Prescribing in Pregnancy, Breastfeeding and Paediatrics eBook

Question 1

Preconception advice

Answer 1

 Avoid drugs (where possible), alcohol (although this is a controversial area!), smoking (definitely), vitamin A products
 Decrease caffeine intake
 Consider taking folic acid 400mcg per day as prophylaxis against neural tube defects(if the woman has epilepsy or has had a child previously with NTD then this should be 5 mg per day and should be prescribed by her GP)
 Check whether the patient has been immunised against rubella (German measles). Rubella is not dangerous to the mother but is very dangerous to the unborn foetus
 If the patient has a chronic illness such as epilepsy, she should consult with her GP prior to becoming pregnant as dosages of regular medications may need to be adjusted. In many cases, inadequate treatment of the underlying medical condition is more dangerous to the foetus than the drugs used to treat the condition

Question 2

The trimesters of pregnancy

Answer 2

In medical terms, a woman’s pregnancy is described in weeks with the average pregnancy being 38-40 weeks in length. Each pregnancy passes through the three trimesters:
 1st Trimester: 0 – 12 weeks
 2nd Trimester: 12 – 28 weeks
 3rd Trimester: 28 – 40 weeks

Question 3

Stages of foetal development

Answer 3

 Pre-embryonic (days 1 – 17): this is the time taken from fertilisation through cell division to arrive at the embryonic stage
 Embryonic (days 18 – 56): organogenesis (the development of the primary organs) occurs during this time period
 Foetal (from day 56 – i.e. week 8 – onwards): maturation, development and growth

Question 4

Physiological changes during pregnancy

Answer 4

Vascular resistance changes from conception onwards. Initially there is a decline in maternal blood pressure until mid-way through the 2nd trimester (about 24 weeks) when
blood pressure begins to rise again towards pre pregnancy levels by the end of the pregnancy. The decrease in vascular resistance is compensated for by a gradual increase in heart rate and stroke volume during pregnancy and labour.

Maternal plasma volume increases by approximately 40% during pregnancy, part of which is due to an increase in red cell volume of about 15%. This increase in plasma volume decreases blood viscosity. There are also changes in the coagulation cascade with an increase in coagulation factors and a decrease in fibrinolysis. These changes are to minimise blood loss during labour, but also increase the risk of VTE during pregnancy.
Because of the increased plasma volume, renal blood flow is increased as is the glomerular filtration rate. This means that drugs which are renally excreted may be cleared much more quickly, particularly after the end of the first trimester, and upward dose adjustments may need to be made.
Serum albumin levels can decrease by up to 80% of normal by the end of pregnancy which means that drugs which are extensively plasma protein bound may be affected. Blood levels of such drugs should be adjusted for these lower albumin levels.
Increased progesterone levels during pregnancy relax smooth muscles, including those of
the oesophageal sphincter and the gut. Upward pressure from the uterus, combined with the relaxation of the oesophageal sphincter result in oesophageal reflux. Decreased gastrointestinal motility means that pregnant women are more prone to constipation and bloating

Question 5

Teratogenicity

Answer 5

Harm to the foetus during pregnancy is very unlikely – less than 1% of birth defects can be attributed to prescription drugs. Most foetal damage occurs during the first trimester of pregnancy whilst organogenesis is in process. Teratogenicity is the term used to describe
the effects of drugs causing birth defects and is derived from the Greek “teratos” meaning monster.
The most common teratogenic effects are spina bifida (a neural tube defect), cleft lip and/or palate, renal failure, growth retardation

Question 6

Spina bifida

Answer 6

Spina bifida means “cleft spine” and is an incomplete closure of the spinal column. The most severe form of spina bifida is myelomeningocele where a portion of the spinal cord itself protrudes through the back. In some cases the sacs are covered with skin; in others, tissue and nerves are exposed.

