Chapter 49 Pharmacology and childbirth
Most women are exposed to drugs of one type or another during pregnancy. The drugs may be prescribed or bought over the counter. They may be given as part of the management of the pregnancy itself or that of a coincidental medical problem. However, when considering the use of any drugs in a pregnant or breastfeeding woman, it is important to consider the effects of the drug not only on the woman herself, but also on the fetus or neonate. Many drugs have undesirable effects on the fetus and should therefore be avoided during pregnancy. On the other hand, some drugs are given to the woman because of their therapeutic effects on the fetus. For example betamethasone or dexamethasone are given to women at risk of preterm birth because of their effects on fetal lung maturation. It is therefore important to have a working knowledge of the issues surrounding the use of drugs in pregnancy and the puerperium so that women can be correctly informed and advised regarding the potential benefits and risks.
A drug administered to a pregnant woman or a breastfeeding mother will, in most cases, be present in the blood circulating around her body. Exceptions are certain types of drugs that are not absorbed from the area where they are administered – for example some (but not all) skin creams. The maternal blood circulation will then take the drug to the placenta or breast, which are organs designed to allow the passage of substances from maternal blood into either fetal blood or milk, respectively. Drugs will pass across into the fetus or neonate in greater or lesser quantities depending on the characteristic of the drug molecules themselves. Some drugs will not pass across into the fetus or milk at all, whereas others will pass freely. The factors influencing passage across the placenta and breast are the size of the molecule, the ionization of the molecule, the lipid or water solubility and the protein binding. In general, large molecules do not cross the placenta and small molecules cross very easily.
There are many physiological changes in pregnancy that influence the way in which the mother’s body handles the drugs administered to her. These can result in differences in the circulating concentrations of the drug compared with those in a non-pregnant woman. The transit time in the gut is prolonged compared with that in the non-pregnant woman and this may result in changes in absorption of orally administered drugs (Parry et al 1970). The circulating plasma volume is increased and this results in an increased volume in which a defined dose of drug is distributed which leads to a decrease in the plasma concentration of the drug. Because there is an increase in the blood flow to the kidneys (Dunlop 1976), which are responsible for the elimination of many drugs, there may be an increase in the rate of excretion of a drug. The amounts of total body water and fat are increased (McFadyen 1989) and this may alter the distribution of the drug. Some metabolic pathways in the liver increase and therefore may result in quicker metabolism of a drug. There are also major changes in the levels of plasma proteins to which some drugs bind and this may affect the amount of drug that is available to exert its effect on the body.
Many drugs have adverse effects during pregnancy. These vary depending on the stage of pregnancy. One of the major problems in giving advice to women is the paucity of information available regarding the effects of drugs in pregnancy and breastfeeding. In most cases it is not ethical to perform randomized trials of drugs in pregnancy where their effects are unknown. Drug companies are also reluctant to promote or to license the use of their drugs because of the potential problems and the cost of subsequent litigation. Therefore, most evidence regarding the safety or otherwise of drugs in pregnancy and breastfeeding is accumulated through inadvertent use, or use in unlicensed circumstances. Indeed, many of the drugs that are now commonly used in pregnancy are still not licensed for use. Because of the way information is accumulated, there is a bias towards reporting of adverse events. In general, when choosing a drug to use in pregnancy, clinicians should use those agents that have been available for longest and about which most information has been collected. New agents should be avoided if possible.
The word ‘teratogen’ refers to a substance that leads to the birth of a malformed baby. Organogenesis occurs between approximately 18 and 55 days’ post-conception (i.e. 4–10 weeks of pregnancy). A drug can cause a structural abnormality in a fetus only if it is present in the body during this time. This is an important consideration since it is a stage of pregnancy when a woman may not be aware that she is pregnant or may not have attended her midwife or doctor for advice. It is often the case, therefore, that exposure to a potentially teratogenic drug may have already happened before the woman is seen for the first time.
Identifying teratogenic drugs is not an easy process. It is unethical to expose human fetuses to drugs with unknown effects as part of a trial. Drug companies will often try to overcome this by performing animal studies. However, this will neither confirm nor refute that a drug is teratogenic in humans since there is wide interspecies variation. A well-known example of this is the drug thalidomide, which was marketed in the 1960s for sickness in pregnancy. Some 10 000 cases of limb abnormalities were reported before thalidomide was identified as a teratogen. No toxic effects had been noted in animal experiments because thalidomide is a teratogen only in primates.
