Letter: L

Lumacaftor is a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator licensed for the treatment of cystic fibrosis.

Lacosamide is an antiseizure medication (ASM) licensed for use in monotherapy or as an adjunct in the treatment of partial-onset seizures, with or without secondary generalisation, and as an adjunct for the treatment of primary generalised tonic-clonic seizures.

It is important that epilepsy remains well-controlled during pregnancy.

There is limited evidence regarding the safety of lacosamide use in pregnancy, with data provided by a small number of studies and uncontrolled case series/reports which collectively describe the outcomes of ~1,200 exposed pregnancies.

Although the limited available evidence does not suggest that lacosamide is a major teratogen, further studies are required to allow for a more accurate risk assessment. The available data do not clearly indicate increased risks of other adverse pregnancy or fetal outcomes following maternal lacosamide use in pregnancy; however, these data are highly limited, and better-quality studies are required before a more accurate safety assessment can be provided. Additionally, no controlled studies have investigated the risk of longer-term adverse outcomes such as childhood neurodevelopmental impairment.

Case series/reports have described neonatal complications, including NICU/hospital admission, low Apgar score, bradycardia, hypoglycaemia, hyperbilirubinemia, poor feeding/GI disturbance, and sedation following exposure to lacosamide during pregnancy. However, confounding due to concomitant medication exposure is likely. 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 neonatal intensive care facilities.

Use of lacosamide during pregnancy may adversely impact upon fetal folate status. UK guidelines state that women who take any ASM should be prescribed high-dose folic acid (5mg/day).

More research is required to define the pregnancy safety profile of lacosamide. Pregnant women and women of childbearing potential should be made aware of the limited data for most pregnancy outcomes. Lacosamide should only be used during pregnancy if there is no suitable alterative ASM with a more favourable pregnancy safety profile. In view of the limited human pregnancy data, close monitoring of mother and fetus should be considered following lacosamide use in pregnancy. 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 consideration of such factors when performing case-specific risk assessments.

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 acute and chronic diarrhoea, and fecal incontinence.

The evidence relating to the possible fetal effects of loperamide derives from three studies which collectively include >800 exposed infants.

There are conflicting findings regarding malformation risk, and data are likely confounded by the effects of underlying maternal illness and potential medication co-exposure. One small study, only sufficiently powered to detect a major teratogenic effect, found no increased risk of major malformation. However, a better powered population-based study noted a 1.5-fold increased risk of any severe malformation. The latter study also described an increased risk of hypospadias but did not replicate a previously reported association between loperamide exposure and cardiac defects. Further studies are required to confirm or refute these findings.

No evidence of increased risks of miscarriage, low infant birth weight, preterm delivery, or neonatal complications has been provided by these studies, although their findings require confirmation. Risks of intrauterine death/stillbirth, neurodevelopmental impairment, or childhood cancer have not been assessed following loperamide exposure.

The decision to use loperamide during pregnancy should be based on an individualised assessment of the benefits of treatment, the limited available data regarding fetal risk, and the potential adverse effects of inadequately managed maternal disease on both the woman and fetus.

 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 published data do not suggest an increased risk of miscarriage, infant congenital malformation, stillbirth or preterm delivery following in utero exposure to loratadine in pregnancy, and do not provide convincing evidence of an association with small for gestational age infants. However, some of the available data are methodologically limited, meaning further research is required. There are no data regarding infant neurodevelopment following in utero exposure to loratadine.

If local topical therapy fails to control symptoms, oral antihistamines can be considered for use in pregnancy. Non-sedating antihistamines tend to be used first-line due to potential risks associated with maternal drowsiness, with cetirizine and loratadine generally being preferred due to a larger volume of reassuring human pregnancy data.

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. Street names include acid, blotter, blotter acid, blue cheer, electric Kool-Aid, hits, Lucy in the sky with diamonds, mellow yellow, microdots, purple haze, sugar cubes, sunshine tabs, and window pane.

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 relating to congenital malformation risk following gestational labetalol exposure are extremely limited. No studies have assessed the overall congenital malformation risk following labetalol exposure in pregnancy. Although single studies have found no association between gestational exposure to labetalol and congenital heart defects or hypospadias, these findings remain to be confirmed, and are likely confounded. 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. Limited data do not raise concern that gestational labetalol exposure increases the risk of stillbirth. Data on 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 antiseizure medication (ASM) 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 27,000 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 indicate 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 these observations.

Lamotrigine is a weak folate antagonist; 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 ASM should be prescribed high dose folic acid (5mg) prior to conception and during the first trimester.

Use of any centrally acting drug throughout pregnancy or near delivery may be associated with an increased risk of poor neonatal adaptation syndrome. 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 reduce placental perfusion, raising concerns regarding their use during pregnancy. However, latanoprost is administered via the ocular route and therefore a clinically relevant systemic concentration is not expected with the recommended therapeutic dose of 1.5 micrograms/eye/day.

There are no large epidemiological studies on the use of latanoprost eye drops during pregnancy, and as such, it is not possible to provide a robust evidence-based evaluation of fetal risk. Case series, case reports and a small cohort study describe the outcomes of only 53 exposed pregnancies (19 confirmed use during the first trimester), with no clear indication of an association with adverse effects. Although the cohort study indicated a possible association with infant low birth weight, this finding is likely confounded, and the study was methodologically limited. A disproportionality analysis of adverse event reporting data also indicated a possible safety signal for miscarriage following exposure to latanoprost eye drops. However, the methodological biases inherent to this type of study mean that this association may not be causally related to maternal latanoprost use.

When latanoprost eye drops are being considered for use in pregnancy, any potential fetal risks need to be considered against the likely low level of fetal exposure following maternal ocular use and the potential consequences 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.