Letter: H

Hydroxychloroquine (HCQ) is a quinine derivative indicated for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, discoid and systemic lupus erythematosus (SLE), and dermatological conditions caused or aggravated by sunlight.

Guidance from the British Society for Rheumatology (BSR) states that HCQ can be used throughout pregnancy at doses of ≤400mg/day and is a drug of choice for women with rheumatic disease who are planning a pregnancy.

A single study found that daily doses of HCQ ≥400mg were associated with a 30% increase in risk of congenital malformation (equating to an ~4% malformation risk following exposure), whereas lower doses were not associated with increased risk. These data are likely confounded by maternal disease severity and are of limited relevance to most patients as HCQ doses above 400mg/day are not generally recommended for the treatment of rheumatic disease. The available data overall do not demonstrate that HCQ exposure in pregnancy increases the risks of miscarriage, stillbirth, preterm delivery (PTD), or low infant birth weight. Protective effects against PTD have been inconsistently observed. HCQ treatment of SLE and/or antiphospholipid syndrome during pregnancy has been associated with reduced disease flare and improved pregnancy and neonatal outcomes, including reductions in preterm birth, intrauterine death, neonatal lupus, and congenital heart block. There are limited but reassuring data relating to childhood neurodevelopment following HCQ exposure.

Exposure to HCQ at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, women with rheumatic disease may require closer monitoring during pregnancy including serial fetal growth measurement. Other risk factors which could independently increase the risk of adverse pregnancy outcome may also be present in individual cases and should be considered when performing case-specific risk assessments.

Histamine H₂-receptor antagonists (H2RAs) (cimetidine, famotidine, nizatidine and ranitidine) reduce gastric acidity through inhibition of gastric acid production. H2RAs are used in the symptomatic relief of episodic dyspepsia and gastro-oesophageal reflux disease, in the prevention and treatment of gastric or duodenal ulceration, and prior to general anaesthesia in patients at risk of acid aspiration. H2RAs may be considered for use in pregnancy after lifestyle modification, first-line antacid or alginate treatment and second-line PPI treatment (with omeprazole) have proved unsuccessful in controlling symptoms, or are not considered appropriate.

Data regarding the risk of adverse pregnancy or fetal outcomes following exposure to H2RAs as a class are drawn from studies reporting over 4,600 pregnancy exposures collectively. The majority of these studies do not analyse pregnancy outcomes for the individual H2RAs separately. There are more data available for ranitidine (over 1,500 pregnancy exposures) and less data available for cimetidine, famotidine and nizatidine.

There is no evidence of an overall increase in the risk of congenital malformation for H₂-antagonists. Nor is there good evidence of increased risks of specific malformations. Risks of miscarriage, intrauterine death, low infant birth weight, neonatal complications or adverse neuro-developmental outcomes do not appear to be increased following exposure to H2RAs. A meta-analysis has suggested a small increased risk of preterm delivery following H2RA use in pregnancy; however, the data are likely confounded by indication and therefore a causal link is unlikely. Studies of individual drugs are too small to draw definitive conclusions.

An increased risk of childhood asthma following maternal exposure to H2RAs has been reported; however, as data are conflicted and likely confounded, further research is required.

Exposure to H2RAs at any stage of pregnancy would not 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.

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Use of proton pump inhibitors (PPIs) in pregnancy

Haloperidol is a butyrophenone derivative ‘typical’ antipsychotic used in the treatment of a range of psychotic disorders, including schizophrenia, psychoses, mania, agitation, anxiety, and violent or dangerously impulsive behaviour. Haloperidol is also licensed for the treatment of severe tic disorders (including Tourette’s syndrome), intractable hiccups, nausea and vomiting, and chorea associated with Huntington’s disease.

Although haloperidol exposures are included in a number of studies which report fetal outcomes for cohorts of pregnant women exposed to various antipsychotics, the percentage and absolute number of haloperidol exposures in each of these cohorts is generally very small and separate analysis for haloperidol is rarely undertaken. 

The data on which to assess fetal risk of exposure to haloperidol in human pregnancy are mainly derived from published case reports, an uncontrolled case series, three controlled cohort studies, and are limited.   

No studies have been published which investigate the risk of miscarriage or stillbirth/intrauterine fetal death following in utero exposure to haloperidol specifically. Although the available data do not suggest that haloperidol use in pregnancy is associated with an increased risk of congenital malformation or abnormal birth weight, and limited data regarding neurodevelopmental outcomes are, on the whole, reassuring, increased risks for these outcomes have been reported for antipsychotics as a class of therapeutics and can therefore not be discounted. Furthermore, data are available which have also suggested increased risks of preterm delivery following typical antipsychotic exposure. However, these data are likely affected by unadjusted confounding.

Adverse neonatal effects, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorders have been reported following maternal haloperidol use in pregnancy. As such, delivery should be planned in a unit with adequate neonatal facilities for the management of poor neonatal adaptation syndrome (PNAS).

