Treatment of migraine attacks during pregnancy

overview

Non-pharmacological approaches should always be attempted as a first-line treatment for migraines during pregnancy. Mild migraine attacks can be treated non-pharmacologically during pregnancy through sensory deprivation, rest, relaxation, and ice packs. Metoclopramide can be used throughout pregnancy to treat nausea and vomiting. The choice of medication for attack therapy requires an individual assessment of the expected benefits and potential risks for the pregnant woman and the unborn child. A general 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 monitoring of the course and effectiveness of treatment should be conducted. Careful and comprehensive periconceptional counseling is essential to promote a safe and healthy pregnancy and postpartum period for both mother and child. The following table provides an overview of the different treatment situations and the benefit-risk assessment of medication for attack therapy. The rationale for the classification is explained below.

Rating :
A: High benefits – low risks
B: Medium benefits – moderate risks
C: Low benefits – controversial risks
k: Contraindicated

Migraine and pregnancy

Up to one in four women of childbearing age suffers from migraine, which, however, improves spontaneously in up to 80% of cases during pregnancy [5, 82, 89, 104]. Approximately 25% of migraine patients continue to experience attacks during pregnancy, with hyperemesis, pathological pregnancy, and menstrual migraine before pregnancy being associated with a lack of improvement [89]. It remains 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 pregnancies. They should be carefully informed, monitored, and treated accordingly [7]. A recent comprehensive umbrella review [96] shows that women with migraine generally have a higher likelihood of preeclampsia, low birth weight, premature birth, placental abruption, and mental illness during pregnancy. The risk is increased by >50% in cases of severe migraine. Severe migraine constitutes a high-risk pregnancy [7, 97, 108]. Pregnancy and migraine share hypercoagulability: During pregnancy, hypercoagulability is a significant risk factor for serious cardiovascular events, including venous thromboembolism and cerebrovascular accidents. There is a 13-fold increased risk of hypertensive disorder [67, 97]. A severe course of migraine may necessitate an individual work restriction. Preventive drug treatments during pregnancy are limited; they should only be considered in the most severe cases [5].

Non-pharmacological approaches should always be attempted as a first-line treatment for migraine during pregnancy [89]. Mild migraine attacks during pregnancy can be treated non-pharmacologically through sensory avoidance, rest, relaxation, and ice packs. Acute migraine medications should only be used in pregnant women if the expected benefit to the mother outweighs any potential risk to the child. A general rule should be to aim for the lowest effective dose and the shortest possible duration of treatment. Self-medication should be avoided during pregnancy, and medical monitoring of the course and effectiveness of treatment should be conducted. Careful and comprehensive periconceptional counseling is essential to promote a safe and healthy pregnancy and postpartum period for both mother and child [5]. Given the widespread use of analgesics, it is important that there is clarity regarding the potential benefits and risks of analgesic use during pregnancy [66]. The explanation that the use of some over-the-counter analgesics is considered safe during most stages of pregnancy due to historical reputation is often based on an incomplete review of current literature [129].

Treatment of nausea and vomiting

Women who suffer from severe nausea and vomiting during pregnancy have a poor quality of life and an increased risk of maternal and fetal complications. Metoclopramide can be used to treat nausea and vomiting throughout pregnancy. However, high doses of metoclopramide towards the end of pregnancy can lead to extrapyramidal syndrome in the newborn. Therefore, metoclopramide should be avoided in late pregnancy. If metoclopramide is necessary, neonatal monitoring is essential.

In cases of severe nausea and ineffectiveness of metoclopramide, ondansetron may be used during the second and third trimesters of pregnancy under strict indication [38].

Comparison of benefits in attack therapy

The selection of medication for migraine attacks requires an individual assessment of the expected benefits and potential risks for the pregnant woman and the unborn child. A standardized, general first-line therapy is not appropriate due to the highly variable clinical symptoms of migraine and the need for differential treatment. Medication for migraine attacks should only be used if the desired benefit outweighs the risks. The assessment of individual benefits begins with knowledge and comparison of the expected efficacy. The expected efficacy is listed below based on the Number Needed to Treat (NNT) compared to placebo [5, 30, 31, 85, 98, 128]. The NNT indicates the number of treatments required to achieve a positive effect compared to placebo. Ideally, the NNT is 1, meaning that every patient would benefit from treatment with the active drug compared to placebo.