Question 7

The most common teratogenic drugs

Answer 7

 Anti-epileptics
o Phenytoin
o Valproate
o Carbamazepine
 Lithium
 Warfarin
 Retinoids such as isotretinoin
 Danazol

Question 8

Drugs which affect later pregnancy

Answer 8

 ACE inhibitors. These may cause renal failure in the foetus
 Antithyroid drugs (carbimazole, propylthiouracil). These may cause hypothyroidism in the foetus
 Benzodiazepines. When these are taken in the third trimester, these can cause severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, reluctance to suck, apnoeic spells, cyanosis, seizures and impaired metabolic responses to cold stress. Benzodiazepine withdrawal syndrome can persist from hours to months after birth and requires careful management.
 B-blockers (atenolol, but inferred for others). These may cause growth retardation. They may also cause neonatal hypoglycaemia and bradycardia. However, labetalol is
frequently prescribed for hypertension of pregnancy, but usually only in the 3rd trimester.
 NSAIDs. These can cause closure of the ductus arteriosus in later pregnancy. The ductus arteriosus is the foetal blood vessel which joins the aorta and pulmonary artery in utero allowing the respiratory circulation to be bypassed as this is redundant as the source of blood oxygenation in the womb. In normal circumstances the ductus arteriosus closes soon after birth.
 Warfarin. This affects both early and later pregnancy and can cause bleeding into the foetal brain.

Question 9

How do we decide what to prescribe and what to avoid? examples

Answer 9

 Paracetamol should be the only non-prescription analgesic recommended during pregnancy.
 The safer antibiotics are the penicillins and cephalosporins. Urinary tract infections are common during pregnancy but the first line antibiotic, trimethoprim, is a folate antagonist and so should be avoided in the first trimester; cefalexin is therefore the preferred agent.
 Heartburn is a common problem in pregnancy and very few pregnant women make it through without resort to an antacid of some sort! Care should be taken to recommend
those that have a low sodium content to prevent hypertension.
 During pregnancy it is imperative that asthma is controlled as during an asthma attack the reduced oxygen that the mother receives also affects the foetus

Question 10

Complications in pregnancy - Hyperemesis

Answer 10

More commonly known as ‘morning sickness’, hyperemesis affects approximately 70% of pregnant women during their first trimester. Hyperemesis tends to resolve by 20 weeks, but it can continue for longer in some women. Approximately 1% of women will develop
hyperemesis gravidarum, the cause of which is not fully understood. This severe nausea and vomiting can result in dehydration, weight loss and patients are often hospitalised as a result.

Morning sickness should be managed, wherever possible, by non-pharmacological methods including:
 Eating smaller meals, more frequently
 Avoiding spicy foods
 Avoiding caffeine
 Preventing fatigue
 Provision of emotional support

The first three points on this list also help in the non-pharmacological management of oesophageal reflux.

In severe cases of hyperemesis, pharmacological management may be required. Antihistamines, such as cyclizine and promethazine, are the preferred first line options with metoclopramide, ondansetron and prochlorperazine reserved for second line treatment.
Intravenous fluids may also be required as well as nutritional supplementation.

Question 11

Complications in pregnancy - acid reflux

Answer 11

Up to 80% of women may be affected by acid reflux during pregnancy. First line management includes the avoidance of trigger factors such as spicy or fatty foods, tight clothing, big meals and smoking. If this is not sufficient or successful, then an antacid with or without an alginate may be recommended. Second line pharmacological therapy includes omeprazole or ranitidine, neither of which has been shown to be harmful to the foetus.

Question 12

Complications in pregnancy - Hypertension and pre-eclampsia

Answer 12

Pregnancy-induced hypertension (PIH) is defined as a BP of greater than 140/90 mmHg beyond 20 weeks of pregnancy, resolving upon delivery. PIH affects about 10% of pregnancies.
Pre-eclampsia is defined as hypertension accompanied by pregnancy-induced proteinuria.
All pregnant women should have their BP checked and urine dipped for protein at each antenatal appointment to allow early detection of PIH and pre-eclampsia. Labetalol is the pharmacological treatment of choice for PIH; nifedipine or methyldopa may be used if labetalol is not tolerated or suitable.

Question 13

Complications in pregnancy - Gestational diabetes

Answer 13

This condition is on the increase in the UK, most likely due to the increasing number of pregnant women who are obese. A urine dipstick test at each antenatal appointment will allow for early detection of the condition, which should resolve after delivery. If untreated, the risks of PIH, pre-eclampsia, premature birth and neonatal hyperglycaemia at birth are all increased.
Diet and lifestyle modifications are the first line treatment, with the aim of reducing the fasting blood glucose level to less than 5.3 mmoL/L. If this is unsuccessful, drug treatment should be started as soon as possible to prevent the complications listed above with oral metformin being used first-line. Insulin therapy may be used if treatment with metformin is unsuitable or unsuccessful.