It is important to ensure that maternal mental health is treated appropriately. Where a patient is stabilised on haloperidol, either prior to conception or during pregnancy, the risk of discontinuing or changing medication, or reducing the dose, should be carefully weighed against the risk of maternal relapse. Clinicians are encouraged to discuss the advantages and disadvantages of continued haloperidol use during pregnancy with the patient. Where the benefit of continued treatment is considered to outweigh any potential or known risks, haloperidol may be prescribed for use in pregnancy. Where use of haloperidol is clinically indicated in an emergency situation, it should not be withheld on account of pregnancy.

Exposure to haloperidol 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.

Head lice (Pediculus humanus capitis) are parasitic insects that infest the hairs of the human head and feed on blood from the scalp. Head lice can be eradicated by ‘wet combing’ the lice and eggs from the hair with a fine-toothed comb and conditioner, using dimeticone-based treatments, or malathion, a chemical insecticide.

Exposure to topical head lice treatments would not be expected to cause fetal harm as they will not enter the maternal bloodstream in appreciable amounts.

The most commonly used topical head lice treatments are based on dimeticone (derived from silicone), an inert chemical widely found in antacid medications and cosmetics. There are no human pregnancy exposure data but adverse effects are not anticipated.

Malathion-based insecticide treatments for head lice are also available. There are two case reports of pregnancy outcomes following topical malathion use in pregnancy, with one malformed infant and one uneventful outcome described. Resistance to malathion has also been noted and it may be preferable, at least initially, to use other means to treat head lice during pregnancy.

Exposure to head lice treatments 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.

Hepatitis A vaccine is an inactivated vaccine and is available in the United Kingdom as a monovalent vaccine, or in combination with hepatitis B or typhoid vaccines.

Hepatitis A is generally a short-lived, self-limiting infection and serious complications are uncommon, although 10-15% of symptomatic individuals can have prolonged or relapsing disease lasting up to six months.

Hepatitis A vaccination is indicated for people at increased risk of contracting the infection (such as travellers to certain areas, or those with occupational risk), or of fulminant hepatitis, should infection occur.

Hepatitis A infection during pregnancy is not believed to pose a risk to embryofetal development, although there is some evidence that acute infection during the second and third trimesters of pregnancy is associated with gestational complications and preterm labour.

Data relating to hepatitis A vaccination in pregnancy is provided by cohort studies and clinical trials that collectively detail the outcomes of approximately 1,800 exposed pregnancies. Up to ~700 additional exposed pregnancies are detailed as case reports, largely from post-marketing surveillance/adverse event reporting systems.

Overall, the available data do not raise concern of increased risks of adverse pregnancy outcomes following gestational exposure to hepatitis A vaccines. Data relating to non-live vaccines as a class are similarly reassuring.

The UK Health Security Agency recommends that hepatitis A vaccine can be given to pregnant women if clinically indicated. Inadvertent exposure to hepatitis A vaccine at any stage in pregnancy is not 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.

Hepatitis B vaccine is an inactivated vaccine which is available in the United Kingdom as a single vaccine or as a combination vaccine against both hepatitis A and B. Hepatitis B is a blood-borne virus that is transmitted by parenteral exposure to infected blood or body fluids, including by sexual contact.

Pregnancy does not appear to alter the course of hepatitis B infection for the mother. Infection has not been associated with an increased risk of most adverse pregnancy outcomes, although increased rates of preterm delivery (often iatrogenic) have been noted. Perinatal transmission of the hepatitis B virus from mother to infant may result in infection of the neonate, with a high risk of chronicity.

Data relating to hepatitis B vaccination in pregnancy is provided by two population-based cohort studies (1,605 exposed pregnancies) and uncontrolled case reports, largely from post-marketing surveillance/adverse event reporting systems, which collectively include ~600 additional exposed pregnancies.

Overall, the available data do not raise concern of increased risks of adverse pregnancy outcomes following gestational exposure to hepatitis B vaccines. Data relating to non-live vaccines as a group are similarly reassuring.

The Department of Health in the UK recommends that hepatitis B vaccine can be given to pregnant women if clinically indicated.

Exposure to hepatitis B vaccines at any stage in pregnancy would not 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.

Hyoscine (scopolamine) is an anticholinergic agent used to relieve symptoms of smooth muscle spasm. There are two derivatives: hyoscine butylbromide (butylscopolamine, Buscopan), which is used for the symptomatic relief of irritable bowel syndrome, and hyoscine hydrobromide, which is used preoperatively to control secretions and to prevent travel/motion sickness.

There are limited data on the use of hyoscine during pregnancy, with the available data predominantly relating to off-label use for prolonged labour. Two small studies have not described associations between first-trimester hyoscine exposure and increased malformation risk. No studies have investigated risks of miscarriage, stillbirth, preterm delivery or fetal growth. Use of hyoscine derivatives during labour has been inconsistently associated with fetal tachycardia, and anticholinergic symptoms may occur in the neonate.

Data relating to the use of hyoscine, particularly in early pregnancy, are too limited to provide an evidence-based assessment of fetal risk. Therefore, the use of hyoscine during pregnancy should be reserved for cases where there is a clear clinical indication. Exposure to hyoscine derivatives 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.

