of 432 pregnant women exposed to triptans collected via the German Embryotox system, pregnancy outcomes were compared to a non-migraine comparison cohort. Primary outcomes were major birth defects and spontaneous abortions; Secondary endpoints included preterm birth, birth weight, pregnancy complications, and rate of elective termination of pregnancies. This showed that the rates were not increased in pregnancies exposed to triptan. The authors conclude from the data that sumatriptan, the most studied triptan, appears to be an acceptable treatment option if necessary during pregnancy [111].

According to the current specialist information on sumatriptan, the findings to date do not indicate an increased risk of congenital malformations. Animal experiments have shown no evidence of direct teratogenic or damaging effects on peri- and postnatal development.

Lasmiditan

There is limited information about the use of lasmiditan in pregnant women. Animal studies have shown that lasmiditan can have reproductive toxic effects. The effects of lasmiditan on human fetal development are unknown. According to the current product information, taking lasmiditan during pregnancy is not recommended.

Rimegepant

Rimegepant should not be taken during pregnancy because, according to the current Rimegepant package leaflet, the effects of this medicine on pregnant women and on the development of the human fetus are unknown.

Analgesics

Painkillers are often necessary during pregnancy. Because of their widespread use, many pregnant women choose over-the-counter (OTC) analgesics. The active ingredients and their metabolites can easily cross the placenta and reach the developing fetus. Despite advice on cautious use, painkillers are increasingly being used during pregnancy [68, 81, 129]. Approximately 56% of women report taking analgesics during pregnancy, making them the most commonly used medication class in pregnancy [66]. Clinical guidelines are often based on historical reputation and previous limited evidence about the long-term effects of these drugs on the fetus [66]. Data regarding the safety or association of use with possible adverse health outcomes are conflicting, complicating care decision-making. An overview of the current state of knowledge is given below.

A retrospective cohort study using the Aberdeen Maternity and Neonatal Databank analyzed 151,141 pregnancies between 1985 and 2015 [130]. The association between in utero exposure to five over-the-counter analgesics (acetaminophen, ibuprofen, acetylsalicylic acid, diclofenac, naproxen) and adverse neonatal outcomes was determined. 83.7% of women taking over-the-counter analgesics reported taking them in the first trimester when specifically asked about them during their first antenatal clinic visit. Pregnancies taking at least one of the five analgesics were significantly unrelated to each other with an increased risk of preterm birth <37 weeks (adjusted OR (aOR)=1.50, 95% CI 1.43 to 1.58), one Stillbirth (aOR=1.33, 95% CI 1.15 to 1.54), one neonatal death (aOR=1.56, 95% CI 1.27 to 1.93), a birth weight <2500 g (aOR= 1.28, 95% CI 1. 20 to 1.37), birth weight >4000 g (aOR=1.09, 95% CI 1.05 to 1.13), admission to the neonatal unit (aOR=1.57, 95% CI 1.51 to 1.64), APGAR score <7 after 1 minute (aOR=1.18, 95% CI 1.13 to 1.23) and 5 minutes (aOR=1.48, 95% CI 1.35 to 1.62), neural tube defects (aOR=1.64, 95% CI 1.08 to 2.47) and hypospadias (aOR=1.27, 95% CI 1.05 to 1.54 only in men). The overall prevalence of over-the-counter analgesic use during pregnancy was 29.1%, but increased rapidly over the 30-year study period such that over 60% of women were taking analgesics in the final 7 years of the study. Use of over-the-counter analgesics during pregnancy was associated with a significantly higher risk of adverse perinatal health outcomes in offspring. Taking paracetamol in combination with other non-steroidal anti-inflammatory drugs was associated with the highest risk. The authors conclude that the increased risk of adverse neonatal outcomes associated with the use of non-prescription, over-the-counter analgesics during pregnancy suggests that guidelines for pregnant women on the use of analgesics need to be urgently updated.