Question 14

Complications in pregnancy - Venous thromboembolism

Answer 14

As stated earlier in this eBook, the risk of VTE in pregnancy is increased due to the changes in the coagulation cascade which occur to minimise the loss of blood during labour. All women should receive a VTE assessment in early pregnancy to establish any risk factors and to initiate any treatment measures if necessary. Women at an increased risk of VTE should
be prescribed a low molecular weight heparin (LMWH) as prophylaxis, often for the duration of their pregnancy.

Question 15

Drugs in breastfeeding

Answer 15

It is widely acknowledged that breastfeeding is highly beneficial for newborn babies and so it is best that drug therapy fits around this.

All drugs distribute into the breast milk to a greater or lesser extent except very large molecules such as insulin and warfarin. The extent of transfer to breast milk depends upon:
 pKa. Basic drugs are more likely to cross into breast milk
 Protein binding. Highly protein bound drugs are less likely to cross into breast milk
 Lipophilicity. Highly lipophilic drugs are much more likely to cross into breast milk.

Therefore drugs that are acidic, highly protein bound and with a low lipophilicity are least likely to cross into the breast milk – e.g. NSAIDs.
Those drugs that are likely to exhibit a high concentration in breast milk are those that are basic, with low plasma binding and high lipophilicity – e.g. sotalol.
Younger babies may be at greater risk from drugs in breast milk as they are fed smaller amounts more often than older babies. However, the dilutional effect of the breast milk itself and the amount actually swallowed do reduce potential ill effects.
Maternal drug therapy is rarely a reason to avoid breast feeding. It is best to feed the baby immediately before a dose of a drug is taken. If non-compatible drugs are unavoidable, then the mother should express and discard any milk and wait for the elimination time for the drug (i.e. 4 x the half life) before feeding.

Question 16

Drugs to avoid whilst breastfeeding

Answer 16

 Amiodarone
 Aspirin
 Barbiturates
 Benzodiazepines
 Carbimazole
 Combined oral contraceptives
 Cytotoxics
 Ephedrine
 Tetracyclines

Question 17

Some myths to dispel….

Answer 17

1. Corticosteroids are teratogenic. There is no evidence that there is any influence on the foetal endocrine system.
2. Oral contraceptives are teratogenic. There is no evidence for this.
3. Some anti-epileptics are safer during pregnancy. Untrue. The safest drug is that which is prescribed at the lowest dose to control seizures. Monotherapy should be aimed for and patients should be counselled to plan pregnancies where possible. Folic acid 5 mg daily should be prescribed. The mother should be screened for alpha-fetoprotein and should have a second trimester ultrasound scan.
   Carbamazepine and phenytoin both have the risk of causing neonatal bleeding and so the mother should receive vitamin K prophylactically prior to delivery and the
   baby should also receive vitamin K upon delivery.
4. Warfarin is unsafe in breast feeding. Concentrations in breast milk are very low and there is no evidence for any ill-effect

Question 18

Definitions - 
Preterm neonate 
Term neonate 
Post-term neonate
Neonate 
Infant 
Child
Adolescent

Answer 18

• Preterm neonate Born at < 37 weeks gestation
• Term neonate Born at 37 to 42 weeks gestation
• Post-term neonateBorn at ≥42 weeks gestation
• Neonate From 0 up to 28 days of age (or first 4 weeks of life)
• Infant From 28 days up to 24 months of age
• Child From 2 years up to 12 years of age
• Adolescent From 12 years up to 18 years of age

 Neonate Birth to one month
 Infant one month to one year
 Child one year to twelve years

Question 19

Drug handling in neonates

Answer 19

Enteral drug absorption is erratic and in ill babies can be non-existent as the stomach does not empty. There are developmental differences in secretion of gastric acid, drug metabolising enzymes in the wall of the intestine and the motility of the gastrointestinal tract; thus influencing the rate and extent of oral drug absorption.
Most drugs are therefore given intravenously, although some are given rectally. Intramuscular injections are avoided because there is very little muscle mass on a neonate and IM injections can therefore be very painful

Question 20

Definition of terms for neonates

Answer 20

• Normal length of pregnancy 37 – 42 completed weeks of gestation
• Pre-term < 37 weeks of gestation at birth
• Post-term > 42 weeks onwards
• Low birth weight < 2500 g
• Very low birth weight < 1500 g
• Extremely low birth weight < 1000 g

