Analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), muscle relaxants, and antigout medications

Pharmacology

Paracetamol is a centrally acting analgesic and antipyretic drug lacking anti-inflammatory properties. It acts by inhibiting central prostaglandin synthesis and by elevating pain threshold, but the exact mechanism of action is unknown. Paracetamol passes the placenta and fetal drug concentrations equal that of the mother ( ).

Toxicology

Paracetamol use during the first trimester was not associated with an increased risk of major overall or specific birth defects in a population-based, case-control study which included more than 11,000 case infants of whom more than 5,000 had been exposed prenatally to paracetamol mono-preparations ( ). In that study, the risk for selected malformations, including neural tube defects and orofacial clefts, anotia or microtia, and gastroschisis decreased when paracetamol was used for a febrile illness, suggesting a beneficial effect in lowering temperature. According to all data published to date there is no indicative evidence that paracetamol is teratogenic in humans ( ).

Contrary to these reassuring findings, research in experimental studies has shown that prostaglandins are important in testosterone-dependent differentiation of the male genital tract ( ), and a recent ex vivo study in cultured rat testes indicated that paracetamol, even in low concentrations, is a potent inhibitor of testosterone synthesis ( ). While testosterone is important in programming normal testis descent, low testosterone levels during a critical phase of development could consequently affect this event occurring in a later phase of pregnancy ( ). Several studies based on this hypothesis have recently been published. Data on 47,400 male offspring, including 980 boys with a diagnosis of cryptorchidism confirmed from the patient register, were included in a study based on the Danish National Birth Cohort during the years 1996–2002 ( ). Paracetamol exposure continuing for more than 4 weeks and occurring during the eighth- to fourteenth-gestation weeks was associated with cryptorchidism; however, no association remained when only cases needing operative treatment were included ( ). In another study with possibly partly overlapping study material and including nearly 500 boys from Denmark and a cohort of nearly 1,500 boys from Finland, paracetamol use for 2 weeks or longer during the first and second trimester was associated with an increased risk of cryptorchidism in the Danish cohort, while no association was observed in the Finnish cohort ( ). Further, a population-based study from the Netherlands included more than 3,000 boys with follow-up visits until at least 6 months’ of age, observed an association with paracetamol use during the fourteenth to twenty-second gestational weeks and cryptorchidism ( ). Even if unconfirmed, together with the published experimental data, these findings are suggestive of a possible causal association.

Several epidemiological studies have observed an association between prenatal exposure to paracetamol and wheezing or asthma in offspring ( ). The Avon Longitudinal Study, with prospectively collected exposure data, observed a statistically significant risk for childhood asthma after exposure to paracetamol during the latter half of pregnancy, while no risk was observed if exposure was before 20 gestational weeks ( ). The risk for persistent wheezing until age 7 was highest after exposure occurring in the first trimester in another population-based prospective cohort study ( ), while a prospective study including 1,500 women observed a significantly lower risk for asthma at 6 years’ of age after exposure to paracetamol during the first or third trimester ( ). Confounding by indication (e.g. maternal illness) and exposure to paracetamol during infancy remains a major concern when interpreting conflicting results ( ). A recent meta-analysis of published studies and a recent review both concluded that prenatal exposure to paracetamol is associated with an increased risk of childhood asthma, but causation still remains to be established ( ). The putative biological mechanisms that have been proposed to play a role in pathogenesis include epithelial cell damage caused by the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), or by selective cyclooxygenase-2 (COX-2) inhibition, together with paracetamol-induced depletion of glutathione, an important antioxidant in the airways ( ). However, as the respiratory epithelium develops later in pregnancy, damage is not expected to occur during the first trimester ( ). Further, the capacity of the fetal liver to metabolize paracetamol to NAPQI is limited. To conclude, a causal association between prenatal paracetamol exposure and childhood wheezing has not been established, but neither can it be ruled out.

Use of paracetamol during pregnancy has also been associated in a single study with an increased risk of preeclampsia and thromboembolic diseases, both conditions in which reduction in prostacyclin production may play a role ( ). Causality cannot be confirmed on the basis of this study. No association was observed between acetaminophen, ASA, or NSAID use during pregnancy and the risk for childhood leukemias ( ).

A Norwegian mother and child cohort study with siblings found an association between long-term use (>28 days) of paracetamol during pregnancy and several adverse neurodevelopmental outcomes at 3 years of age, including delayed motor development with externalizing and internalizing behaviors ( ). Another population-based study from Denmark linking prospectively collected data from maternal interviews together with hospital and prescription registers, and adjusting for several important confounders found an association between paracetamol use and hyperkinetic disorders ( ). Use of paracetamol for 20 weeks or more, and exposure during the second and third trimester showed the highest risk estimates, but use of 2–5 weeks was also associated with an increased risk ( ). The biological mechanism by which paracetamol might affect fetal neurodevelopment is not established, and causality cannot be confirmed on the basis of these observational studies. Further research should address the effect of dosing and the critical time window for neurodevelopmental outcomes, while focusing on a possible genetic susceptibility predisposing for the suspected adverse effects. The findings from these two studies should not change practice, but suggest that paracetamol should be used during pregnancy only when clearly indicated.