A systematic meta-analysis examined whether medication use during pregnancy is associated with the risk of gastroschisis in offspring [10]. 18 studies with data on 751,954 pregnancies were included in the meta-analysis. The pooled risk ratios (RRs) showed significant associations between acetylsalicylic acid (RR 1.66, 95% CI 1.16-2.38; I2 = 58.3%), ibuprofen (RR 1.42, 95% CI 1.26). -1.60; I2 = 0.0%) and gastroschisis. No association was found between paracetamol and gastroschisis (RR 1.16, 95% CI 0.96-1.41; I2 = 39.4%). The results suggest that exposure to over-the-counter medications such as acetylsalicylic acid and ibuprofen during the first trimester of pregnancy may be associated with an increased risk of gastroschisis. However, these associations are significant only in certain subgroups defined by geographic location, adjustment variables, and type of control.

Taking NSAIDs from 20 weeks of pregnancy or later can cause rare but serious kidney problems in the unborn child, which in turn can lead to low amniotic fluid levels and possible pregnancy-related complications [15, 27, 28, 41, 72, 94, 106 ]. After about 20 weeks of pregnancy, the unborn child's kidneys begin to produce most of the amniotic fluid, so kidney problems in the fetus can lead to low amniotic fluid levels. Oligohydramnios can be detected after taking the drug for days or weeks, but also as early as two days after starting to take NSAIDs regularly. This condition usually disappears when the pregnant woman stops taking the NSAID. Intake should therefore be limited from the 20th week of pregnancy. If it is necessary to take NSAIDs between 20 and 30 weeks of pregnancy, use should be limited to the lowest effective dose and for the shortest possible duration. Contraindications for NSAIDs have previously been in effect from the 30th week of pregnancy, as these can lead to premature closure of the ductus arteriosus in the unborn child and thereby cause pulmonary hypertension in the child.

In humans, genital malformations in newborn boys, such as cryptorchidism and hypospadias, as well as reproductive disorders in adults, have increased over the last three decades [84, 101]. There is increasing evidence that non-steroidal anti-inflammatory and analgesic drugs such as paracetamol may promote genital malformations in newborn boys and later reproductive disorders [101]. A mouse model was used to investigate whether in utero exposure to therapeutic doses of the widely used paracetamol-ibuprofen combination during sex determination results in early differentiation and reduced proliferation of male embryonic germ cells. It was shown that in postnatal testes the maturation of Sertoli cells is delayed, the Leydig cell compartment is hyperplastic and the spermatogonia A pool is reduced. This causes reduced production of testosterone and defects in epididymal sperm parameters. The study suggests that use of these drugs during the critical period of sex determination impairs germline development and may lead to adverse effects that could be passed on to offspring. Paracetamol and ibuprofen have an important influence on germ cell development in the mouse and the development and maturation of germ cells in the embryonic testis. This can induce intergenerational effects that can be inherited. Data suggest that the use of these analgesics by pregnant women, particularly during the critical period of sex determination, could lead to adverse effects in humans [24, 101]. Due to the widespread use of analgesics for various indications in pregnancy, the results suggest that the safe therapeutic doses of these drugs should be reevaluated and measures should be taken to limit their use during the first trimester [101].

Additional data demonstrate that exposure of human fetal ovaries or testes to therapeutically relevant concentrations of acetaminophen and ibuprofen can cause a consistent decrease in fetal germ cell number in addition to effects on gene expression and potentially epigenetic changes [26]. These effects are highly reproducible, documented in various model systems in rats and humans, and likely result from disruption of PGE2 action. Extrapolation of the results to human pregnancy should be viewed with caution, but they add to a growing body of evidence on possible effects of analgesics during pregnancy on human development [54, 64, 73, 79, 87, 118]. Accordingly, there is a connection between the timing and duration of taking analgesics during pregnancy and the risk of cryptorchidism. These results were supported by the antiandrogenic effects in rat models leading to impaired masculinization. These results suggest that intrauterine exposure to analgesics may be a risk factor for the development of male reproductive disorders.[64]