The figures clearly show that sumatriptan 6 mg subcutaneously has the highest benefit, with a number needed to treat (NNT) of 2.3. If sumatriptan 100 mg is administered orally for mild pain at the onset of an attack, the NNT is 3.0. If sumatriptan 100 mg is administered orally for moderate or severe pain later in the attack, the NNT is 4.7. For ibuprofen 400 mg and aspirin 900-100 mg, the NNT is 7.2 and 8.2, respectively. Paracetamol has by far the lowest benefit, with an NNT of 12. This means that 12 pregnant women would need to be treated with paracetamol 1000 mg to achieve pain relief in one patient after two hours. The vast majority of patients would not experience any expected benefit from paracetamol 1000 mg.

The compilation indicates that sumatriptan is the preferred treatment for acute migraine attacks during pregnancy, based on the expected benefit. It should be administered as early as possible in the attack. If severe nausea and vomiting with impaired gastric absorption are present, subcutaneous administration of sumatriptan 6 mg can be considered. Lower subcutaneous doses of 3 mg or, as a compounded medication, 2 and 4 mg are also available. Less extensive data are available for the other triptans, which is why this overview is limited to sumatriptan. The current prescribing information for sumatriptan does not list any contraindications for its use during pregnancy; it refers to the individual benefit-benefit assessment with the statement, "The drug should only be used in pregnant women if the expected benefit to the mother outweighs any potential risk to the child." Similar wording can be found for the other triptans; frovatriptan is the exception and is not recommended during pregnancy. The following table lists the guidelines of the product information regarding use during pregnancy and breastfeeding:

Alternatives for mild to moderate migraine attacks during the first two trimesters of pregnancy include ibuprofen and aspirin. However, these medications should not be used after the 20th week of pregnancy.

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

In a large US longitudinal study on medication use during pregnancy, 859,501 pregnancies were examined, of which 8,168 women had migraine. Discontinuation of triptans during pregnancy leads to increased use of non-specific medications for migraine attack treatment, primarily opioids and acetaminophen [49]. The results suggest that recommendations to discontinue migraine-specific medications could lead to an increase in the use of other medications perceived as safer. 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 benefit of such switches. Inadequately treated headaches can lead to stress, sleep deprivation, inadequate food intake, depression, medication overuse, progression, and chronicity, which in turn can have negative consequences for both mother and child [89].

Risk comparison in attack therapy

Triptans

Sumatriptan was the first triptan approved in Germany in 1993. Its effects on in utero exposure were investigated in a concurrent worldwide pregnancy registry. The final results of the 16-year Sumatriptan, Naratriptan, and Treximet (combination of sumatriptan and naproxen) Pregnancy Registry were published [37]. The pregnancy registry was closed because no further findings were expected. The main objective was to look for signs of teratogenicity by determining the risk for all major birth defects following in utero exposure to sumatriptan, naratriptan, and the combination drug sumatriptan/naproxen sodium (marketed in the US as Treximet). Furthermore, the registry looked for unusual patterns of defects that might indicate teratogenicity. In this prospective observational study, healthcare professionals worldwide voluntarily enrolled women who had taken sumatriptan, naratriptan, or the combination drug sumatriptan/naproxen sodium during pregnancy. Only pregnancies whose outcome was unknown at the time of study enrollment were analyzed. A total of 680 evaluable pregnancies 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%]). In one case of first-trimester exposure to naratriptan, a major birth defect was reported in an infant who was also exposed to sumatriptan and naratriptan (risk of birth defect: 2.2% (1/46 [95% CI 0.1%–13.0%)). No other major malformations were reported in the five cases of first-trimester exposure to the sumatriptan/naproxen sodium combination. The pregnancy registry for sumatriptan, naratriptan, and the sumatriptan/naproxen combination has found no evidence of a teratogenic effect of sumatriptan leading to major birth defects. This finding is consistent with the results of other observational studies that included various control groups [34, 35, 85, 96, 123, 128]. These studies concluded that pregnant women can take triptans [33]. The risk rates for major birth defects are similarly high. as in the general population (3-5%) [89]. Accordingly, the product information no longer contains any formal contraindications for use during pregnancy and refers to an individual benefit assessment.

