Letter: H

Histamine H₂-receptor antagonists (cimetidine, famotidine, nizatidine and ranitidine) reduce gastric acidity through inhibition of gastric acid production. H₂-receptor antagonists 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. The British National Formulary (BNF) suggests ranitidine as the preferred H₂-receptor antagonist for use in pregnancy after lifestyle modification and antacid or alginate treatment have proved unsuccessful in controlling symptoms, or are not considered appropriate.

Data regarding the risk of adverse pregnancy or fetal outcomes following exposure to H₂-receptor antagonists 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 H₂-receptor antagonists 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 spontaneous abortion, intrauterine death, low infant birth weight, preterm delivery, neonatal complications or adverse neuro-developmental outcomes do not appear to be increased following exposure to H₂-receptor antagonists. However, studies of individual drugs are too small to draw definitive conclusions.

An increased risk of childhood asthma following maternal exposure to H₂-receptor antagonists has been reported; however, as data are conflicted and possibly confounded, further research is required.

Exposure to H₂-receptor antagonists 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 motor tics, intractable hiccups, nausea and vomiting, and Tourette syndrome.

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, a controlled cohort study, and are extremely limited.   

No studies have been published which investigate the risk of spontaneous abortion, stillbirth/IUD or neurodevelopmental impairment 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 anomaly or abnormal birth weight, increased risks for these outcomes have been reported for antipsychotics as a group and can therefore not be discounted. Furthermore, data are available which have also suggested increased risks of preterm delivery and neurodevelopmental impairment following typical antipsychotic exposure. However, the possibility of data confounding cannot be excluded.

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 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 relapse of the maternal condition. Where clinically appropriate, 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 Department of Health in the UK 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 one population-based cohort study (n= 1,400 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.

Heroin (Diamorphine hydrochloride) is a synthetic opiate used legitimately as an analgesic for severe pain and illicitly as a drug of abuse.  Heroin is mainly abused intravenously but it can also be snorted, smoked or ingested.

Reports of heroin use during human pregnancy are confounded by poor nutritional and health status, exposure to other drugs of abuse, alcohol, cigarettes and other lifestyles that may negatively influence pregnancy outcome.  Despite these added risk factors, most of the data concerning heroin use in human pregnancy provides no convincing evidence for an increased risk of structural malformations.  There is evidence to suggest that in utero exposure to heroin may be associated with impaired neurodevelopment in the offspring, however this research also suffers from similar confounders as those mentioned above.

Intrauterine growth retardation (IUGR) and low birth weight are frequently observed in infants of heroin users and studies have also suggested an increased risk of sudden infant death syndrome (SIDS).

Acute heroin withdrawal has been associated with spontaneous abortion, preterm labour and perinatal mortality.  Substitution with methadone maintenance treatment appears to improve neonatal outcomes although the period of neonatal withdrawal symptoms may be prolonged.  If methadone substitution is used, the lowest effective dose should be given, especially near term, to minimise neonatal withdrawal.

Use of heroin near term may cause neonatal respiratory depression and long-term use may be associated with neonatal abstinence syndrome.  Following maternal use of heroin during pregnancy it is advisable that the baby is observed for at least 72 hours after delivery.

The use of heroin should be avoided during pregnancy, however inadvertent exposure would not be grounds for termination of pregnancy or any additional diagnostic procedures.

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

There are limited data on the use of hyoscine during pregnancy, with the available data predominantly relating to use at the time of delivery. Two small studies have not described associations between first trimester hyoscine exposure and an increased risk of malformation. No studies have investigated risks of miscarriage, stillbirth, preterm delivery or impaired fetal growth. Maternal administration of hyoscine derivatives during labour has been inconsistently associated with fetal tachycardia, and anticholinergic symptoms may occur in the neonate. The use of hyoscine during pregnancy may be justified if 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.

Allergic rhinitis results when allergenic materials such as dust or pollen are inhaled by a sensitised individual. The immune response involves the production of immunoglobulin E (IgE) which binds to mast cells causing the release of histamine. Histamine release results in mucus production, swelling and itching of the nasal membrane. Atopic conjunctivitis and secondary effects, as well as exacerbation of pre-existing asthma can also occur.

Based on The British Society for Allergy and Clinical Immunology (BSACI) guidelines for the diagnosis and management of allergic and non-allergic rhinitis (2017), initial treatment of allergic rhinitis would be via non-pharmacological measures such as allergen avoidance, use of barrier ointment around the nares/nasal filters and nasal saline irrigation. In pregnant patients, if these measures are insufficient, topical (intranasal/ocular) mast cell stabilisers such as sodium cromoglicate or intranasal corticosteroids should then be considered. These preparations act locally and have lower systemic absorption than oral preparations, therefore reducing fetal exposure. Where local topical therapy fails to control symptoms, oral antihistamines may be considered. Antihistamines for which human pregnancy data are available should ideally be used in preference to those for which epidemiological data are very limited or not available. The sedating effects of chlorphenamine should also be considered and the risks associated with maternal drowsiness taken into account before use in pregnancy is suggested.

Use of decongestants should be avoided due to theoretical concerns of vasoconstrictive effects affecting placental and fetal perfusion. Due to the lack of data, leukotriene receptor antagonists should also be avoided for the treatment of allergic rhinitis alone; however, they may be continued if they are already being used to treat concomitant asthma.

The available pregnancy safety data and its limitations 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.

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.