Letter: L

Loperamide is a synthetic piperidine derivative that acts via cholinergic, non-cholinergic, opiate and non-opiate receptor-mediated pathways. It is used as a smooth muscle relaxant for the symptomatic treatment of irritable bowel syndrome, acute and chronic diarrhoea, and in ileostomy patients.

The available evidence regarding the fetal effects of loperamide use in pregnancy is currently limited to three studies which collectively report the outcomes of more than 800 exposed infants. These studies report conflicting findings concerning the risk of malformation. One small study, which was only sufficiently powered to detect a major teratogenic effect, reported no increased risk of major malformations overall while a more sufficiently powered population-based study found an approximate 1.5 times increased risk in the occurrence of any severe malformation. The later study also described an increased risk of hypospadias specifically, but refuted an earlier finding of a possible association between maternal loperamide use in early pregnancy and an increased risk of cardiac defects. Due to possible data confounding from the underlying maternal condition and concomitant medication exposure, it is not currently possible to conclude that maternal loperamide use in early pregnancy increases the risk of severe malformation or hypospadias specifically. Further studies are required to confirm or refute these findings.

No evidence of an increased risk of miscarriage, low birth weight, preterm delivery or neonatal complications has been provided by these studies. No studies investigating intrauterine death/stillbirth, neurodevelopmental impairment or childhood cancer risks have been located in the literature. However, the limited and conflicting nature of these data, and confounding factors present in the studies, mean that it is difficult to draw definitive conclusions regarding the safety of use of loperamide during pregnancy.

Use of loperamide in pregnancy should, where possible, involve discussion with the patient about the limited nature of the data and should be avoided unless the clinical benefits outweigh the as yet undetermined risks. Exposure to loperamide at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Loratadine is a non-sedating antihistamine used for the symptomatic relief of allergic conditions including rhinitis (hay fever) and chronic idiopathic urticaria.

The available data do not provide evidence that loratadine use in pregnancy is associated with an increase in overall congenital malformation rate amongst exposed offspring. A single study has suggested an association between first trimester loratadine exposure and an increased risk of hypospadias in male infants, but more recent studies, which together describe the outcomes of a large number of exposed pregnancies, have failed to confirm this finding. A single study reported a possible association with transverse reduction limb defects but involved only a small number of loratadine-exposed infants, therefore this finding may reflect confounding as a result of the methodology employed. As such, the available data do not provide conclusive evidence that loratadine use in pregnancy is associated with an increased risk of any specific congenital malformation but are too limited to exclude an association.

Data regarding the risk of spontaneous abortion after exposure to loratadine are conflicting but currently do not provide strong evidence of an association. The limited published data do not suggest associations with intrauterine death, intrauterine growth restriction, preterm delivery or neonatal complications. There are no data regarding infant neurodevelopment after in utero exposure to loratadine.

Where use of a non-sedating antihistamine is required in pregnancy, and loratadine is being considered, patients should be made aware of the limitations in the available data relating to the fetal safety of gestational loratadine use. Exposure to loratadine at any stage of pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Lysergic acid diethylamide (LSD) is a synthetic tryptamine used recreationally for its highly potent hallucinogenic properties thought due to its activity at 5-hydroxytryptamine 1A and 2A receptors. 

There are no published prospective studies which specifically investigate fetal outcome following use of LSD in pregnancy. The available data are derived from case reports or small case series published mainly during the 1970s. These describe limb, CNS and ocular defects in infants exposed to LSD in utero. However, LSD has not been adequately studied and there are currently insufficient data to assign a causal association or quantify risk of adverse pregnancy outcome with use during pregnancy.

Exposure to LSD at any stage of pregnancy would not usually be regarded as medical grounds for termination of pregnancy. The need for additional fetal assessment will depend on individual circumstances, but should be considered where prolonged or high dose LSD exposure has occurred. Other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Labetalol is a non-selective beta-blocker with additional alpha adrenoceptor blocking properties. It is licensed for the treatment of mild to severe hypertension, hypertension in pregnancy, and angina pectoris with existing hypertension. NICE guidelines state that where clinically appropriate, labetalol is recommended as first-line antihypertensive treatment in pregnancy.