Regarding pregnancy outcomes in women treated with migraine medication, triptans were the only medications included in a meta-analysis [96]. Marchenko et al. [85] showed that the likelihood of miscarriage was 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 to the general population in their meta-analysis. However, they reported pooled prevalences of pregnancy complications in women with migraine, comparing those treated during pregnancy with those who did not. In agreement with Marchenko et al. [85], this review found no significant difference in the prevalence of miscarriages associated with triptan use (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 who received triptans). However, the prevalence of miscarriages was higher in patients who received NSAIDs (22.6% (95% CI = 20.7–24.9%)).

In a Norwegian mother-child cohort study, 41,173 live births without major malformations underwent a 36-month follow-up examination after birth. 396 of these infants had taken 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 with exposure during the first trimester. The absolute risks were small, 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 and registered via the German Embryotox system, pregnancy outcomes were compared with a non-migraine control cohort. Primary endpoints were major birth defects and spontaneous abortions; secondary endpoints included preterm births, birth weight, pregnancy complications, and the rate of elective termination of pregnancy. The results showed that rates were not increased in triptan-exposed pregnancies. The authors conclude from the data that, if necessary during pregnancy, sumatriptan, as the best-studied triptan, appears to be an acceptable treatment option [111].

According to the current prescribing information for sumatriptan, current findings do not indicate an increased risk of congenital malformations. Animal studies have not revealed any evidence of direct teratogenic or harmful effects on peri- and postnatal development.

Lasmiditan

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

Rimegepant

Rimegepant should not be taken during pregnancy, as the effects of this drug on pregnant women and on the development of the human fetus are unknown according to the current information leaflet for Rimegepant.

Analgesics

Pain medication is frequently needed during pregnancy. Due to their widespread use, many pregnant women opt for over-the-counter (OTC) analgesics. The active ingredients and their metabolites can easily cross the placenta and reach the developing fetus. Despite advice to use them cautiously, pain medication is increasingly used during pregnancy [68, 81, 129]. Approximately 56% of women report using analgesics during pregnancy, making them the most frequently used class of medication during pregnancy [66]. Clinical guidelines are often based on historical reputation and previous limited knowledge about the long-term effects of these medications on the fetus [66]. Data on the safety or association of their use with potential adverse health outcomes are conflicting, complicating care decisions. The following provides an overview of the current state of knowledge.

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, aspirin, diclofenac, naproxen) and adverse neonatal outcomes was determined. 83.7% of women who took over-the-counter analgesics reported having taken them during the first trimester when specifically asked about it at their first prenatal visit. Pregnancies in which at least one of the five analgesics was taken were significantly, independently of each other, associated with an increased risk of preterm birth <37 weeks (adjusted OR (aOR)=1.50, 95% CI 1.43 to 1.58), stillbirth (aOR=1.33, 95% CI 1.15 to 1.54), neonatal death (aOR=1.56, 95% CI 1.27 to 1.93), 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 intensive care unit (aOR=1.57, 95% CI 1.51 to 1.64), and Apgar score <7 at 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 in males only). 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 using analgesics in the last 7 years of the study. Over-the-counter analgesic use during pregnancy was associated with a significantly higher risk of adverse perinatal health outcomes in offspring. The highest risk was associated with the use of paracetamol in combination with other nonsteroidal anti-inflammatory drugs. The authors conclude that the increased risk of adverse neonatal outcomes associated with the use of nonprescription analgesics during pregnancy suggests that guidelines for pregnant women regarding analgesic use urgently need to be updated.

A systematic meta-analysis investigated whether the use of medications during pregnancy is associated with the risk of gastroschisis in offspring [10]. Eighteen studies with data from 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 only significant in certain subgroups defined by geographic location, adjustment variables, and type of control.