Magnus et al. 2016 [83] examined the connection between prenatal and childhood (in the first six months) paracetamol exposure and the development of asthma, controlling the indication as a confounding variable. They used information from the Norwegian Mother-Child Cohort Study, which included 53,169 children for assessment of current asthma at age three, 25,394 for current asthma at age seven, and 45,607 for dispensing asthma medication at age seven Norwegian prescription database. There were independent, small associations between asthma at age three and prenatal paracetamol exposure (adj. RR 1.13; 95% CI: 1.02-1.25) and paracetamol use in infancy (adj. RR 1.29; 95% CI: 1.16-1.45). The results were also consistent for asthma at age seven. The associations with prenatal acetaminophen exposure were observed for various indications (pain, respiratory tract infections/influenza and fever). Maternal pain during pregnancy was the only indication associated with both and without paracetamol use. Maternal paracetamol consumption outside of pregnancy and paternal paracetamol consumption were not associated with the development of asthma. In a secondary analysis, prenatal ibuprofen exposure was positively associated with asthma at three years of age but not with asthma at age seven. This study provides evidence that prenatal and childhood acetaminophen exposure are independently associated with asthma development. The results suggest that the associations cannot be fully explained by indication bias.

Extensive experimental and epidemiological research suggests that prenatal exposure to acetaminophen may have effects on fetal development. The consequence could be an increased risk of neurodevelopmental, reproductive and urogenital disorders [11, 13, 63, 65]. In a comprehensive review, 89 international experts from relevant fields of medicine and science [14] analyzed the available epidemiological and animal experimental studies that examined neurological, genitourinary and reproductive consequences that were associated with maternal and perinatal ingestion of paracetamol [13 ]:

Fig. 1 Summary of a) epidemiological and b) animal studies on neurological, urogenital and reproductive consequences of in utero exposure to paracetamol. (Adapted from [13])

• Human observational epidemiological studies suggest that prenatal acetaminophen exposure may be associated with both reproductive and neurobehavioral abnormalities in both sexes (see Fig. 1a). Paracetamol exposure during pregnancy could increase the risk of abnormalities of the male urogenital and reproductive tract, as studies have shown an increased risk of undescended testicles (cryptorchidism) and a reduced distance between the anus and the base of the penis, called the anogenital distance (AGD). will have determined. Both reduced AGD and cryptorchidism are indicators of impaired masculinization and risk factors for reproductive disorders later in life. Prenatal acetaminophen exposure has also been associated with earlier female pubertal development. In addition, epidemiological studies consistently suggest that prenatal acetaminophen exposure may increase the risk of adverse neurodevelopmental and behavioral effects, such as: E.g. Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder, Speech Delay (in Girls) and Reduced Intelligence Quotient. Overall, the studies indicate that the timing and duration of maternal paracetamol intake are important factors [13].
• In vivo, in vitro and ex vivo studies have shown that paracetamol directly disrupts hormone-dependent processes (see Fig. 1b). This leads to impaired reproductive and neurodevelopment in both sexes. In rodents, fetal exposure has been experimentally demonstrated to cause reproductive abnormalities in the male urogenital tract, including abnormalities in testicular function, abnormalities in sperm, and sexual behavior. Experiments have shown that the development of female ovaries is disrupted, leading to a reduced number of eggs and subsequent early ovarian failure and therefore reduced fertility. Fetal exposure to paracetamol has been proven in animal experiments to lead to changes in neurotransmission in the brain, which are reflected in altered cognitive functions, behavior and movement patterns. The studies have shown that the effect of paracetamol is dependent on the timing of exposure in relation to certain developmental processes and the duration and dose [13].

The effects of in utero exposure to paracetamol on the respiratory tract were not included because systematic reviews suggest confounding variables such as the presence of respiratory tract infections [22, 40, 122].

