Principles of drug use and management in pregnancy

The tragedy of thalidomide, a drug that was used to treat nausea and vomiting in pregnancy but caused severe limb deformities in babies in the 1950s and 1960s, led to the creation of the UK’s Committee on the Safety of Drugs (later, the Committee on the Safety of Medicines) and the Medicines Act of 1968​[1,2]​. Thalidomide was withdrawn from use in the UK in 1961, after being on the market for five years​[1,2]​.

In addition to that legislation being passed, a range of supporting resources have been developed to improve the safety of drug use in pregnancy, including:

• Websites (e.g. TOXBASE);
• National guidelines (e.g. National Institute for Health and Care Excellence guidance and Royal College of Obstetricians and Gynaecologists ‘Green-top’ guidelines);
• Medication safety alerts relating to pregnancy from the Medicines and Healthcare products Regulatory Agency (MHRA);
• Academic resources that collate and synthesise findings from different clinical studies;
• Drug company datasheets that include information relevant to pregnancy;
• Specialised centres, such as the UK Teratology Information Service​[3]​.

Despite this improved knowledge base, prescribing in pregnancy remains challenging for healthcare professionals. There are concerns about teratogenicity and how the physiological changes of pregnancy affect the pharmacokinetics and pharmacodynamics of medications​[4]​. A lack of robust clinical trials, owing, in part, to the ethical difficulties for recruiting pregnant women in studies, can result in limited information regarding potential adverse foetal effects and pregnancy outcomes of new medications​[4,5]​.

In the UK, more than 80% of women report taking medicines during their pregnancy​[5]​. Recent studies in the UK estimated 65% of pregnant women had been prescribed at least one medication​[4]​. Congenital malformations are present in 2–3% of newborn babies, with approximately 1–2% of this total being associated with exposure to a teratogen​[4,6]​.

The number of women needing to take medicines during pregnancy is increasing, partly because of advancing maternal age, increased incidence of pre-existing medical conditions that require pharmacotherapy (e.g. lupus, heart disease, transplant recipients), and/or the development of obstetric complications during pregnancy (e.g. gestational diabetes, obstetric cholestasis, COVID-19 infection)​[4,6–9]​. Hence, the provision of medical and pharmaceutical care in this group of patients becomes more complex.

It is important for the obstetric pharmacist to work closely with doctors, nurses, midwives and patients on care plans that optimise the safety and efficacy of drug use during pregnancy, and to provide patient counselling services when needed. It is also crucial for the specialised pharmacist to have a sound grasp of the literature and problem-solving skills when addressing queries on drug use in pregnancy.

Most of the drugs used in pregnancy are unlicensed in terms of the indications and the specific patient group because of a lack of robust clinical trials. However, the available national guidance, online evidence-based databases, relevant academic resources and professional advice available from specialised centres can all help healthcare professionals with decision-making on treatment options for pregnant women. There is also useful information available for patient counselling regarding drugs use in pregnancy​[3]​.

Teratogenicity

Teratogenicity is the ability of a drug to cause foetal abnormalities or deformities​[10]​. Teratogens are defined as agents or factors that cross the placenta causing congenital malformations​[6]​. They can directly or indirectly cause structural or functional abnormalities in the foetus or in the infant after birth, some of which may not be apparent until later in the child’s life​[5,6,10]​. Examples of late-onset effects include adenocarcinoma of the vagina after puberty in females exposed to diethylstilbestrol in the womb, and adverse effects on intellectual, social and functional development​[10]​.

Teratogens can cause harmful effects on the embryo or foetus at any time during pregnancy, but they do not always cause abnormalities in all foetuses that have been exposed​[5]​. For example, thalidomide caused abnormalities in less than half of all foetuses exposed during the critical period (for this drug, 20–36 days after fertilisation)​[6]​.

The foetal response to a teratogen is influenced by factors such as the dose, route and timing of exposure, and genetic and environmental factors​[4,6,11]​. An example of dose-dependent teratogenicity is the incidence of major congenital malformations with carbamazepine​[6]​. In addition, the risk of teratogenicity may also increase if the number of concomitant drugs is increased; for example, the incidence of foetal malformations increases with the number of antiepileptics taken​[6]​. The timing of exposure to a drug is a critical factor to determine the extent of any adverse effects and the type of birth defect. The three important phases in human development are illustrated in Table 1​[4,6]​.

Most drugs cross the placenta to reach foetal circulation by simple diffusion​[6]​. The extent to which compounds will cross the placenta depends on their molecular size, degree of ionisation, protein binding and lipid solubility​[6]​. Non-ionised, lipid-soluble drugs will cross in preference to polar, ionised, hydrophilic compounds​[6]​.

Drugs with higher molecular weight tend not to cross the placenta, but there are exceptions, such as infliximab and adalimumab​[6]​. Since adalimumab can cross the placenta into the serum of infants born to women treated with this drug, the manufacturer states that these infants may be at increased risk of infection. Therefore, administration of live vaccines to infants exposed to adalimumab in utero is not recommended for five months following the woman’s last adalimumab dose during pregnancy​[12]​.