Taking NSAIDs from the 20th week of pregnancy onwards can lead to 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 producing most of the amniotic fluid, so fetal kidney problems can lead to low amniotic fluid levels. Oligohydramnios can be observed after days or weeks of taking the drug, but also as early as two days after starting regular NSAID use. This condition usually resolves when the pregnant woman stops taking the NSAID. Therefore, use should be restricted from the 20th week of pregnancy onwards. If NSAID use is necessary between the 20th and 30th weeks of pregnancy, it should be limited to the lowest effective dose and the shortest possible duration. Contraindications for NSAIDs already applied from the 30th week of pregnancy onwards, as these can lead to premature closure of the ductus arteriosus in the unborn child and thus 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 growing evidence that nonsteroidal anti-inflammatory and analgesic drugs, such as paracetamol, may promote genital malformations in newborn boys and, later, reproductive disorders [101]. Using a mouse model, we investigated whether in utero exposure to therapeutic doses of the widely used paracetamol-ibuprofen combination during sex determination leads to early differentiation and reduced proliferation of male embryonic germ cells. The results showed that in postnatal testes, the maturation of Sertoli cells was delayed, the Leydig cell compartment was hyperplastic, and the spermatogonia A pool was reduced. This resulted in decreased testosterone production and defects in epididymal sperm parameters. The study suggests that the use of these medications during the critical period of sex determination may impair germline development and lead to adverse effects that could be passed on to offspring. Paracetamol and ibuprofen have a significant impact on germ cell development and the development and maturation of germ cells in the embryonic testis in mice. This can induce intergenerational effects that may be inherited. The data suggest that the use of these analgesics by pregnant women, particularly during the critical period of sex determination, could lead to harmful effects in humans [24, 101]. Given the widespread use of analgesics for various indications during pregnancy, the findings suggest that the safe therapeutic doses of these medications should be reassessed and measures should be taken to limit their use during the first trimester [101].

Further data demonstrate that exposure of human fetal ovaries or testes to therapeutically relevant concentrations of paracetamol and ibuprofen can cause a consistent decrease in fetal germ cell number in addition to effects on gene expression and possibly epigenetic changes [26]. These effects are highly reproducible, documented in various rat and human model systems, and likely result from disruption of PGE2 activity. Extrapolating these findings to human pregnancy requires caution, but they fit into a growing body of evidence for the potential effects of analgesics during pregnancy on human development [54, 64, 73, 79, 87, 118]. Accordingly, there is an association between the timing and duration of analgesic use during pregnancy and the risk of cryptorchidism. These findings have been supported by antiandrogenic effects observed 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] investigated the association between prenatal and infant (during the first six months) paracetamol exposure and asthma development, controlling for indication as a confounding variable. They used information from the Norwegian Mother-Child Cohort Study, which included 53,169 children for the assessment of current asthma at age three, 25,394 for current asthma at age seven, and 45,607 for asthma medication dispensed at age seven in the Norwegian prescription database. Independent, small associations were found between asthma at age three and prenatal paracetamol exposure (adj. RR 1.13; 95% CI: 1.02–1.25) and paracetamol use during infancy (adj. RR 1.29; 95% CI: 1.16–1.45). The results were consistent for asthma at age seven. Associations with prenatal paracetamol exposure were observed for various indications (pain, respiratory infections/influenza, and fever). Maternal pain during pregnancy was the only indication for which an association was found both with and without paracetamol use. Maternal and paternal paracetamol use outside of pregnancy were not associated with the development of asthma. In a secondary analysis, prenatal ibuprofen exposure was positively associated with asthma at age three, but not with asthma at age seven. This study provides evidence that prenatal and childhood paracetamol exposure are independently associated with asthma development. The findings suggest that the associations cannot be fully explained by indication confounding.

Extensive experimental and epidemiological research suggests that prenatal exposure to paracetamol may have effects on fetal development. This could result in 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 studies investigating neurological, urogenital, and reproductive consequences associated with maternal and perinatal paracetamol use [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])

• Epidemiological observational studies in humans suggest that prenatal paracetamol exposure in both sexes may be associated with reproductive and neurological/behavioral abnormalities (see Fig. 1a). Paracetamol exposure during pregnancy may increase the risk of male urogenital and reproductive tract abnormalities, as studies have found an increased risk of undescended testicles (cryptorchidism) and a reduced distance between the anus and the base of the penis, known as the anogenital distance (AGD). Both reduced AGD and cryptorchidism are indicators of impaired masculinization and risk factors for reproductive disorders later in life. Prenatal paracetamol exposure has also been associated with earlier female pubertal development. Furthermore, epidemiological studies consistently indicate that prenatal exposure to paracetamol may increase the risk of adverse effects on neurological development and behavior, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, speech delay (in girls), and reduced intelligence quotient. Overall, the studies suggest that the timing and duration of maternal paracetamol use 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 disorders in the male urogenital tract, including abnormalities in testicular function, sperm, and sexual behavior. Experiments have shown that the development of the female ovaries is disrupted, resulting in a reduced number of oocytes and subsequent early ovarian insufficiency, and thus reduced fertility. Fetal paracetamol exposure has been shown in animal experiments to cause changes in neurotransmission in the brain, manifesting as altered cognitive functions, behavior, and motor patterns. The studies have shown that the effects of paracetamol depend on the timing of exposure with respect to specific developmental processes, as well as on the duration and dose [13].