The studies suggest that in the majority of pregnant women who use paracetamol during pregnancy, its use is not indicated and has little effectiveness for conditions such as chronic pain, back and knee pain, as well as migraines and headaches [36, 70, 88, 105 , 112]. However, pregnant women believe that paracetamol has the lowest risk and the greatest benefit [64].

Aware of the limitations of the existing epidemiological literature, the authors conclude that, based on the extensive experimental and epidemiological data, the potential for harm from continued inaction is greater than the harm that could result from precautionary measures regarding the use of paracetamol in pregnancy [13].

There is considerable evidence that paracetamol can disrupt the development of the reproductive tract in animals and humans from fetus to adulthood in both sexes [63, 65]. In animal models, fetal exposure has been experimentally demonstrated to cause disorders of the male urogenital tract through a reduction in androgen action [65]. Experimental models have consistently shown disruption of ovarian development leading to reduced fertility at the same or similar dose as in pregnant women [6, 102].

Large observational studies in six cohorts with more than 130,000 mother-child pairs from different parts of the world analyzed the association between prenatal paracetamol exposure and urogenital and reproductive anomalies [39, 42, 43, 55, 57, 64, 79, 80, 99 , 107, 110, 121]. The results of five of these studies suggest that prenatal acetaminophen exposure is associated with abnormalities of the male genitourinary and reproductive tract by causing an increased risk of non-descending testes (cryptorchidism) [57, 64, 110] and reduced anogenital distance (AGD) [43, 79] show. Another study demonstrated an association between prenatal APAP exposure and early female puberty [39]. The data suggest that the timing and duration of maternal acetaminophen use are important factors. Short-term paracetamol use may pose limited risk. Markers of female pubertal development such as: B. Pubic and axillary hair appear earlier with increasing number of weeks of prenatal acetaminophen exposure in a dose-dependent relationship [39]. These observational studies controlled for numerous confounding factors. Overall, there is increasing evidence that prenatal paracetamol exposure is associated with abnormalities of the male urogenital and reproductive tract [11, 13]. Consistent with the results from epidemiological studies, exposure to paracetamol has been associated with abnormalities in testicular function, sperm abnormalities and the development of male reproductive disorders in a number of studies using in vitro, ex vivo and in vivo models brought [50, 51, 53]. In utero acetaminophen exposure can result in a reduction in primordial germ cells and delayed meiotic entry, leading to a reduced number of follicles in the adult ovaries and subsequent infertility due to early-onset ovarian insufficiency [29, 51, 53, 60].

The associations between prenatal paracetamol exposure and adverse neurodevelopmental outcomes have been examined worldwide in 29 observational studies in 14 cohorts involving over 220,000 mother-infant pairs [8, 9, 17, 20, 21, 23, 44, 45, 58, 59, 69, 71, 74, 75, 76, 77, 78, 93, 100, 103, 109, 113, 114, 115, 116, 117, 120, 127]. Twenty-six of these studies found a positive association between acetaminophen exposure during pregnancy and a number of neurodevelopmental disorders. These include attention deficit hyperactivity disorder (ADHD) [9, 23, 44, 45, 58, 59, 71, 75, 77, 78, 113, 114, 116, 127] and related behavioral problems [17, 21, 116, 117, 120], autism spectrum disorders (ASD) [8, 58, 78], language delays [20, 21, 109, 120], reduced IQ [74], cerebral palsy [93], oppositional defiant behavior [103], reduced executive functions [74, 100] and behavioral disorders [103]. Effect sizes were generally small, but because exposure is very common, even a small effect size could impact large numbers of affected children. Dose-response relationships were revealed in 16 of these studies [8, 9, 20, 44, 58, 59, 74, 93, 100, 109, 117], with longer duration of exposure being associated with increased risk.

Possible potential confounding variables such as the indication for acetaminophen use, genetic factors and bias due to misclassification of exposure and outcomes, as well as loss of study participants to follow-up, were controlled for by various analytical methods, with results remaining largely unchanged [11, 91 ]. Likewise, sibling controls, polygenic risk scores, and negative controls were used to control for genetic confounding variables, which had little impact on the reported associations in all but two of these studies [71, 117].