Table 2 lists drugs that are absolutely contraindicated in pregnancy​[3,10,13–16]​.

Most drugs with a molecular weight of less than 1,500 Da can cross the placenta and potentially affect a foetus​[16]​.

Drugs that are relatively contraindicated in pregnancy

Other drugs with proven teratogenic effects in humans that are advised to be avoided during pregnancy include:

• Lithium
• Antibiotics
  • Tetracyclines (e.g. tetracycline, doxycycline, oxytetracycline). All tetracyclines are contraindicated in the second and third trimesters. These drugs can cause discolouration of deciduous teeth and may have transient effects on foetal bone growth. Tetracyclines may also exacerbate fatty liver of pregnancy. In animal studies, effects on skeletal development have been documented in the first trimester.
  • Quinolones (e.g. ciprofloxacin, levofloxacin, moxifloxacin, nalidixic acid, norfloxacin and ofloxacin). Quinolones have been shown to cause arthropathy during neonatal exposure in animal studies.
  • Chloramphenicol (oral and injection). Owing to the risk of serious haematological side effects, systemic use of chloramphenicol is reserved for the management of life-threatening infections. There are concerns that use near term may be associated with a risk of neonatal ‘grey baby syndrome’, in which the baby has a life-threatening reaction to chloramphenicol, one sign of which is an ashen grey colour of the skin; however, there are no well-documented cases of this occurring. The available data do not indicate that use of ocular chloramphenicol is associated with an increased incidence of congenital malformations; however, other outcomes have not been sufficiently studied to exclude a risk.
  • Nitrofurantoin (avoid near term). There is a risk of causing haemolytic anaemia in newborns when used near term.
• Terbinafine (antifungal). Although the animal reproduction data are encouraging, the lack of human pregnancy experience does not allow a full assessment of the foetal risk from terbinafine. If possible, it would be safer to wait to start treatment until after a pregnancy has completed.
• Anticoagulants
  • Warfarin
  • Newer oral anticoagulants
• Dapsone (antileprotic; avoid in third trimester)
• Anti-malarials (avoid in first trimester)
  • Mefloquine
  • Primaquine
  • Atovaquone with proguanil
  • Artemether with lumefantrine
• Anticonvulsants
  • Phenobarbitone
  • Phenytoin
  • Sodium valproate
• Valproate (anti-epileptic)
• Cardiovascular drugs
  • Beta blockers (avoid the use of atenolol in first trimester)
  • Minoxidil
  • Diuretics (but appropriate to be used in treatment of pulmonary oedema)
  • Spironolactone (feminisation has been observed in male rat foetuses)
• Endocrine drugs
  • Octreotide
  • Chlorpropamide​[3,10,11,13,17–20]​.

If the benefit clearly outweighs the risk (e.g. in life-threatening disease), some ‘relatively contraindicated’ drugs can be used in pregnancy under specialist advice​[13]​. For example, warfarin is used in women with prosthetic heart valves disease, and anti-epileptic drugs are used in women with epilepsy​[13]​. The anti-epileptic drugs lamotrigine and levetiracetam are safer than other anti-epileptic drugs in pregnancy​[20]​. Such decisions should be agreed with the patient in a multidisciplinary team setting of senior clinical staff and after extensive patient counselling, if a less-teratogenic option is not available.

Role of the obstetric pharmacist

The role of the obstetric pharmacist has evolved from supplying medicines, screening in-patient drug charts and providing discharge prescriptions, to more advanced responsibilities​[21,22]​. Pharmacists address queries from patients, midwives and doctors in relation to drug use in pregnancy and breastfeeding, using the latest clinical evidence, and counsel patients when needed in the hospital and after discharge. Other roles include clinical guidelines review and patient group direction development, which involve: close liaison with the multidisciplinary team; evaluation of new drug applications; critical appraisal of unlicensed drugs use; antimicrobial stewardship; training and education for midwives, doctors and junior pharmacists; electronic prescribing enhancement; research and development, including pharmacogenetic areas, involvement of medication incidents management and suggestion of improvement action plans; and service development and quality improvement in a multidisciplinary team setting.

How pregnancy affects pharmacokinetics

Substantial anatomical and physiological changes occur during pregnancy. These changes can affect the pharmacokinetics (absorption, distribution, metabolism and excretion) of drugs in pregnant women​[18,29,30]​. Changes in pharmacokinetics during pregnancy can have an impact on drug efficacy and toxicity.

The overall changes in physiological parameters during pregnancy take place progressively throughout three trimesters​[30,31]​. The increase in cardiac output, total body water, fat compartment and glomerular filtration rate, as well as the decrease in plasma albumin concentration and altered activity of drug-metabolizing enzymes, are all reported to be at the highest level during the third trimester​[30,31]​.

The major changes in pharmacokinetics during pregnancy are outlined in Table 3​[18,30,32–37]​.

COVID-19 management in pregnancy

The majority of COVID-19-positive pregnant women are either asymptomatic or experience mild to moderate cold or flu-like symptoms​[37]​. Pregnant or recently pregnant women with COVID-19 are more than twice as likely to require admission into intensive care or require invasive ventilation, compared with non-pregnant women​[38]​. COVID-19 infection is also associated with an increased risk of pre-term birth and, although rare, stillbirth​[37,39]​.