Because prospective research on teratogenicity in humans is unethical, we rely on case reports and case studies. These can be misleading, however. If a woman has a baby with an abnormality and she took a certain drug in the first trimester, inevitably an association would be drawn. However, there is a background rate of fetal abnormalities of around 2–3% and an association cannot exclude a chance relationship. Larger cohort studies of several women exposed to the same drug who have offspring with the same abnormality are more reliable indicators.
Some of the commonly used drugs known to be teratogens are detailed in Table 49.1.
Table 49.1 Commonly used drugs that are teratogens
| Drug | Effect |
|---|---|
| Lithium | Cardiac defects |
| Warfarin | Facial anomalies, CNS anomalies |
| Sodium valproate | Neural tube defects |
| Phenytoin | Craniofacial abnormalities |
| Retinoic acid derivatives | Craniofacial, cardiac and CNS anomalies |
Drugs may also exert other adverse effects on pregnancy. Any process that occurs during development of the fetus can be affected. For example β-blockers affect fetal growth (Butters et al 1991), angiotensin-converting enzyme (ACE) inhibitors cause fetal renal failure (Kreft-Jais et al 1988) and iodine affects fetal thyroid function. Some drugs may not cause a problem at one stage of pregnancy but may do so at another. For example, there is a risk that the commonly used antibiotic, trimethoprim, is teratogenic when given in the first trimester because it interferes with folate metabolism; however, it is safe in later pregnancy. On the other hand, non-steroidal antiinflammatory drugs (NSAIDs), such as ibuprofen and diclofenac may be relatively safe if used in the first trimester but can cause premature closure of the ductus arteriosus and oligohydramnios if used in the third trimester. The most difficult effects to quantify are those which relate to neurodevelopment and behaviour. There is growing concern about the relationship between some drugs taken in pregnancy and neurodevelopmental and behavioural problems in later childhood.
Where possible, drugs should be avoided in the first trimester. Obviously, this is not always possible, and in some women it is imperative that a drug that is known to be teratogenic is not stopped abruptly during pregnancy. For example, a woman with epilepsy who is controlled with sodium valproate should not stop her medication abruptly despite the risk of neural tube defects as a prolonged seizure could have devastating effects on both her and her fetus. Where a woman on long-term medication is planning a pregnancy it is advisable for her to attend for pre-pregnancy counselling where plans can be made to minimize the risk.
If a new drug is to be started in pregnancy, one should be chosen that is ‘safe’. Women should be informed about the potential risks of any medication they are prescribed. Where a woman is exposed to a teratogen during the first trimester then discussion with an appropriate consultant should be offered to explore the possible outcomes and allow the woman to make informed choices about her pregnancy.
Many drugs are prescribed for therapeutic reasons in pregnancy. It is therefore useful for the midwife to have a working knowledge of the drugs, their possible side-effects and contraindications. In the following sections, where specific references are not given, much of the information is gained from Briggs et al (2005) and Weiner and Buhimschi (2004).
It is recommended that all women planning a pregnancy should take folic acid in a dose of 400 μg daily and that this should continue throughout the first trimester. Folic acid is a vitamin that is involved in the process of cell growth and division. Demand for folate increases in pregnancy. It has been shown that peri-conception folic acid supplementation reduces the risk of neural tube defects (Lumley et al 2000). In addition, folic acid deficiency can lead to maternal anaemia so folic acid supplementation in later pregnancy can also be beneficial. The recommended dose in the general population is 400 μg daily, but women at risk of neural tube defects (e.g. with a previously affected fetus, or on carbamazepine or sodium valproate) should receive 5 mg daily. There are no risks associated with folic acid at this dose.
Iron deficiency anaemia is common in pregnancy and iron preparations are frequently prescribed. There are many preparations on the market based on either ferrous sulphate or ferrous gluconate. Some are combined with folic acid. Commonly experienced side-effects are constipation (occasionally diarrhoea) and indigestion. Stools are coloured black. When side-effects are a problem, it may be worth trying a different preparation. It should be noted that absorption of iron is reduced by antacids and by some foods (e.g. tea).
Antacids are alkalis that act by reducing the acidity of stomach acid. Modern antacid drugs are mostly based on calcium, magnesium and aluminium salts, which are relatively non-absorbable. They are often combined with alginates, which coat the lining of the oesophagus and stomach and therefore reduce contact with stomach acid. Because they are relatively non-absorbable, they are safe for use in pregnancy. Older antacids such as sodium bicarbonate can cause systemic alkalosis and should be avoided.