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

Studies indicate that for the majority of pregnant women who use paracetamol during pregnancy, its use for conditions such as chronic pain, back and knee pain, migraine, and headaches is not indicated and is of little effect [36, 70, 88, 105, 112]. However, pregnant women often perceive paracetamol as offering 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 to use paracetamol during 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, it has been experimentally demonstrated that fetal exposure causes disturbances of the male urogenital tract by reducing androgenic activity [65]. Experimental models have consistently shown a disruption of ovarian development, leading to reduced fertility at the same or a similar dose as in pregnant women [6, 102].

Extensive observational studies in six cohorts with more than 130,000 mother-child pairs from various parts of the world analyzed the association between prenatal paracetamol exposure and urogenital and reproductive abnormalities [39, 42, 43, 55, 57, 64, 79, 80, 99, 107, 110, 121]. The results of five of these studies suggest that prenatal paracetamol exposure is associated with male urogenital and reproductive tract abnormalities by showing an increased risk of undescended testes (cryptorchidism) [57, 64, 110] and a reduced anogenital distance (AGD) [43, 79]. Another study demonstrated an association between prenatal APAP exposure and early female puberty [39]. The data suggest that the timing and duration of maternal paracetamol use are important factors. Short-term paracetamol use may be associated with a limited risk. Markers of female pubertal development, such as pubic and axillary hair, appear earlier with increasing weeks of prenatal paracetamol exposure in a dose-dependent relationship [39]. These observational studies controlled for numerous confounding factors. Overall, there is growing evidence that prenatal paracetamol exposure is associated with abnormalities of the male urogenital and reproductive tracts [11, 13]. Consistent with the results of epidemiological studies, exposure to paracetamol has been associated with abnormalities of testicular function, sperm abnormalities, and the development of male reproductive disorders in several studies using in vitro, ex vivo, and in vivo models [50, 51, 53]. In utero exposure to paracetamol may lead to a reduction in primordial germ cells and delayed meiotic entry, resulting in 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 effects on neurological development have been investigated worldwide in 29 observational studies across 14 cohorts with over 220,000 mother-child 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]. In 26 of these studies, a positive association was found between paracetamol exposure during pregnancy and a range 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], speech delays [20, 21, 109, 120], reduced IQ [74], cerebral palsy [93], oppositional defiant disorder [103], reduced executive functions [74, 100] and behavioral disorders [103]. Effect sizes were generally small; however, because exposure is very common, even a small effect size could have an impact on a large number 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 exposure duration being associated with an increased risk.

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

In a prospective cohort study from 2020, children who were exposed to paracetamol prenatally (measured in meconium) had an increased risk of medically diagnosed ADHD and hyperactivity at six and seven years of age [9]. Compared to children without paracetamol exposure, the detection of paracetamol in meconium was associated with twice the likelihood of ADHD. A dose-response association was observed.

Animal studies, analogous to epidemiological data, show that perinatal exposure to paracetamol, 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 epidemiological data, experimental studies show that the strongest effects of long-term use 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 suggests that an active ingredient is of concern, rather than waiting for definitive proof that it harms offspring. Evidence of any kind of toxicity to neurological development—epidemiological, toxicological, or mechanistic—should in itself be a sufficient signal to trigger prioritization and a certain level of action [4, 16]. This situation applies to acetaminophen. Extensive animal studies and human trials in recent years raise significant doubts about the safety of acetaminophen during all stages of pregnancy. Pregnant women must be informed about this extensive evidence, even if it is controversial, so that they can make an informed and autonomous decision about its use for themselves and their unborn child. The data provide sufficient evidence and grounds to warn against the supposedly safe and indispensable use of acetaminophen for migraine.

