A Textbook of Clinical Pharmacology and Therapeutics

ANTICOAGULATION

Warfarinhas been associated with nasal hypoplasia and chon-
drodysplasia when given in the first trimester, and with CNS
abnormalities after administration in later pregnancy, as well
as a high incidence of haemorrhagic complications towards
the end of pregnancy. Neonatal haemorrhage is difficult to
prevent because of the immature enzymes in fetal liver and
the low stores of vitamin K. It is not rcommended for use in
pregnancy unless there are no other options. Low molecular
weight heparin (LMWH), which does not cross the placenta,
is the anticoagulant of choice in pregnancy in preference to
unfractionated heparin. LMWHhas predictable pharmacoki-
netics and is safer – unlike unfractionated heparin there has
never been a case of heparin-induced thrombocytopenia/
thrombosis (HITT) associated with it in pregnancy. Moreover
there has only been one case of osteoporotic fracture world-
wide, whereas there is a 2% risk of osteoporotic fracture with
nine months use of unfractionated heparin (see Chapter 30).
LMWHis given twice daily in pregnancy due to the increased
renal clearance of pregnancy. Women on long-term oral anti-
coagulants should be warned that these drugs are likely to
affect the fetus in early pregnancy. Self-administered subcuta-
neousLMWHmust be substituted for warfarinbefore six
weeks’ gestation. Subcutaneous LMWHcan be continued
throughout pregnancy and for the prothrombotic six weeks
post partum. Patients with prosthetic heart valves present a
special problem, and in these patients, despite the risks to the
fetus,warfarinis often given up to 36 weeks. The prothrom-
bin time/international normalized ratio (INR) should be mon-
itored closely if warfarinis used.

thiazide diuretics in women with essential hypertension, who

are already stabilized on these drugs. Modified-release prepara-

tions of nifedipineare also used for hypertension in preg-

nancy, but angiotensin-converting enzyme inhibitors and

angitensin II receptor antagonists must be avoided.

HORMONES

Progestogens, particularly synthetic ones, can masculinize the

female fetus. There is no evidence that this occurs with the small

amount of progestogen(or oestrogen) present in the oral con-

traceptive – the risk applies to large doses. Corticosteroids do

not appear to give rise to any serious problems when given via

inhalation or in short courses. Transient suppression of the

fetal hypothalamic–pituitary–adrenal axis has been reported.

Rarely, cleft palate and congenital cataract have been linked

with steroids in pregnancy, but the benefit of treatment usually

outweighs any such risk. Iodineand antithyroid drugs cross

the placenta and can cause hypothyroidism and goitre.

TRANQUILLIZERS AND ANTIDEPRESSANTS

Benzodiazepines accumulate in the tissues and are slowly

eliminated by the neonate, resulting in prolonged hypotonia

(‘floppy baby’), subnormal temperatures (hypothermia), peri-

odic cessation of respiration and poor sucking. There is no evi-

dence that the phenothiazines, tricyclic antidepressants or

fluoxetineare teratogenic. Lithiumcan cause fetal goitre and

possible cardiovascular abnormalities.

NON-THERAPEUTIC DRUGS

Excessiveethanolconsumption is associated with spontaneous

abortion, craniofacial abnormalities, mental retardation, con-

genital heart disease and impaired growth. Even moderate

alcohol intake may adversely affect the baby – the risk of hav-

ing an abnormal child is about 10% in mothers drinking

30–60 mL ethanol per day, rising to 40% in chronic alcoholics.

Fetal alcohol syndrome describes the distinct pattern of abnor-

mal morphogenesis and central nervous system dysfunction

in children whose mothers were chronic alcoholics, and this

syndrome is a leading cause of mental retardation. After birth,

the characteristic craniofacial malformations diminish, but

microcephaly and to a lesser degree short stature persist.

Cigarette smoking is associated with spontaneous abortion,

premature delivery, small babies, increased perinatal mortal-

ity and a higher incidence of sudden infant death syndrome

(cot death). Cocainecauses vasoconstriction of placental ves-

sels. There is a high incidence of low birth weight, congenital

abnormalities and, in particular, delayed neurological and

behavioural development.

50 DRUGS IN PREGNANCY

Key points

• Pregnancy is associated with a hypercoagulable state.


• Warfarinhas been associated with nasal hypoplasia and
  chondrodysplasia in the first trimester, and with CNS
  abnormalities in late pregnancy, as well as haemorrhagic
  complications.


• Heparindoes not cross the placenta. Low molecular
  weight heparins (LMWH) are preferable as they have
  better and more predictable pharmacokinetics, are
  safer with no evidence of heparin-induced thrombo-
  cytopenia and thrombosis (HITT) and osteoporotic
  fracture is very rare.


• Refer to the guidelines of the Royal College of
  Obstetricians for thromboprophylaxis and management
  of established venous thromboembolism in pregnancy.

CARDIOVASCULAR DRUGS

Hypertension in pregnancy (see Chapter 28) can normally be
managed with either methyldopawhich has the most exten-
sive safety record in pregnancy, or labetalol. Parenteral
hydralazine is useful for lowering blood pressure in pre-
eclampsia. Diuretics should not be started to treat hypertension
in pregnancy, although some American authorities continue