Regarding overdoses during suicide attempts see Chapter 2.22 . Regarding the combination with Codeine see Section 2.1.5 (C).

Pharmacology

Acetylsalicylic acid (ASA), also known as aspirin, acts by irreversibly inhibiting the platelet cyclooxygenase (COX) enzyme, resulting in inhibition of platelet thromboxane A2 (TXA-2) synthesis. TXA-2 has vasoconstriction activity with increased platelet aggregation, and inhibition results in opposite effects, favorable in preventing arterial thrombosis. A dose of 160–325 mg is sufficient to nearly completely (90%) inhibit platelet COX enzyme, and this effect lasts for the platelet life span (7–10 days). Higher doses, however, also inhibit the synthesis of prostacyclin in blood vessel endothelial cells. Contrary to TXA-2, prostacyclin acts as a vasodilator and inhibits platelet aggregation. Prostacyclin also acts as a modulator in inflammatory processes. These dose-dependent effects of ASA are consequently reflected in different indications for use.

After oral intake, salicylates are quickly absorbed and reach the fetus via the placenta. Doses of 500 mg and higher close to delivery can significantly reduce fetal prostacyclin synthesis. In users, a 100 mg dose reduces thromboxane A2 synthesis but has no effect on prostacyclin synthesis. ASA is hydrolyzed to salicylic acid and further metabolized to glucuronide conjugates in the liver.

Use and effectiveness of low-dose ASA

Low doses (50–150mg/day) have been used during pregnancy to prevent several pregnancy complications. By reducing vasoconstriction and platelet aggregation, low-dose ASA could be beneficial in preventing pregnancy induced hypertension and preeclampsia. A randomized trial including more than 9,000 women assigned to take low-dose ASA (60 mg/day) or placebo, did not find a significantly reduced rate of preeclampsia or intrauterine growth retardation, but risk for preterm birth was significantly lower in the ASA group (the Collaborative Low-Dose Aspirin in Pregnancy Study, ). A decline in the rate of preeclampsia was also observed in women who had started ASA treatment prior to 20 weeks gestation. Low-dose aspirin was safe and there was no evidence of excess bleeding during delivery. A recently published meta-analysis reported that use of low-dose ASA was significantly associated with risk reduction for preeclampsia, intra-uterine growth retardation and preterm birth, but only if treatment was started at 16 weeks gestation or earlier ( ). A more recent review and meta-analysis stated that low-dose ASA when initiated at or before 16 weeks reduces the risk of severe preeclampsia, while no effect to reduce the risk for mild preeclampsia has been confirmed ( ).

The pathophysiology of preeclampsia includes impaired trophoblast invasion and abnormal placental development starting early in pregnancy. It is therefore biologically plausible that treatment, particularly during early gestation would be beneficial. The protective effect of low-dose ASA on hypertensive pregnancy complications, including preeclampsia and preterm delivery, however, could not be replicated in a meta-analysis based on individual patient data and investigating ASA use (100 mg/day). This study followed a group of women from the preconception stage, and focused on IVF pregnancies ( ). The American College of Chest Physicians recommends low-dose ASA treatment starting from the second trimester for those who are at risk for pre-eclampsia ( ).

The possible benefits of low-dose ASA in treating women with recurrent unexplained miscarriages were investigated in a randomized prospective trial, which included nearly 300 women receiving either ASA alone (dose 80 mg/day), ASA and nadroparin (a low molecular weight heparin) or placebo. The treatment began as soon as a viable pregnancy could be demonstrated. There was no difference in live birth rates between the groups, indicating no beneficial effects of either treatment ( ). In patients with thrombophilia, the presence of antiphospholipid antibodies (APLA) is known to be associated with adverse pregnancy outcomes, including an increased risk of miscarriage ( ). According to current guidelines by the British Committee for Standards in Haematology and the American College of Chest Physicians, women with APLAs who have experienced > 3 miscarriages are recommended antenatal administration of heparin combined with low-dose aspirin throughout pregnancy ( ). Treatment should be started as soon as pregnancy has been confirmed ( ).

Toxicology

In experimental studies, acetylsalicylic acid given in high doses to animals has been associated with developmental toxicity including structural malformations. Conflicting results regarding humans have been obtained in epidemiological settings. Population-based data from the Swedish Birth Registry did not observe an association between ASA use during early pregnancy and cardiovascular malformations ( ), and several other publications did not observe an increased risk of overall malformations ( ). Three case-control studies observed an association between acetylsalicylic acid use in early pregnancy and a risk for gastroschisis ( ); this was also reported in a meta-analysis by . However, a further study by failed to repeat the previously observed association. Other malformations that have been associated with ASA use include limb reduction defects corresponding to the amniotic band syndrome ( ), and holoprosencephaly ( ). Several limitations, including the potential for recall bias and confounding by indication, limit the relevance of these findings. An increased risk of cryptorchidism was observed in a Danish study after use of ASA in the first or second trimester; however, this association was statistically significant only when use had lasted for more than 2 weeks ( ). In another part of the same study assessing the risk in Finnish boys, no association was found between the use of mild analgesics and cryptorchidism. Neither was an association observed in a larger study from Denmark, with possibly partly overlapping study material ( ). Further, mild analgesic use during the second trimester was associated with an increased risk for cryptorchidism but not for hypospadias in a Dutch population-based cohort study, but use of ASA was not specifically analyzed ( ). No further conclusions can be drawn from these conflicting results. Another study did not find an association between the intake of acetaminophen, ASA, or NSAIDs during pregnancy and the risk for leukemia during childhood ( ).