Question 21

Drug distribution in neonates

Answer 21

This is very difficult to predict. Compared to adults, extracellular fluid and total body spaces results in an increased apparent volume of distribution of drugs, distributing into these locations (e.g. aminoglycosides). This means that there may be a reduced plasma
concentration for the same weight-based dose. Distribution of hydrophilic drugs depends upon the amount of body water which in turn is determined by
the weight of the baby. The GFR of the baby increases with age and has done so logarithmically since the formation of the kidneys in the womb. The distribution of lipophilic drugs depends upon the amount of body fat. Babies that are born 10 weeks early (or more) and any baby that has growth restriction will have less body fat than normal babies. Babies born to diabetic mothers may have more body fat. Drugs which are extensively protein bound are affected by the amount of albumin produced and this is directly related to gestation. Babies born more than 12 weeks pre-term only have about two thirds of the
albumin of older gestation babies. This should be considered in particular when prescribing highly protein-bound drugs including phenytoin, phenobarbital and furosemide

Question 22

Drug metabolism in neonates

Answer 22

The rates of drug metabolism in neonates are no different to those of older babies and children. The efficiency of the mechanisms may be impaired however. For example
neonatal hyperbilirubinaemia (“baby jaundice”) is very common and is due to unconjugated bilirubin which competes for binding sites and glucuronate. It therefore affects drug metabolism for as long as it exists (usually no more than a week).
Immaturity of the liver or the kidneys may result in slow elimination of some drugs. Slow elimination of drugs means that dosing intervals need to be reduced. This affects drugs with narrow therapeutic indexes particularly. This may be useful with some longer acting drugs (e.g. phenobarbital) meaning that only one or two doses need to be given for a long term effect. Trough levels of gentamicin are most important (as in adults) as these indicate accumulation and so blood samples need to be taken a carefully calculated time intervals.

Question 23

Drug distribution in paediatrics

Answer 23

For drugs that are administered orally, gastric emptying times gradually become equivalent to those of an adult over the first six months of life. Stomach acid production takes slightly longer to develop; usually 1-2 years.
The intramuscular route of administration is more successful than in neonates as there is a greater muscle bulk and increased blood flow. However it is still very painful in small children and so should be avoided where possible. The intranasal route may be a useful alternative.

Question 24

Drug metabolism in paediatrics

Answer 24

At birth, the majority of drug metabolism pathways are absent or operate at much reduced capacity compared to adults and older children. However these pathways become more efficient throughout childhood and between the ages of 1-9 years may be enhanced when compared to an adult. Some metabolic pathways are more significant than in adults. A good example of this is the metabolism of paracetamol. 70% of the metabolism of paracetamol in adults is carried out through glucuronidation. In the early newborn where glucuronidation is deficient, the pathway may be as low as 20% efficient. The more pronounced sulphate conjugation seems to compensate for this and the half-life of paracetamol in newborns is normal. Paracetamol seems to be less toxic in children than adults, possibly because of this compensation mechanism.

Question 25

Renal function in paediatrics

Answer 25

GFR is low in babies but gradually increases to become that of an older child or an adult at about 8 months of age. This principally affects doses of renally excreted drugs in younger babies.

Question 26

Drug dosing in neonates and paediatrics

Answer 26

Drug doses should be obtained from a recognised paediatric formulary such as the BNF for Children. Extrapolation from adult doses is not an accurate method. Body surface area (BSA) can be used, but often manufacturers don’t quote doses using this method. However, cytotoxics are an example where they do. In babies of less than 1 year though, the BSA is not accurate as they have a comparatively larger BSA than other children. Doses should therefore be calculated by body weight to avoid overdose.
Take care when labeling products to minimise ambiguity. The person administering the medicine should be clear regarding the dose required, this is important to minimise the risk of mls and mgs being confused. The parent / adolescent needs to also be counselled effectively to reduce the risk of a dosing error. Ensure that appropriate dosing instruments are provided in order to measure an accurate dose (e.g. syringes of appropriate sizes).
Counselling on the correct use of dosing instruments is also required.

Question 27

Estimation of renal function cannot be done using adult formulae as these have not been validated in children. There are three main formulae for estimating GFR:

Answer 27

 Traub & Johnson (1 – 18 years)
 Counhahan (2 months – 14 years)
 Schwartz et al (birth – 16 years)

Question 28

What is increased during pregnancy

Answer 28

• Heart rate
• Stoke vol
• Maternal plasma vol (by 40%)
• Red cell vol (by 15%)
• Progesterone levels (leads to relaxation)
• Coagulation factors
• Renal blood flow
• GFR
• Risk of VTE

Question 29

What is decreased during pregnancy

Answer 29

• Fibrinolysis
• Blood viscosity
• GI motility
• Serum Albumin
• Vascular resistance