The compilation of evidence and the interpretation of the data by Bauer et al. [13, 14] has sparked controversy. A contrary opinion is expressed in the correspondence to the article [3, 25, 90]. These authors do not share the position of Bauer et al. [13] and believe that the presented evidence is weak, inconsistent, and methodologically inadequate. They argue that their literature review promotes uncertainty, anxiety, and guilt among pregnant women. This could lead to the use of less safe alternatives, such as nonsteroidal anti-inflammatory drugs (NSAIDs), during pregnancy. The authors do not address the differentiated indications for use, the lack of expected efficacy in most pregnant women, the absence of approval for severe pain, and possible alternatives such as triptans for migraine. In their response [12], Bauer et al. point out that despite the large amount of available data, limitations and uncertainties remain, which is why they avoided drawing conclusions about causality regarding the epidemiological studies. However, they believe that the available data provide sufficient grounds for concern and a recommendation for precautionary measures. The availability of a large body of animal studies, largely consistent with epidemiological observational data, is also an important aspect of the assessment. In the latter, confounding variables are controlled for, and they are a vital source for demonstrating and substantiating causality. Given the current state of research, inaction could have serious consequences. They believe that precautionary measures should be taken when scientific evidence suggests that a drug is a cause for significant concern. Evidence of toxicity, particularly when epidemiological, toxicological, and mechanistic data are consistent, should be a sufficient signal to initiate action. The extensive studies cited show consistent signals from all three areas of research. Many people view paracetamol as a negligible risk and not as a “real drug” with potential adverse effects. For these reasons, the authors would reaffirm their belief that women should be warned in early pregnancy to use paracetamol only when indicated, at the lowest dose and for the shortest possible time, and to consult their doctor or pharmacist if they are unsure about its use.

A study by Ahlqvist et al. 2024 [1] found no increased risk of autism, ADHD, or intellectual disability in children of physician-prescribed paracetamol taken during pregnancy in Sweden between 1995 and 2019. The study was a nationwide cohort study 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 physician-prescribed paracetamol during pregnancy. The absolute crude risks at age 10 for the non-exposed versus the exposed paracetamol 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 control, regular use of paracetamol 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%]). Analyses of sibling controls revealed no evidence that paracetamol 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%]). The study provided no evidence of a dose-response pattern. The authors generalize that paracetamol use during pregnancy is not associated with an increased risk of autism, ADHD, or intellectual disability in children.

This study cannot refute the widespread concern about a possible link between in-utero exposure to paracetamol and developmental disorders. It was a retrospective review of women who were prescribed paracetamol during pregnancy. Data from women who took paracetamol through self-medication are unknown. It is also unknown whether the pregnant women took the prescribed paracetamol at all, and if so, in what dose and for how long. Information on medication use from medical records alone is insufficient to investigate the effects of sporadically taken medications during pregnancy on perinatal outcomes [92]. Studies suggest that up to 60% of women take paracetamol through self-medication during pregnancy [68, 81, 129]. This study does not address this widespread use outside of a prescription. Furthermore, only effects on autism, ADHD, and intellectual disability were examined, and no effects were found. Not finding something, however, does not mean that one can rule out what has been found in numerous other studies. The authors themselves state regarding 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 specifically concerns migraine and headache sufferers who self-treat. These individuals were not included in the study. The study data do not address information regarding the effects of prenatal exposure to paracetamol on later fertility and genital malformations. However, numerous animal and human studies have warned of precisely these risks, including those associated with prenatal exposure to paracetamol. Finally, the study by Ahlqvist et al. (2024) [1] found that acetylsalicylic acid has a protective effect against all subtypes of neurodevelopmental disorders when controlled for by siblings. This would be a further reason not to prefer paracetamol until the 20th week of pregnancy. The frequency of paracetamol use during pregnancy varies internationally. In Denmark, a previous study found that only 6.2% of pregnant women used it. In the USA, the prevalence is ten times higher. Approximately 11% of US children aged five to 17 years have been diagnosed with attention deficit hyperactivity disorder (ADHD). This is based on data from the National Health Interview Survey conducted between 2020 and 2022 [48].