Data on overall rates of fetal structural malformation following first trimester use of labetalol are too limited to permit an evidence-based risk assessment. Although single studies have found no association between gestational exposure to labetalol and congenital heart defects or hypospadias, these findings remain to be confirmed. It is noteworthy that while some women with chronic hypertension may be switched to labetalol during early pregnancy, gestational hypertension is, by definition, diagnosed after 20 gestational weeks and its treatment will therefore pose a low risk of structural anomaly.

Overall, the available studies do not suggest that gestational labetalol exposure increases the risks of fetal growth restriction or preterm delivery; however, because maternal hypertension is associated with both of these outcomes, analysis is complex. Very limited data do not raise concern that gestational labetalol exposure increases the risk of stillbirth, but this remains to be confirmed. Data on rates of miscarriage and neurodevelopmental outcomes are too limited to permit a risk assessment.

Use of beta-blockers near term may result in beta-adrenoceptor blockade, leading to neonatal bradycardia, hypotension and hypoglycaemia. Although data are conflicting, with some studies not identifying increased risks, one large study which utilised advanced methods to control for confounding variables described 1.8- and 1.3-fold increased risks of neonatal hypoglycaemia and bradycardia respectively following maternal use of labetalol in pregnancy. Assessment of the neonate for these effects is therefore advised.

Exposure to labetalol at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. In pregnancies complicated by maternal hypertension and/or where labetalol has been administered, careful monitoring of fetal growth is advised. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of considering such factors when performing case-specific risk assessments.

Lamotrigine is an anticonvulsant used either as sole treatment or as adjunctive treatment of focal and generalized seizures, including tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome. Lamotrigine is also used in the treatment of bipolar disorder.

The available data on lamotrigine use in pregnancy are derived mainly from studies of women with epilepsy. Overall congenital malformation rates have been studied in over 12,800 infants exposed to lamotrigine in early pregnancy; the majority of the data do not provide evidence that lamotrigine use is associated with an increased risk of overall malformation or a number of specific malformations.

There is currently no credible evidence suggesting an increased risk of miscarriage, stillbirth, premature delivery or small for gestational age infants following exposure to lamotrigine. Data regarding adverse neurodevelopmental outcomes following prenatal exposure to lamotrigine are generally reassuring. There are currently no studies which provide evidence of an increased rate of autism diagnoses following prenatal exposure to lamotrigine; however, some studies have reported an increased rate of autism symptoms. Further research is required to confirm or refute this finding.

Lamotrigine is a weak folate antagonist and a single study has reported a statistically significant increased risk of overall malformation in children born to mothers taking lamotrigine who were prescribed <5mg folic acid per day. UK guidelines state that women who take any antiepileptic medication should be prescribed high dose folic acid (5mg).

Use of any centrally acting drug throughout pregnancy or near delivery may be associated with an increased risk of poor neonatal adaptation syndrome (PNAS). These symptoms are likely to be more severe in infants exposed in utero to more than one CNS acting drug. Where lamotrigine has been used during the latter stages of pregnancy, particularly in combination with other CNS acting medications, delivery should be planned in a unit with adequate neonatal facilities.

Plasma concentrations of lamotrigine have been shown to decline as pregnancy progresses and regular clinical review of women taking lamotrigine is therefore recommended. The lamotrigine dose may need to be increased on the basis of plasma-drug concentration monitoring or according to clinical response to maintain seizure control, particularly in later pregnancy.

Lamotrigine should only be used during pregnancy where the benefits of treatment are considered to outweigh any potential risks. Other risk factors may be also present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Latanoprost is a prostaglandin analogue used topically in the treatment of ocular hypertension and open-angle glaucoma. Systemic prostaglandins can increase uterine tone, have known abortifacient effects, and may also cause reduced placental perfusion, raising concerns regarding their use during pregnancy. However, latanoprost is administered via the ocular route and a high systemic concentration would therefore not be expected at the recommended therapeutic dose of 1.5 micrograms/eye/day.