Nausea and vomiting may be particularly troublesome in the first trimester but may occur at other times in pregnancy. Where possible, women with mild ‘morning sickness’ should be encouraged to try non-pharmacological methods of controlling nausea such as eating small amounts frequently. If vomiting is a significant problem then it is preferable to use an antiemetic drug rather than risk dehydration and, in the most severe cases, malnutrition. Most of the commonly used antiemetics are considered safe to use in pregnancy and, as always, the older preparations have a longer established safety profile.
The drugs fall into four main categories:
Rarely, in young people these, e.g. prochlorperazine, may cause a dramatic side-effect known as a ‘dystonic’ reaction or ‘occulogyric crisis’, where there is uncontrolled spasm of the muscles of the face and neck.
This is a relatively new class of antiemetics, e.g. ondansetron. There is now one reasonable sized study of its use in pregnancy without any increase in fetal abnormalities (Einarson et al 2004). However, it should be used with caution, only in those whose vomiting fails to respond to other drugs.
Antibiotics are one of the most commonly prescribed groups of drugs in pregnancy. They are a diverse group of compounds and have different indications and risks. There are definite indications for the use of antibiotics, but care should be taken as some are safe and others are contraindicated. Table 49.2 indicates some of the antibiotics with which caution should be exercised. Table 49.3 indicates those antibiotics considered safe for use in pregnancy.
Table 49.2 Antibiotics that can cause adverse effects in pregnancy
| Antibiotic group (examples) | Risk |
|---|---|
| Tetracyclines (tetracycline, oxytetracycline, doxycycline) | Discoloration and dysplasia of fetal bones and teeth when used in second and third trimester |
| Aminoglycosides (gentamicin, netilmicin) | Risk of ototoxicity but often used in serious maternal infection where benefit outweighs risk |
| Chloramphenicol | ‘Grey baby syndrome’ when used in second and third trimester |
| Nitrofurantoin | Haemolysis in fetus at term – avoid during labour and birth but safe at other times |
| Quinolones (ciprofloxacin, ofloxacin) | Arthropathy in fetus – most of this evidence has been obtained from animal studies |
Table 49.3 Antibiotics that are considered safe in pregnancy
| Antibiotic | Notes |
|---|---|
| Penicillins (benzyl penicillin, phenoxymethyl penicillin, ampicillin, amoxicillin, co-amoxyclav, flucloxacillin) | Alternatives if allergic |
| Cephalosporins (cephradine, cephalexin, cefuroxime, cefotaxime) | |
| Erythromycin | |
| Clindamycin | |
| Trimethoprim | Avoid in first trimester |
It is relatively common for a pregnant woman to require analgesia during pregnancy. This may be for something as simple as a headache, a more significant problem such as rheumatoid arthritis, or for a pregnancy-related condition, such as pelvic girdle pain. However, many of the available analgesics, including ‘over-the-counter’ preparations, are not considered safe in pregnancy, so it is often difficult to control chronic pain satisfactorily.
This is one of the drugs which has a long and unblemished safety record when taken in therapeutic doses. It should be the recommended first-line analgesic agent in pregnancy. However, in overdose it can be potentially lethal to the mother or fetus, or both, as it causes liver failure.
Ibuprofen is widely available as an over-the-counter preparation. These drugs may be relatively safe in the first trimester but have the potential to cause fetal renal dysfunction, premature closure of the ductus arteriosus, necrotizing enterocolitis and intracerebral haemorrhage (Norton et al 1991). Indomethacin has been used on a short-term basis as a tocolytic agent and to reduce liquor volume in polyhydramnios, but should not be used in the long-term because of the above risks. These drugs are safe in breastfeeding.
When used in analgesic doses, there is no clear evidence of teratogenesis with these drugs, e.g. pethidine, morphine, diamorphine, codeine, dihydrocodeine. For acute episodes there is probably little risk with the use of these drugs. However, with long-term use there is a risk of neonatal withdrawal after birth, in a similar pattern to the withdrawal symptoms seen with opiate abuse. This neonatal withdrawal can be demonstrated even in women using relatively moderate doses of codeine such as those available in over-the-counter preparations. When given in large doses in labour there is a risk of respiratory depression.