In summary, according to currently available data it can be concluded that there is no serious evidence of teratogenic effects of ASA.

ASA use at the time of conception was associated with an increased risk for miscarriage in a prospective cohort study, including more than 1,000 women who were recruited as soon as a pregnancy test was positive ( ). The rate of miscarriage was 23% in those exposed to ASA ( n = 22) compared to 15% in non-exposed controls. As prostaglandins are important in the implantation process, drugs inhibiting prostaglandin synthesis, including ASA, could adversely affect this process. However, this association has not been confirmed, and miscarriage rates have been documented to be in this range normally without exposure to ASA.

A cohort study including more than 600 children exposed prenatally to low-dose ASA and born very preterm (prior to 33rd week of gestation), evaluated the neurodevelopment up to 5 years’ of age. The study did not observe negative effects in the neurocognitive development of these children. Instead, the results suggested rather a protective effect for behavior abnormalities, including hyperactivity ( ). Regarding overdoses in suicide attempts, see Chapter 2.22 .

Prior to parturition

A sensitivity of the ductus arteriosus to prostaglandin inhibitors increases from 28 gestation weeks onward. Repeated use of prostaglandin inhibitors, including ASA, can produce a narrowing or premature closure of the ductus, which in normal circumstances is not closed until soon after birth. This effect is both time- and dose-dependent, and was first documented with the use of another prostaglandin inhibitor, indomethacin (Section 2.1.6 (A)). Individual susceptibility to prostaglandin inhibitors obviously varies, and repeated analgesic doses of ASA are best avoided after 28 weeks.

As prostaglandin inhibitors decrease uterine contractility, salicylates can prolong duration of pregnancy and labor by decreasing the activity of contractions. Consequently, salicylates have been used for tocolysis in the past. Because analgesic doses (500 mg and higher) increase the risk for bleeding, such dosing should be avoided beginning at least 2 weeks before the expected date of delivery. Risk for bleeding applies to the mother (increased bleeding during delivery) and the infant.

Low-dose ASA does not constrict the ductus arteriosus nor does it increase the risk for bleeding in the mother or the infant ( ).

Pyrazolone compounds

Metamizol ( dipyrone ), phenazone and other pyrazolone compounds have largely lost their role as analgesics and antipyretics because of their potentially life threatening hematologic adverse effects, and have been replaced accordingly by pharmaceuticals with greater effectiveness and safety. Pyrazolone compounds are prostaglandin inhibitors, and as other drugs in this class, repeated use after 28 weeks gestation can cause premature closure of the fetal ductus arteriosus. Prostaglandin inhibitors can also affect fetal renal tubular function resulting in decreased amniotic fluid volume. There are two case reports describing the development of oligohydramnion in pregnant women taking high doses of metamizol shortly before the end of their pregnancy ( ). In the case presented by Weintraub, a reversible narrowing of the ductus arteriosus was also observed.

While experience of use during early pregnancy is limited, there has been no suggestion of an increased risk for malformations in humans after exposure to metamizol. A prospective follow-up study including more than 100 women treated in the first trimester with metamizol did not observe an increased risk for major malformations when compared to non-exposed controls ( ). Another prospective study from Brazil, which included more than 500 exposed pregnancies, observed no increased risk for malformations or perinatal complications, including preterm birth or low birth weight ( ).

An increased risk of Wilm’s tumor after prenatal exposure to metamizol was observed in a Brazilian study ( ). No other studies assessing the risk for this outcome have been published. In two retrospective case-control studies, metamizol use during pregnancy was more common among mothers with infants with acute leukemia than among mothers with healthy children ( ). Contrary to these findings, a subsequent study did not observe a significant association between mothers’ metamizol use and childhood leukemia ( ).

Propyphenazone was not teratogenic in experimental testing in animals (rats). There are no data regarding propyphenazone or phenazone use during pregnancy in humans.

Phenylbutazone is a prostaglandin inhibitor with analgesic, anti-inflammatory and antipyretic properties. Phenylbutazone has been used primarily in the treatment of ankylosing spondylitis and rheumatoid arthritis (RA). As with pyrazolone compounds, phenylbutazone is rarely used today because of potentially serious adverse effects related to its use (renal failure, hematologic effects, and potent accumulation with a biological half-life of 50 to 100 hours). Animal experiments have reported teratogenic effects. There are insufficient data regarding malformation risk in humans, but a major teratogenic potential appears unlikely. As an inhibitor of prostaglandin synthesis, phenylbutazone, like ASA and NSAIDs, can produce premature closure of ductus arteriosus when used in the last trimester, and potentially affect fetal renal function.