Maternal risk factors associated with both COVID-19 infection and admission to hospital include:

• Being unvaccinated;
• Age ≥35 years;
• Black or ethnic minority background;
• Body mass index ≥25kg/m²;
• Any pre-pregnancy comorbidity (e.g. chronic hypertension or diabetes)​[37–39]​.

Recommendations for COVID-19 vaccination in pregnancy

COVID-19 vaccination is strongly advised for all pregnant women by the Royal College of Obstetricians and Gynaecologists​[37,40]​. Pregnant women should be offered the primary and reinforcing vaccination; the Pfizer-BioNTech or Moderna mRNA vaccines are the preferred options because of the large post-marketing experience​[37,40]​. Vaccination can be offered at any time during pregnancy​[37]​. If one dose of the Oxford/AstraZeneca vaccine is given, then the course should be completed either with a further dose of the same vaccine or an mRNA vaccine​[37,40]​.

Patients should be advised of the benefits of vaccination during pregnancy, which include:

• Reduced risk of developing severe COVID-19 infection and requiring hospitalsation;
• Potential reduced risk of pre-term birth associated with COVID-19;
• Potential reduced risk of stillbirth associated with COVID-19;
• Potential protection for neonate via passive antibody transfer;
• Potential reduced risk of transmission to vulnerable household members​[37]​.

Use of mRNA COVID-19 vaccines has been shown to produce similar antibody titres between pregnant and non-pregnant women and generate greater antibody titres, in comparison with active infection during pregnancy​[41,42]​. Vaccine-generated antibodies were found in umbilical cord blood and breast milk, indicating the passive transfer of antibodies from mother to neonate​[37,41,42]​.

Although pregnant patients were not included in the large clinical trials investigating the safety profile of COVID-19 vaccines, current available data do not indicate any safety concerns associated with use in pregnancy​[37,40,43,44]​. The side effect profile of COVID-19 vaccines is similar between pregnant and non-pregnant women​[41,44]​. Pregnancy outcomes (specifically premature delivery, low birth weight and stillbirth) were similar in women vaccinated during pregnancy compared with pregnant women who were not vaccinated​[44]​.

Research involving the safety, immunogenicity and scheduling of COVID-19 vaccines in pregnant women is ongoing​[37]​. This includes a worldwide, randomised, controlled trial in which pregnant women will receive either Pfizer-BioNTech vaccine or placebo to obtain safety and immunogenicity data (women given the placebo will be offered the vaccine once they give birth)​[37,45]​. The HORIZON 1 trial by Janssen plans to investigate the dosing schedule of the Ad26.COV2.S vaccine​[37,45]​. Lastly, the Preg-CoV trial, led by St George’s, University of London, aims to give pregnant women different vaccines on different schedules to identify the optimal vaccination schedule​[37,46]​.

Management of COVID-19 in pregnancy

Pregnant women admitted to hospital with COVID-19 infection should be managed in the same manner as non-pregnant women: by using oxygen, venous thromboembolism prevention, corticosteroids, interleukin-6 inhibitors and monoclonal antibodies (where appropriate and if NHS England commissioning criteria are met)​[37]​. As the treatment of COVID-19 is constantly evolving, pharmacists must keep up to date with national recommendations from the Royal College of Obstetricians and Gynaecologists and the NHS. Table 4 outlines the current drug therapies available for COVID-19 and NHS England recommendations for use in pregnant women​[21,37,38,47–62]​.

UK COVID-19 Antivirals Pregnancy Registry

As the safety of COVID-19 antivirals in pregnancy has not been established, healthcare staff, pregnant women and their partners are all advised to report use of antivirals taken around conception or during pregnancy (both maternal and paternal use) to the UK COVID-19 Antivirals Pregnancy Registry.

The UK COVID-19 Antivirals Pregnancy Registry is being operated by the MHRA in collaboration with the UK Teratology Information Service to collect information about exposures to COVID-19 antivirals in pregnancy and enable follow-up of any reported pregnancies; the registry is also collecting information on outcomes for pregnancies where conception occurred during or shortly after paternal exposure to antiviral treatment​[63]​.

Summary

The antenatal and postnatal care of women is becoming increasingly complex, especially during the COVID-19 pandemic. The increased use of medications during pregnancy makes it a challenging area for healthcare professionals. The role of the obstetric clinical pharmacist has evolved from supply and prescription screening to that of a more advanced practitioner. The pharmacist is now required to be actively involved in patient care by collaborating closely with the multidisciplinary team and adopting an evidence-based approach. The specialised pharmacist also participates in guideline development, research and development, service improvement in the multidisciplinary team setting and critical evaluations of unlicensed drugs use. With these emerging clinical leadership roles, obstetric clinical pharmacy has become a rewarding and exciting career for pharmacists who have a special interest in this field and who enjoy working with a dedicated team of doctors, midwives, nurses and other healthcare staff.