In analgesic doses, aspirin has been shown to increase the risk of maternal, fetal and neonatal bleeding because of its effect as an antiplatelet agent. Aspirin at an analgesic dose is therefore contraindicated in pregnancy. A common analgesic dose is 600 mg every 6 hrs. Aspirin in these doses is present in many commercially available cold remedies and analgesic preparations.
However, in low doses (75 mg daily) aspirin is used in pregnancy for treatment of women with recurrent miscarriage, thrombophilias (inherited risk of thromboembolism), and prevention of pre-eclampsia and intrauterine growth restriction. In low dose, there is evidence to suggest that there is no increased risk of maternal or neonatal haemorrhage (CLASP Collaborative Group 1994). Aspirin exerts its antiplatelet effect for around 10 days after administration and may prolong the bleeding time. Some clinicians therefore prefer to discontinue aspirin 3–4 weeks prior to birth to prevent complications as a result of this.
Antihypertensive drugs may be prescribed in pregnancy for pre-existing hypertension, pregnancy-induced hypertension or pre-eclampsia. Several of the drugs which are used in young women outside pregnancy are contraindicated in pregnancy and it is therefore important to recognize this and arrange for alternative medication if necessary.
These drugs, e.g. captopril, enalapril, lisinopril, are known to cause oligohydramnios, fetal anuria and stillbirth when used in the second and third trimester and are therefore contraindicated in the second part of pregnancy. Many young women are on these drugs and until now have been informed to stay on them until they are confirmed to be pregnant and change thereafter to a different agent. However, recent evidence suggests that there is an increased risk of fetal abnormalities when they are taken in the first trimester (Cooper et al 2006) and therefore, ACE inhibitors should be used only with caution even in the first trimester.
This drug has been available for many years. There is extensive experience with its use in pregnancy and there is no evidence of adverse effects on the fetus. It is one of the first-line antihypertensive drugs for use in pregnancy. The disadvantage is the maternal side-effect profile, which includes lethargy, drowsiness and depression. These side-effects may be dose dependent. It is given in 2–4 divided doses from a starting dose of 250 mg three times daily up to a total of 3 g daily. The onset of action is slow and it is therefore not suitable for acute blood pressure control. Caution should also be taken when stopping methyldopa in women who have been taking it for several weeks as sudden withdrawal may cause insomnia and anxiety symptoms. It should therefore be stopped gradually. It is safe in breastfeeding.
β-blockers, e.g. propranolol, atenolol, labetalol (which also has some α-blocking activity), act by reducing heart rate and stroke volume and therefore reducing cardiac output. Although they cross the placenta and may slightly reduce fetal heart rate, there is no significant change in variability. If commenced before 28 weeks’ gestation they have been shown to cause a reduction in fetal growth in up to 25% of cases (Butters et al 1991). They are therefore good antihypertensive drugs for use in the third trimester, but caution should be taken earlier in pregnancy. β-blockers are contraindicated in women with asthma as they may cause bronchoconstriction. β-blockers are excreted into breastmilk and some (e.g. atenolol) may actually be concentrated in breastmilk. However, there are no reports of adverse effects on neonates and they are therefore considered safe in breastfeeding.
These, e.g. nifedipine, nicardipine, reduce blood pressure mainly by vasodilatation. Nifedipine is increasingly used as an agent in pregnancy. Nifedipine can be given in a rapid release formulation orally to reduce blood pressure quickly in acute situations. However, care should be taken as serious hypotensive reactions have been reported, especially in association with magnesium sulphate (Waisman et al 1988). In general, nifedipine should be given in slow release formulations as these have a more gradual onset and longer period of action. The major side-effect is a headache, which may cause difficulty when determining symptoms of pre-eclampsia. Nifedipine is considered safe in breastfeeding.
These drugs, e.g. glibenclamide, gliclazide, should be avoided since they cross the placenta and exert an effect on the fetus.
The drugs commonly used in the treatment of asthma include: inhaled bronchodilators (e.g. salbutamol, salmeterol, ipratropium), inhaled chromoglycate, inhaled and oral corticosteroids and theophyllines. All of these drugs are considered safe. Indeed, in either an acute asthmatic attack or in an exacerbation of asthma, the benefits of the medication outweigh the risks to mother and fetus.
A degree of anticoagulation may be required in some women in pregnancy in several situations, such as a history of a previous thromboembolic problem, an acute event, a known thrombophilia or heart valve replacement. There are two main anticoagulant drugs: heparin and warfarin.