Hypnotic benzodiazepine receptor agonists (HBRAs), including zolpidem and zopiclone, are licensed for the short-term treatment of debilitating or distressing insomnia.

Controlled studies describe the outcomes of more than 6,900 unique pregnancies where mothers used HBRAs in pregnancy, with more than 4,500 having been confirmed to have been exposed in the first trimester. For specific HBRAs, studies collectively describe more than 3,000 zolpidem-exposed and 1,600 zopiclone-exposed pregnancies, with confirmed first trimester exposure in more than 1,000 and 1,500 respectively. Of note, the majority of the available data are provided by studies which utilised general population unexposed pregnancies in their control groups and, as such, the possibility of data confounding cannot be excluded.

The available data do not currently provide evidence that gestational use of HBRAs as a class, or zolpidem/zopiclone specifically, is associated with an increased risk of congenital malformation overall. Individual studies investigating HBRAs as a class or HBRA/benzodiazepine use have identified possible associations with intestinal malformations, pyloric stenosis and, separately, oesophageal, anal or small gut atresia as a composite outcome. However, further research is required to confirm these observations.

Increased risks of small for gestational age and preterm delivery have been identified for both HBRAs as a class and for zolpidem specifically. Data investigating these risks for zopiclone are provided by a single small study, and while a crude increased risk of preterm delivery was described, this did not reach statistical significance, mainly due to the small study sample size.

Adverse neonatal effects of HBRA use in late pregnancy have also been described and these have included increased rates of neonatal complications overall, 5-minute Apgar scores being less than seven, neonatal respiratory complications, hypoglycaemia and CNS complications.

No controlled studies assessing the risk of miscarriage, intrauterine death, neurodevelopmental impairment or carcinogenicity have been located in the literature. The risk of these effects following HBRA exposure in pregnancy is therefore largely unknown.

Management of gestational insomnia should firstly be attempted through good sleep hygiene and/or referral to cognitive-behavioural therapy where available. Pharmacotherapy should generally be reserved for cases where these methods are ineffective, or insomnia is moderate-to-severe and impacting daily life. Alternative pharmacological treatment options, such as sedating antihistamines, antidepressants or short-acting benzodiazepines, may be preferable to the use of HBRAs for the management of insomnia in pregnancy. Discussion with UKTIS is advised in all cases.

Exposure to HBRAs at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. Due to the evidence indicating a possible association between HBRA use and impaired fetal growth, enhanced monitoring may be considered on a case-by-case basis following prolonged HBRA use in pregnancy. Neonatal monitoring may be warranted following maternal HBRA use prior to delivery. Where multiple CNS acting medications have been used around the time of delivery, synergistic effects may be expected. 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.

Haemorrhoids (piles) occur due to prolapse of the anal cushions. They are often asymptomatic; however symptoms can manifest if the haemorrhoidal veins undergo enlargement and swelling. Both over-the-counter and prescription-only topical haemorrhoid preparations are available and may contain antiseptic agents, astringents, lubricants, local anaesthetics, corticosteroids, and heparinoids in various combinations.

None of these products are licensed for use in pregnancy, although many are used routinely on the basis that the active ingredients will likely only reach the fetus in small amounts and their use is generally only recommended for short periods. Haemorrhoids usually do not manifest in pregnancy until after the first trimester and use of these products beyond this stage of pregnancy would not be expected to increase risk of structural teratogenicity. However, to allow informed choice, women wishing to use these products should be made aware of the lack of data regarding pregnancy outcomes.

Exposure to topical haemorrhoid treatments 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.

Allergic rhinitis is caused by allergens such as dust or pollen triggering an IgE-mediated immune response, leading to mast cell activation and histamine release. This results in nasal itching, swelling, and increased mucus production. Symptoms may be accompanied by conjunctivitis. Allergic rhinitis can also exacerbate asthma.

Where appropriate, non-pharmacological measures can be used for the initial treatment of allergic rhinitis, including allergen avoidance where possible, and the use of saline nasal irrigation.

If pharmacological treatment is required during pregnancy, local intranasal or ocular treatments are generally considered first-line options as these have good evidence of efficacy and low systemic absorption, which is expected to minimise fetal exposure. Options include:

• Sodium cromoglicate eye drops
• Intranasal corticosteroids:
  • Beclomethasone
  • Fluticasone
  • Budesonide

Oral antihistamines can be used during pregnancy, with second-generation agents generally preferred because of their more favourable side-effect profile. Options include:

• Cetirizine and loratadine — not known to cause harm during pregnancy
• Fexofenadine — less data than for other antihistamines, but may be considered if other treatments do not provide adequate relief
• Chlorphenamine — preferred where a sedating option is required

Montelukast may be continued during pregnancy when prescribed for co-existing asthma. Decongestants are avoided during pregnancy because of the theoretical risk that their vasoconstrictive effects could alter placental perfusion.

The available pregnancy safety data for each treatment option, together with the limitations of these data, should be discussed with the patient. 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.