There are no large epidemiological studies on the use of latanoprost during pregnancy and an evidence-based evaluation of risk to the fetus with maternal use during pregnancy is not currently possible. Case series, case reports and a small cohort study describe the outcomes of only 20 pregnancies (19 during the first trimester). One small cohort study found a possible association with low birth weight, however further studies are required to confirm/refute this finding. Any risks to the fetus should be weighed against the potential adverse effects of untreated maternal glaucoma, including permanent loss of vision.

Exposure to latanoprost at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Leflunomide is currently licensed for the treatment of rheumatoid and psoriatic arthritis. Its use is generally contraindicated during pregnancy due to teratogenicity in several animal models.

The active metabolite of leflunomide is highly protein bound and undergoes extensive enterohepatic recycling, prolonging the half-life of the drug. The manufacturer currently recommends a two-year waiting period after discontinuation of leflunomide before attempting to conceive. If a woman becomes pregnant while taking leflunomide, or within two years of discontinuation, the manufacturer recommends an 11-day washout protocol using colestyramine or activated charcoal to enhance drug elimination.

The available human data comprise a case-control study, a small prospective cohort study, and several case reports/series that collectively describe the outcomes of approximately 500 unique pregnancies exposed to leflunomide. In almost all cases, leflunomide was discontinued upon recognition of pregnancy, usually early in the first trimester. In the majority of exposures, a washout procedure was carried out which potentially limits the level and duration of exposure. Data on miscarriage, low infant birth weight, and preterm delivery following exposure are limited but are currently reassuring.

Leflunomide does not appear to be a major human teratogen if the drug is discontinued and a drug washout procedure is carried out. While malformations have been observed in some exposed pregnancies, there is no obvious pattern suggestive of a specific embryopathy. However, the teratogenicity of leflunomide in humans is undetermined. If in utero exposure to leflunomide has occurred, washout treatment to enhance drug elimination and a detailed structural fetal ultrasound are advised.

Levetiracetam is an anticonvulsant used either in monotherapy, or as adjunctive therapy for focal or partial onset seizures with or without secondary generalisation, myoclonic seizures in juvenile myoclonic epilepsy, and primary generalised tonic-clonic seizures.

Overall, congenital malformation rates have been studied in approximately 2,000 infants prenatally exposed during the first trimester to levetiracetam monotherapy, with no evidence of any increased risk, although in some cases study methodologies limit conclusions. There are also currently no identified associations between levetiracetam exposure and a small number of specific malformations. Although some studies have shown that use of levetiracetam in polytherapy may be linked to an increased risk of malformations compared to levetiracetam monotherapy, data are conflicting and, in some cases, potentially confounded by co-exposure to sodium valproate, an established teratogen. There is currently no evidence of a dose-effect.

Although generally reassuring, the data relating to miscarriage, stillbirth, premature delivery and infant birth weight are too limited to facilitate an accurate assessment of any potential risks posed by levetiracetam use in pregnancy and women should be made aware of the lack of data for these outcomes. Data regarding adverse neurodevelopmental outcomes following prenatal exposure to levetiracetam are reassuring, however, due to the small number of exposed children analysed, more research is required.

Use of any centrally-acting drug throughout pregnancy or near delivery may be associated with withdrawal symptoms in the neonate and/or poor neonatal adaptation syndrome (PNAS). These symptoms are likely to be more severe in infants exposed in utero to more than one CNS acting drug. Delivery should be planned in a unit with adequate neonatal facilities.

Levetiracetam is not known to impact maternal folate status. However, UK guidelines state that women who take any antiepileptic medication should be prescribed high dose folic acid (5mg).

Plasma concentrations of levetiracetam have been shown to decline as pregnancy progresses and regular clinical review of women taking levetiracetam is therefore recommended. Levetiracetam dose may need to be increased to maintain seizure control, particularly in the third trimester of pregnancy. Levetiracetam should only be used during pregnancy where the benefits of treatment are considered to outweigh any potential risks. Other risk factors may be also present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.