This drug crosses the placenta and is a teratogen, the critical time of exposure being 6–9 weeks’ gestation. The risk of ‘fetal warfarin syndrome’ is around 10% of those exposed but there is also an increase in central nervous system abnormalities. The characteristics of fetal warfarin syndrome are: nasal hypoplasia, epiphyseal abnormality, eye defects, shortening of the extremities, deafness, developmental retardation, congenital heart disease and scoliosis. Women on long-term warfarin should therefore be aware of the risks and should be asked to inform their doctor immediately they become pregnant. In the second and third trimester, there is a risk of fetal intracerebral haemorrhage.
Generally, women on warfarin should be converted to heparin as soon as they become pregnant and will continue on heparin throughout pregnancy. The exception may be women with metal prosthetic heart valves who have an extremely high risk of thromboembolic complications and in whom the maternal risks of stopping treatment may outweigh the fetal risks of continuing on warfarin.
Warfarin is safe in breastfeeding and may be safely commenced in postpartum women.
The drug has a very gradual onset of action and requires a loading dose to be given over 2 or 3 days. The dose required is very variable and it is judged by monitoring the INR (international normalized ratio) in the blood. This gives an index of the prothrombin time in the patient compared with a standard control, which indicates how much longer it takes for certain coagulation pathways to be activated. In other words, it indicates how quickly or slowly the blood is clotting. Also, many other drugs can interact with warfarin so care should be taken when prescribing to women on warfarin.
This does not cross the placenta and it is not excreted into breastmilk. It is therefore safe in pregnancy and breastfeeding. In its ‘unfractionated’ form, which can be given either intravenously or subcutaneously, it is a mixture of large molecules of differing sizes. Because of the variability of the molecular size, the anticoagulant activity can vary. The effectiveness of heparin is monitored by measuring the activated partial thromboplastin time (APTT); this is a measure of the activity of the intrinsic coagulation pathway, which is where heparin exerts its effect. The dose can be altered to keep it within a set level. Heparin is used in pregnancy both for prophylaxis of thromboembolic disease (subcutaneous) and for acute treatment (usually intravenous).
Side-effects of heparin include bleeding, and bruising at the injection site. Some patients have allergic reactions to heparin, which are usually skin rashes. There is a rare but potentially life threatening adverse reaction: heparin-induced thrombocytopenia, so all patients who are commenced on heparin should have a platelet count after 7–10 days of treatment. Long-term heparin therapy is associated with osteoporosis, and this in particular is a reason to weigh up the benefits versus the risk of treatment.
Heparin is now also available in low molecular weight (LMW) preparations, such as enoxaparin, dalteparin, tinzaparin. LMW heparins have a more predictable anticoagulant response and are usually given by once or twice daily subcutaneous injection. For most situations they are replacing unfractionated heparin. In pregnancy they are useful in prophylaxis and in treatment of an acute event. There is now a reasonable amount of evidence to support their use and LMWHs’ are the recommended first line treatment (RCOG 2007). There is a lower incidence of thrombocytopenia and osteoporosis than with unfractionated heparins (Lin & Hu 2000). Some clinicians monitor the effectiveness of LMW heparin by measuring the anti-Xa activity about 4 hrs after a subcutaneous dose. (LMW heparins exert their greatest effect on the coagulation pathway by affecting factor Xa.) One of the disadvantages in pregnancy is that, because of the long duration of action of the drug, most anaesthetists are not happy to site epidural or spinal blocks within 8–12 hrs of an injection because of the risk of haematoma formation.
There is an increasing number of women taking antidepressant drugs during pregnancy (see Ch. 36, Part B). Where possible, as with all drugs, the dose should be minimized or the drug stopped. There is increasing evidence that paroxetine and possibly other SSRIs (selective serotonin reuptake inhibitors) may be associated with fetal abnormalities (Wogelius et al 2005). In addition, there may be withdrawal effects in the neonate if the drugs are taken in the third trimester. These effects may include respiratory distress, jitteriness, cyanosis, hyper-reflexia, irritability and sleeping problems. Paroxetine should therefore only be used with caution. Older tricyclic antidepressant drugs are generally preferred in women who require them.
At present, there are no ‘perfect’ agents for abolishing uterine activity in women in pre-term labour. No agents have been shown to prolong pregnancy significantly. However, tocolytic agents are beneficial for short-term use, either for transfer to a centre with neonatal facilities or for allowing 48 hrs for corticosteroids to be given. All of the following agents have been shown to be effective for short-term use.