In a 2020 prospective cohort study, children exposed prenatally to acetaminophen (measured in meconium) had an increased risk of physician-diagnosed ADHD and hyperactivity at ages six and seven [9]. Compared to children without acetaminophen, detection of acetaminophen in meconium was associated with twice the odds of ADHD. A dose-response association was found.

Animal studies, analogous to epidemiological data, show that perinatal paracetamol exposure, even at low therapeutic doses, can increase the risk of brain and behavioral abnormalities in rodents [18, 19, 50, 62, 95, 119, 129]. Analogous to the epidemiological data, experimental studies show that the strongest effects of long-term consumption and exposure occur at a time corresponding to the beginning of the third trimester of pregnancy and the period around birth in humans [95].

According to the American College of Gynecologists' Committee on Obstetrics, protective measures should be taken when scientific evidence indicates that an active ingredient is unsafe and not wait for clear evidence that it is harmful to offspring. Evidence of neurodevelopmental toxicity of any kind – epidemiological, toxicological or mechanistic – should, in itself, constitute a sufficient signal to trigger prioritization and some degree of action [4, 16]. This situation exists for paracetamol. Extensive animal experimental data and human studies in recent years raise considerable doubts that paracetamol is a safe medication in all phases of pregnancy. Pregnant women must be informed about this extensive evidence, even if it is viewed controversially, so that they can make informed, self-determined decisions about taking it for themselves and their unborn child. The data provide sufficient evidence and reasons to warn against the use of paracetamol for migraines without alternative and supposedly safe use.

The compilation of the evidence and the interpretation of the data by Bauer et al. [13, 14] has caused controversy. A contrary opinion is expressed in the correspondence to the article [3, 25, 90]. These authors share the position of Bauer et al. [13] do not and are of the opinion that the evidence presented is weak, inconsistent and methodologically inadequate. They complain that their literature review would promote insecurity, fear and feelings of guilt in pregnant women. This could lead to the use of less safe alternatives such as nonsteroidal anti-inflammatory drugs during pregnancy. The authors do not address differentiated indications for use, the lack of expected effectiveness in most pregnant women, the lack of approval for severe pain and possible alternatives such as triptans for migraines. Bauer et al. In their answer [12] point out that despite the large amount of available data, limitations and uncertainties still exist, which is why they have avoided drawing causality conclusions regarding the epidemiological studies. However, they believe that the available data provides sufficient evidence to be concerned and to recommend precautionary measures. The availability of a large number of animal experimental data, which largely corresponds to the epidemiological observation data, is also an important aspect of the assessment. In the latter case, confounding variables are controlled and they are an essential source for proving and supporting causality. Given the current study situation, inaction could have serious consequences. They believe that precautionary measures should be taken when scientific evidence suggests that a drug raises significant concerns. Evidence of toxicity, particularly when epidemiological, toxicological and mechanistic data are consistent, should constitute a sufficient signal to initiate action. The extensive studies listed would show consistent signals from all three research areas. Many people would view acetaminophen as a negligible risk rather than a “real drug” with potential adverse effects. For these reasons, the authors would reiterate their belief that women should be warned early in pregnancy to use paracetamol only when indicated, at the lowest dose and for the shortest possible time, and to contact their doctor or pharmacist if you are unsure about how to use it.

A study by Ahlqvist et al. 2024 [1] finds no increased risk of autism, ADHD or intellectual disability in children after taking paracetamol during pregnancy as prescribed by a doctor between 1995 and 2019 in Sweden. A nationwide cohort study was conducted with sibling controls of 2,480,797 children born in Sweden between 1995 and 2019. Paracetamol use during pregnancy was recorded using pregnancy and prescription records. A total of 185,909 children (7.49%) were exposed to medically prescribed paracetamol during pregnancy. The absolute crude risks at age 10 for unexposed versus exposed acetaminophen children were 1.33% versus 1.53% for autism, 2.46% versus 2.87% for ADHD, and 0.70% versus 0.82% for intellectual disability. In models without sibling controls, regular acetaminophen use during pregnancy was associated with a slightly increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD ] at age 10, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]) and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04 % [95% CI, -0.04% to 0.12%]). Analyzes of sibling controls found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0 .14% to 0. 18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]) or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]) was associated. The study gave no evidence of a dose-response pattern. The authors generalize that paracetamol consumption during pregnancy is not associated with an increased risk of autism, ADHD or intellectual disability in children.