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

• Hoover et al. (2015) [52]: Weak associations between prenatal paracetamol exposure and ADHD symptoms in childhood. However, the studies included in this review were limited in their conclusions because variables such as prenatal use of paracetamol for pain relief and fever, which have previously been associated with adverse pregnancy outcomes, were not controlled for. The associations persisted even after adjusting for confounding factors such as maternal pyrexia or psychiatric disorders.
• Bauer et al. (2018) [11] found associations between prenatal paracetamol exposure and risk factors for neurological development, but not for ibuprofen or other analgesics. The included studies controlled for exposure in all trimesters of pregnancy and the indications for paracetamol use (e.g., fever, headache/migraine, infections, pain). All included studies were prospective and statistically controlled for confounding factors such as selection or recall errors.
• Masarwa et al. (2018) [86] found associations between prenatal paracetamol exposure and an increased risk of ADHD and ASD (20-30%). Since covariates and confounding factors were controlled for in both mothers and children in the included studies, the analysis found that the associations were moderated by the duration of exposure, the mother's age, and the child's age at follow-up.
• Gou et al. (2019) [47] In prospective cohort studies, a consistent association between prenatal paracetamol exposure and an increased risk of ADHD (25%) was found. Prenatal paracetamol 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 use due to infections/inflammation during pregnancy, but not other circumstances such as pain relief. Some studies in this review controlled for a wide range of confounding factors using negative controls or sibling-controlled analysis.
• Alemany et al. (2021) [2] found an association between prenatal paracetamol exposure and the risk of ADHD symptoms (12.2%) and associations between paracetamol exposure and autism spectrum disorder (ASD) (12.9%). Stronger associations for ASD and ADHD outcomes were found in males than in females. In all cohort studies, confounding factors were controlled for using harmonized exposure and outcome measures.

All reviews reported significant associations between maternal prenatal paracetamol use and ADHD sequelae (risk ratio: 1.08–1.34; no pooled incidence rate), with a potentially dose-dependent association. Possible sources of heterogeneity included the timing of ingestion and dosage. According to the authors, the results suggest that prenatal paracetamol exposure should be minimized due to the risk of ADHD sequelae [66]. When examining the AMSTAR and GRADE categories, studies in the higher categories showed similar results, indicating that prenatal paracetamol exposure is associated with a risk for neurological development, particularly ADHD. The study designs included cross-sectional, longitudinal, randomized controlled trials, case-control studies, registry-based studies, and cohort studies.

Limitations of the studies include differing parameters for recording clinical symptoms, the duration of paracetamol exposure, the gestational age at exposure, the children's age at follow-up, and the mothers' age, 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 the risk of bias in observational studies.

The authors conclude that pregnant women frequently take pain-relieving medications for a variety of reasons, suggesting that they use these medications readily despite a lack of awareness of the long-term effects on the fetus. Therefore, healthcare professionals should be made more aware of the long-term risks of prenatal paracetamol use. Paracetamol should be used only when necessary, at the lowest effective dose for the shortest possible duration, and the immediate benefit of paracetamol use should be carefully weighed. Pregnant women taking paracetamol should be closely monitored throughout all trimesters of pregnancy, with a focus on reducing excessive use due to its association with the risk of neurodevelopmental disorders [66].

Golding et al. (2023) [46] investigated 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 at two time points: in the first 18 weeks and from 18 to 32 weeks. A multiple regression was performed, taking into account 15 different covariates, including the reasons for medication use and demographic characteristics. Almost all unadjusted and adjusted mean differences were negative (i.e., the children exposed to maternal paracetamol use performed worse). The negative associations for exposures between 18 and 32 weeks of gestation were more pronounced than for exposures at the beginning of pregnancy. Of the later exposures, after adjustment, 12 of the 23 school tests were significantly associated with prenatal paracetamol exposure. These significant adverse effects were found in girls but not in boys. The results of this longitudinal study suggest that maternal paracetamol exposure is associated with disadvantages in the academic performance of offspring in mathematics and reading during secondary school. This raises the question of whether there are longer-lasting effects on academic performance from the age of 15 onwards. The findings add to the growing body of known harmful effects of paracetamol exposure during pregnancy.

Woodbury et al. (2024) [126] prospectively investigated the association between in utero exposure to acetaminophen and attention problems after the 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. Mothers reported their acetaminophen use frequency at six time points during pregnancy. When the children were two, three, and four years old, caregivers completed the Child Behavior Checklist for 1.5 to 5 Years (CBCL). Associations between acetaminophen use during pregnancy and scores on the Attention Problems and ADHD Problems scales, the composite Internalizing and Externalizing Behaviors scale, and the total Problems score were examined. Higher paracetamol exposure during the second trimester of fetal development was associated with higher scores for attention problems, ADHD problems, externalizing behavior, and overall problems at ages two and three. Higher exposure during the second trimester was associated only with higher scores for externalizing behavior and overall problems at age four. Higher cumulative exposure during pregnancy was associated with higher scores for attention problems and ADHD problems at ages two and three. These findings suggest that prenatal paracetamol 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, Campus Kiel, Kiel

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

source:

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

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