These drugs, e.g. ritodrine, terbutaline, salbutamol, are associated with significant maternal side-effects such as palpitations, tremor, nausea, vomiting, headaches, thirst, restlessness, chest pain and breathlessness. Tachycardia is common. The serious complication of pulmonary oedema is a risk but is usually associated with fluid overload. Blood sugar levels may rise and should be monitored; this is a particular risk in women with diabetes where the serious complication of diabetic ketoacidosis may follow. Serum potassium may also fall and urea and electrolytes should also be monitored. Because of these significant side-effects, great care should be taken when administering these drugs and the minimum dose required should be given. For example, ritodrine is given as an intravenous infusion and should be titrated down to the lowest possible rate to abolish uterine activity.
Maternal side-effects of NSAIDs, e.g. indomethacin, include gastrointestinal bleeding, peptic ulceration, thrombocytopenia and allergic reactions. Renal function may also be impaired. Fetal side-effects when used in the long term include oligohydramnios, fetal renal impairment, premature closure of the ductus arteriosus, intraventricular haemorrhage and necrotizing enterocolitis.
These drugs, e.g. nifedipine, have the advantage of oral administration and fewer side-effects than some of the other agents. Profound maternal hypotension is a risk (Tsatsaris et al 2001).
This is commonly used in North America. Flushing, nausea, vomiting, palpitations and headaches are common maternal side-effects. Pulmonary oedema and acute respiratory distress syndrome (ARDS) are rare complications. Magnesium levels need to be monitored because of the risk of hypermagnesaemia, which may cause respiratory depression.
Corticosteroids may be administered in pregnancy for pre-existing maternal disease such as asthma, rheumatoid arthritis and other inflammatory diseases. In such patients the most usual agent is prednisolone, which crosses the placenta in relatively small quantities. It is considered safe for use in pregnancy as there is no clear evidence of adverse effect on the developing fetus. As the drugs are generally used for significant maternal disease the benefits of administration far outweigh the risks.
If corticosteroids are administered, even in moderate doses throughout pregnancy, there is a risk of maternal adrenal suppression. This results in a failure of the normal mechanism of increased endogenous corticosteroid production in labour. Women who are on long-term steroid treatment should therefore receive extra corticosteroids in labour to compensate for this. This is usually given as intravenous hydrocortisone.
Corticosteroids are used in pregnancy for fetal lung maturation in actual or threatened preterm birth. Betamethasone or dexamethasone are used, both of which cross the placenta in higher concentrations than prednisolone. Betamethasone and dexamethasone are generally given as intramuscular injections in divided doses over 24–48 hrs. Different units use widely differing regimens. Treatment with antenatal corticosteroids has been shown to be associated with a substantial reduction in the incidence of respiratory distress syndrome (Crowley 2007). The most significant effect is noticed if 48 hrs has elapsed between administration of the drug and birth. There is a significant reduction in perinatal mortality and intraventricular haemorrhage. With a single course of corticosteroids, there is substantial benefit to the fetus/neonate. However, there is increasing evidence of possible adverse effects with multiple courses.
Magnesium sulphate has been used in the treatment of eclampsia in North America for many years. Following a study that produced convincing evidence of its effectiveness (Eclampsia Trial Collaborative Group 1995), it has become widely used in the UK for the treatment of eclampsia. It probably exerts its effect by acting as a cerebral vasodilator, thereby reversing cerebral vasospasm and increasing cerebral blood flow. Magnesium sulphate can be given intramuscularly or intravenously. There is no consensus as to the dosing regimen, but care should be taken to avoid magnesium toxicity. Because of this, some units monitor serum magnesium levels and aim to keep them below the threshold for toxicity, which is around 5 mmol/L. The clinical signs of magnesium toxicity are loss of the patellar reflexes, a feeling of flushing, somnolence, slurred speech, respiratory difficulty and, in extreme cases, cardiac arrest. The ‘antidote’ to magnesium sulphate is calcium gluconate, which is given intravenously when there is evidence of magnesium toxicity.
Some principles for managing drugs during pregnancy are listed in Box 49.1.
Prostaglandins are lipid molecules responsible for multiple physiological subcellular reactions. They also play a part in some pathological processes. The prostaglandins important in labour and the puerperium are PGE and PGF. They can be administered by any route but have significant side-effects when given orally.