The study cannot address the extensive concern about a possible association between in utero exposure to acetaminophen and developmental disorders. It was retrospectively examined in women who were prescribed paracetamol during pregnancy. The data from women who took paracetamol through self-medication are unknown. It is unknown whether the pregnant women actually took the prescribed paracetamol and in what dose and duration. Information about medication use from medical records alone is not sufficient to examine the impact of medications taken sporadically during pregnancy on perinatal outcomes [92]. Studies estimate that up to 60% of women self-medicate paracetamol during pregnancy [68, 81, 129]. The study says nothing about this extensive use outside of a doctor's prescription. In addition, only effects on autism, ADHD and intellectual disability were examined. Here it was found that no effects could be uncovered. However, not finding something does not mean that you can rule out what has been found in numerous other studies. The authors therefore state even for paracetamol: “… the results should not be interpreted as benchmarks for safety. Dose in this study only reflected dispensed prescriptions and not actual use of those dispensations or OTC use” and “… this study did not have data on conditions that did not require inpatient or outpatient medical care. Many indications for acetaminophen use, such as headache, infection, fever, and other pain, may not rise to a level that warrants seeking medical attention. Thus, capture of potential indications is incomplete.” The latter group in particular affects migraine and headache sufferers who treat themselves. These are not taken into account in the study. The study data does not address information about prenatal exposure to paracetamol on later reproductive function and genital malformations. It is precisely these risks that have been warned about in numerous animal and human studies, including prenatal exposure to paracetamol. Finally, the study by Ahlqvist et al. (2024) [1] as a positive result that acetylsalicylic acid has a protective effect against all subtypes of neurodevelopmental disorders when siblings are controlled. This would be another reason not to prefer paracetamol until the 20th week of pregnancy. In international comparison, paracetamol is taken differently frequently during pregnancy. In Denmark, in a previous study, only 6.2% of pregnant women did. In the USA the prevalence is ten times higher. Approximately 11% of U.S. children ages five to 17 have been diagnosed with attention-deficit/hyperactivity disorder (ADHD). This emerges from data from the National Health Interview Survey conducted between 2020 and 2022 [48].

A very large umbrella review aims to summarize high-quality evidence on prenatal exposure to analgesics and the risk of autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) in children [66]. A comprehensive review of the existing evidence was developed to draw clear conclusions for clinical guidelines. While in the analysis by Bauer et al., 2021 [13] in 26 of 29 studies with 220,000 mother-child pairs positive associations between maternal paracetamol consumption and possible negative effects on neurodevelopment such as ADHD, ASD, reduced IQ and behavioral disorders While the review revealed a possible dose-response relationship in 16 of 19 studies, individual studies that were not adjusted for confounding variables such as parental ADHD and maternal migraine did not find such an association. Because existing evidence for associations between maternal analgesic use in pregnancy and children's neurodevelopmental outcomes appears to be inconsistent, results from systematic reviews and meta-analyses of associations between analgesic use in pregnancy and neurodevelopmental disorders in children have been summarized systematically analyzed [66]. Seven databases were searched from their inception to May 2021 to find relevant reviews of any kind. The AMSTAR 2 and GRADE quality assessment were used to assess risk of bias and heterogeneity. Systematic reviews and meta-analyses examining associations between analgesics and the outcomes of ASD, ADHD, or ASD and ADHD in offspring were included. Animal models were not included in this review. Five systematic meta-analyses met the inclusion criteria. All five meta-analyses addressed paracetamol consumption during pregnancy and examined ADHD as an outcome. Three of the five articles examined ASD outcomes. Only paracetamol consumption was examined because there was insufficient significance for other painkillers such as acetylsalicylic acid, ibuprofen, naproxen, diclofenac and ketoprofen in the selected articles in relation to ADHD and ASD. Four of the meta-analyses included covariates and confounding factors. These include the indication, e.g. B. Pain relief or maternal fever. Additionally, the reviews found that women seeking pain or fever relief were more likely to also take medications other than acetaminophen, which in turn represents another confounding factor in the mechanisms affecting the fetus. Confounders considered in the studies reviewed in the selected articles included variables such as socioeconomic status, maternal education, nicotine and alcohol consumption, psychiatric illness, infection or inflammation during pregnancy, birth weight, and child's gestational age. To control for confounding variables, the authors of the primary studies used several methods to minimize their effects, such as: B. the use of prospective designs with large clinical data sets or the use of propensity score matching or power analyses. The following main results were excerpted:

• Hoover et al. (2015) [52]: Low associations between prenatal paracetamol exposure and ADHD symptoms in childhood. However, the studies included in this review were limited in their conclusions because they did not control for variables such as prenatal use of acetaminophen for pain relief and fever, which have previously been associated with adverse pregnancy outcomes. The associations remained even after adjustment for confounding factors such as maternal pyrexia or psychiatric illness.
• Bauer et al. (2018) [11] Associations were found between prenatal acetaminophen exposure and neurodevelopmental risk factors, but not with ibuprofen or other painkillers. The included studies controlled exposure in all trimesters of pregnancy and the indications for paracetamol use (e.g. fever, headache/migraine, infection, pain). All included studies were prospective and statistically controlled for confounding factors such as selection or recall bias.
• Masarwa et al. (2018) [86] Associations were found between prenatal paracetamol exposure and an increased risk of ADHD and ASD (20-30%). Because the included studies controlled for covariates and confounders in both mothers and children, the analysis found that associations were moderated by duration of exposure, maternal age, and child follow-up age.
• Gou et al. (2019) [47] Prospective cohort studies have found a consistent association between prenatal paracetamol exposure and an increased risk of ADHD (25%). Prenatal acetaminophen use was also associated with a higher risk when it occurred in the third trimester compared to the first and second trimesters. The included studies considered paracetamol consumption due to infection/inflammation during pregnancy, but not other circumstances such as: B. Pain relief. Some studies in this review controlled for a broad range of confounders using a negative control comparison or sibling-controlled analysis.
• Alemany et al. (2021) [2] An association was found between prenatal paracetamol exposure and the risk of ADHD symptoms (12.2%) and associations were found between paracetamol exposure and autism spectrum disorders (ASC) (12.9%) . Stronger associations for ASD and ADHD outcomes were found in men than in women. In all cohort studies, confounding factors were controlled using harmonized exposure and outcome measures.

All reviews reported significant associations between maternal prenatal paracetamol consumption and ADHD outcomes (risk ratio: 1.08-1.34; no pooled incidence rate), with a potential dose-dependent association. Potential sources of heterogeneity included timing of administration and dosage. According to the authors, the results suggest that prenatal paracetamol exposure should be minimized due to the risk of ADHD consequences [66]. When examining the AMSTAR and GRADE categories, studies that fell into the higher categories showed similar results that prenatal acetaminophen exposure is associated with neurodevelopmental risk, particularly ADHD. Study designs included included cross-sectional, longitudinal, randomized control studies, case-control studies, register-based studies, and cohort studies.

Limitations of the studies include different parameters for assessing clinical symptoms, the duration of acetaminophen exposure, the week of pregnancy at exposure, the age of the children at follow-up and the age of the mothers, which may contribute to the heterogeneity of the observed effects. However, most of the included studies used the Newcastle-Ottawa Scale, a rating system that assesses study quality and risk of bias in observational studies.