This is generally given by the vaginal route because of the relative lack of side-effects from this route. It is used for induction of labour and acts on both the cervix and the myometrium. The action on the cervix is not completely understood, but there is probably an alteration in the composition of the cervix as occurs in cervical ripening (Arias 2000). It is given in the form of gel or tablets that are modified-release preparations. Repeat doses should not be given within the time interval determined by the preparation because of the risk of uterine hyperstimulation. There is a potentiation of myometrial stimulation with oxytocin; therefore oxytocin should not be given within at least 3–6 hrs of prostaglandin because of the risk of uterine hyperstimulation.
Misoprostol is a prostaglandin E analogue. It is now widely used for cervical ripening and for management of postpartum haemorrhage. For these purposes it is usually administered vaginally. It is a useful drug world-wide because it is relatively cheap and does not have to be refrigerated. However, it is not licensed for obstetric indications.
Oxytocin is a naturally occurring hormone that exerts a stimulatory effect on myometrial contractility. The effect of oxytocin on the myometrium is mainly dependent on the concentration of oxytocin receptors present. Receptors are not present in non-pregnant myometrium; they appear at around 13 weeks of pregnancy and increase in concentration until term. The highest concentration is in the uterine fundus. Synthetic oxytocin is given antenatally to aid uterine contractility, either in induction of labour or in augmentation of labour, or postpartum for prevention or treatment of uterine atony.
Oxytocin can be given by any parenteral route. In labour, it is generally given by intravenous infusion in order that the amount given can be titrated against its effect. It takes 20–30 min for oxytocin to reach a steady state and the rate of infusion of oxytocin should therefore not be increased at time intervals <30 min. The half-life of oxytocin is 10–12 min (Arias 2000). For treatment and prevention of postpartum haemorrhage, larger doses of oxytocin can be given either by intravenous or intramuscular bolus or by intravenous infusion. Care should be taken when administering intravenous bolus doses, which should be given by slow injection.
The major side-effect of oxytocin is water retention and hyponatraemia, which is particularly relevant in women with pre-eclampsia. This effect is compounded when the vehicle for administration of oxytocin is 5% dextrose.
This is used in the treatment and prevention of postpartum haemorrhage. It is a powerful constrictor of smooth muscle and therefore causes myometrial contraction. It does, however, have the significant side-effects of nausea, vomiting and hypertension. In women with pre-eclampsia it is generally considered to be contraindicated except in exceptional circumstances because of the risk of severe hypertension.
It can be given intramuscularly (i.m.) or intravenously (i.v.). One of the benefits of ergometrine is that it has a sustained action, up to 2–3 hrs. In many areas Syntometrine (oxytocin 5 IU/mL with ergometrine 0.5 mg) is given i.m. for the third stage of labour. This has the advantage of the speed of action of oxytocin (within 3 min) and the sustained action of ergometrine. The disadvantage is the side-effect profile of the ergometrine (see Ch. 29).
It is important to remember that the concerns with drugs do not cease after birth. This applies not only to healthcare professionals but also to the women themselves who may be more relaxed about what they take after the baby has been born.
Most drugs will pass into breastmilk in greater or lesser concentrations. This is not, however, the most important factor in determining the potential effect on the baby – it is the concentration in the infant’s serum that matters. This in turn will depend on the metabolism of the drug within the infant, which will be different to that in the adult.
The amount of a substance passing into breast milk will also depend on the timing of dosing in relation to feeds. Whether the drug is water or fat soluble will determine whether there are higher concentrations in foremilk or hindmilk, and the feeding pattern of the infant will affect how much of the drug is received. Thus a mother taking a largely fat-soluble drug will pass more to an infant that feeds for prolonged periods than to one who feeds little and often because of the relative amounts of the hindmilk consumed.
A detailed list of drugs and whether or not they are safe in breastfeeding is outside the scope of this chapter. Details can be found from the Further reading list, below.
Some drugs may adversely affect milk production and are therefore not recommended in breastfeeding. The most commonly encountered drugs that have this effect are:
Midwives are subject to legislation relating to prescriptions, supply and medicines management (NMC 2007) and to the Midwives rules (NMC 2004, rule 7). Midwives are also expected to comply with the NMC Code (2008).
In the UK, the legislation relating to the prescribing, supply and administration of medicines is set out in the Medicines Act 1968 and in subsequent secondary (amendments) legislation. Medicines are divided into three categories:
Specific drugs, including those normally available only on a prescription, may be supplied to midwives for use in their practice. Midwives are therefore recognized as being exempt from certain restrictions on the sale or supply of medicines under this Act. The products that a midwife can supply and administer have to be from an approved list and include:
This Act covers drugs liable to misuse. Drugs subject to the Act’s control are termed ‘controlled drugs’ and are separated into three classes, A, B or C, depending upon their level of control. Medicinal products containing controlled drugs are still subject to the Medicines Act and are all listed as POMs. They are divided into five schedules which relate to the safe custody, documentation, keeping of records and procedure for destruction.
The Misuse of Drugs Regulations 1973, the Misuse of Drugs (Amendment) Regulations 1974, the Misuse of Drugs Regulations 1985, 2001 and the Misuse of Drugs (Northern Ireland) Regulations 2002, have permitted registered midwives to possess and administer controlled drugs in their professional practice. Subsequent POM Orders specify the list of drugs that can be supplied to midwives for administration without a doctor’s prescription. The Health Act (2006) clarifies regulations for governance and monitoring of controlled drugs (see: http://www.dh.gov.uk/en/Publicationsandstatistics/Legislation/Regulatoryimpactassessment/DH 074272).
Midwives in community practice must use the supply order procedure. With an increase in the illicit use of controlled drugs and the reduction in home births, midwives may prefer not to store and carry controlled drugs themselves but instead ask individual women planning to birth at home to seek a prescription for diamorphine, morphine, pethidine or pentazocine from their GP. In circumstances where a woman is transferred to hospital, drugs obtained under the supply order procedure may not be used. In-hospital local policies, although not required under legislation, have been developed as they provide clear guidelines as to best practice. These policies have traditionally been called ‘standing orders’ but it is now recommended that these are converted to Patient Group Direction (PGD) where the medication is not already subject to Exemption Order legislation.
In 1989 the first Crown report (DoH 1989) was published. This extended the power of prescribing a very limited set of medicines to district nurses and health visitors. It also recommended the supply of certain medicines under group protocols.
In 1998 a report (DoH 1998) was published to tighten regulations relating to group protocols. As a consequence the POM Amendment Order 2000 came into force clarifying the meaning of a ‘patient group direction’ (PGD), which replaced the use of group protocols. In England a Health Service Circular was issued (DoH 2000) to instruct Chief Executives to ‘ensure that any current or new patient group directions comply with new legal requirements’ (p 2). This circular also clarified that midwives are already exempt from certain requirements of the Medicines Act and this was further clarified by an NMC Circular (NMC 2005) entitled ‘Medicine legislation, what it means for midwives’. This includes an explanation that whilst ‘Standing Orders’ is not a legal definition they have often been used to provide local guidelines.
The 1999 Crown report (DoH 1999) recommended extending the authorized list of prescribers, which includes midwives, and establishing two new categories of prescribers:
Midwives who have successfully undertaken an approved programme are permitted to make a diagnosis and prescribe the appropriate medication. This includes all POMs including some controlled drugs but must be within their field of expertise and competence.
Midwives may, where a doctor has made the initial assessment, go on to review the medication and make changes if appropriate to the woman’s clinical care plan.
The formulary used by non-medical authorized prescribers was initially limited but is now so extensive that it is essential that prescribers’ pharmacology knowledge and expertise is kept updated and regular reference made to the British National Formulary (see: http://www.bnf.org/) and Department of Health policy and guidance websites.
It is vital that, for the safety and well-being of the woman, all prescriptions for medication are legible and clear in their instruction. It is equally important that prescribed medicines are given at the appropriate time. This may be crucial in achieving the correct concentration of drug in the circulation. When drugs are administered this should be recorded in a legible fashion. Clarity and legibility are essential for safety. Where women are self-medicating, care should be taken to explain to the woman the importance of dosage and timing and ideally she should record her own medications.
To minimize the risk of human error in the administration of medicines, employers will normally have written policies, protocols and procedures. It is essential that midwives comply with these, and if in doubt about a drug or its dosage prescribed by another practitioner then advice should be sought before it is administered. The consent of the recipient, or parent of a baby, must be obtained before any medicine is given. As well as carefully checking that the drug and dosage are correct, the midwife must also check the expiry date.
The NMC emphasizes the importance of accurate record keeping. Midwives must adhere to the rules, standards, codes and local policy in relation to record keeping. Each midwife’s supervisor of midwives will periodically audit records to maintain and improve standards of practice.
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