The authors conclude that pain-relieving medications are commonly used by pregnant women for a variety of reasons, suggesting that they have little hesitation about using these medications despite ignorance of the long-term effects on the fetus. Therefore, awareness among healthcare professionals about the long-term risks of prenatal paracetamol should be raised. Paracetamol should only be used when necessary, at the lowest effective dose for the shortest possible duration, taking into account the immediate benefits of paracetamol use. Pregnant women taking acetaminophen should be closely monitored throughout all trimesters of pregnancy, with emphasis on reducing excessive consumption as it is associated with the risk of neurodevelopmental disorders [66].

Golding et al. (2023) [46] examined the academic abilities of children exposed to paracetamol during pregnancy. Mothers participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) recorded the frequency of paracetamol use during pregnancy in two periods: the first 18 weeks and from 18-32 weeks. Multiple regression was performed accounting for 15 different covariates, including reasons for medication use and demographic characteristics. Almost all unadjusted and adjusted mean differences were negative (ie, children exposed to maternal acetaminophen performed worse). The negative associations for exposures between 18 and 32 weeks of pregnancy were more significant than for exposures early in pregnancy. Of the later exposures, after adjustment, 12 of the 23 school tests were significantly associated with prenatal acetaminophen exposure. These significant negative effects were found in girls but not in boys. The results of this longitudinal study suggest that maternal acetaminophen exposure is associated with disadvantages in offspring's academic skills in mathematics and reading at secondary school age. This raises the question of whether there are longer-lasting effects on school performance after age 15. The findings add to the growing number of known harmful effects of acetaminophen exposure in pregnancy.

Woodbury et al. (2024) [126] prospectively examined the association of in-utero exposure to acetaminophen with attention problems after trimester of exposure in the Illinois Kids Development Study, a prospective birth cohort. Exposure data were collected between December 2013 and March 2020, with 535 newborns enrolled during this period. The mothers reported how often they had taken paracetamol at six times during pregnancy. When the children were two, three, and four years old, caregivers completed the Child Behavior Checklist for Ages 1.5 to 5 Years (CBCL). Associations between acetaminophen use during pregnancy and scores on the Attention Problems and ADHD Problems scales, the Internalizing and Externalizing Behavior composite scales, and the total problems score were examined. Higher acetaminophen exposure during the second trimester of fetal development was associated with higher scores for attention problems, ADHD problems, externalizing behavior, and total problems at two and three years of age. Higher exposure in the second trimester was only associated with higher externalizing behavior and total problems scores at age four. Higher cumulative exposure during pregnancy was associated with higher scores for attention problems and ADHD problems at two and three years of age. The results suggest that prenatal acetaminophen exposure, particularly during the second trimester, may be associated with attention problems in early childhood.

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Authors
Prof. Dr.med. Dipl.-Psych. Hartmut Göbel MMHM ¹
Dr.med. Axel Heinze MMHM ¹
Priv.-Doz. Dr. med. Anna Cirkel MHD ²
Dr.med. Christoph Cirkel ³
Priv.-Doz. Dr. med. Carl Göbel MMHM MB BChir (Hons) MA (Cantab) ^1.4

¹ Pain Clinic Kiel, Heikendorfer Weg 9-27, 24149 Kiel
² Clinic for Neurology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck
³ Clinic for Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck
⁴ Clinic for Neurology, University Hospital Schleswig- Holstein, Kiel Campus, Kiel

Correspondence address:
Prof. Dr.med.
Dipl.-Psych. Hartmut Göbel MMHM Pain Clinic Kiel
Heikendorfer Weg 9-27
24149 Kiel
Email: hg@krebsklinik.de

source:

H. Göbel, A. Heinze, A. Cirkel, C. Cirkel, C. Göbel (2024): Treatment of migraine attacks during pregnancy. DGNeurology https://doi.org/10.1007/s42451-024-00674-z

https://link.springer.com/article/10.1007/s42451-024-00674-z