The prescription of drugs to a pregnant woman is a balance between possible adverse drug effects on the fetus and the risk to mother and fetus of leaving maternal disease inadequately treated. Effects on the human fetus cannot be reliably predicted from animal studies – hence one should prescribe drugs for which there is experience of safety over many years in preference to new or untried drugs. The smallest effective dose should be used. The fetus is most sensitive to adverse drug effects during the first trimester. It has been estimated that nearly half of all pregnancies in the UK are unplanned, and that most women do not present to a doctor until five to seven weeks after conception. Thus, sexually active women of childbearing potential should be assumed to be pregnant until it has been proved otherwise.
Delayed toxicity is a sinister problem (e.g. diethylstilbestrol) and if the teratogenic effect of thalidomide had not produced such an unusual congenital abnormality, namely phocomelia, its detection might have been delayed further. If drugs (or envi-ronmental toxins) have more subtle effects on the fetus (e.g. a minor reduction in intelligence) or cause an increased incidence of a common disease (e.g. atopy), these effects may never be detected. Many publications demand careful prospective controlled clinical trials, but the ethics and practicalities of such studies often make their demands unrealistic. A more rational approach is for drug regulatory bodies, the pharmaceutical industry and drug information agencies to collaborate closely and internationally to collate all information concerning drug use in pregnancy (whether inadvertent or planned) and associate these with outcome. This will require significant investment of time and money, as well as considerable encouragement to doctors and midwives to complete the endless forms.
Saturday, July 9, 2011
DRUGS IN PREGNANCY
The use of drugs in pregnancy is complicated by the potential for harmful effects on the growing fetus, altered maternal physiology and the paucity and difficulties of research in this field.
There is potential for harmful effects on the growing fetus.
Because of human variation, subtle effects to the fetus may be virtually impossible to identify.
There is altered maternal physiology.
There is notable paucity of and difficulties in research in this area.
HARMFUL EFFECTS ON THE FETUS
Because experience with many drugs in pregnancy is severely limited, it should be assumed that all drugs are potentially harmful until sufficient data exist to indicate otherwise. ‘Social’
drugs (alcohol and cigarette smoking) are definitely damaging and their use must be discouraged.
In the placenta, maternal blood is separated from fetal blood by a cellular membrane. Most drugs with a molecular weight of less than 1000 can cross the placenta. This is usually by passive diffusion down the concentration gradient, but can involve active transport. The rate of diffusion depends first on the concentration of free drug (i.e. non-protein bound) on each side of the membrane, and second on the lipid solubility of the drug, which is determined in part by the degree of ionization. Diffusion occurs if the drug is in the unionized state. Placental function is also modified by changes in blood flow, and drugs which reduce placental blood flow can reduce birth weight. This may be the mechanism which causes the small reduction in birth weight following treatment of the mother with atenolol in pregnancy. Early in embryonic development, exogenous substances accumulate in the neuro-ectoderm. The fetal blood–brain barrier is not developed until the second half of pregnancy, and the susceptibility of the cen-
tral nervous system (CNS) to developmental toxins may be partly related to this. The human placenta possesses multiple enzymes that are primarily involved with endogenous steroid
metabolism, but which may also contribute to drug metabolism and clearance.
The stage of gestation influences the effects of drugs on the fetus. It is convenient to divide pregnancy into four stages, namely fertilization and implantation (Ͻ17 days), the organogenesis/embryonic stage (17–57 days), the fetogenic stage and delivery.
FERTILIZATION AND IMPLANTATION
Animal studies suggest that interference with the fetus before 17 days gestation causes abortion, i.e. if pregnancy continues the fetus is unharmed.
ORGANOGENESIS/EMBRYONIC STAGE
At this stage, the fetus is differentiating to form major organs, and this is the critical period for teratogenesis. Teratogens cause deviations or abnormalities in the development of the embryo that are compatible with prenatal life and are observable postnatally. Drugs that interfere with this process can cause gross structural defects (e.g. thalidomide phocomelia).
Some drugs are confirmed teratogens, but for many the evidence is inconclusive. Thalidomide was unusual in the way in which a very small dose of the drug given on only one or two occasions between the fourth and seventh weeks of pregnancy predictably produced serious malformations.
DELIVERY
Some drugs given late in pregnancy or during delivery may cause particular problems. Pethidine, administered as an analgesic can cause fetal apnoea (which is reversed with naloxone). Anaesthetic agents given during Caesarean section may transiently depress neurological, respiratory and muscular functions. Warfarin given in late pregnancy causes a haemostasis defect in the baby, and predisposes to cerebral haemorrhage during delivery.
There is potential for harmful effects on the growing fetus.
Because of human variation, subtle effects to the fetus may be virtually impossible to identify.
There is altered maternal physiology.
There is notable paucity of and difficulties in research in this area.
HARMFUL EFFECTS ON THE FETUS
Because experience with many drugs in pregnancy is severely limited, it should be assumed that all drugs are potentially harmful until sufficient data exist to indicate otherwise. ‘Social’
drugs (alcohol and cigarette smoking) are definitely damaging and their use must be discouraged.
In the placenta, maternal blood is separated from fetal blood by a cellular membrane. Most drugs with a molecular weight of less than 1000 can cross the placenta. This is usually by passive diffusion down the concentration gradient, but can involve active transport. The rate of diffusion depends first on the concentration of free drug (i.e. non-protein bound) on each side of the membrane, and second on the lipid solubility of the drug, which is determined in part by the degree of ionization. Diffusion occurs if the drug is in the unionized state. Placental function is also modified by changes in blood flow, and drugs which reduce placental blood flow can reduce birth weight. This may be the mechanism which causes the small reduction in birth weight following treatment of the mother with atenolol in pregnancy. Early in embryonic development, exogenous substances accumulate in the neuro-ectoderm. The fetal blood–brain barrier is not developed until the second half of pregnancy, and the susceptibility of the cen-
tral nervous system (CNS) to developmental toxins may be partly related to this. The human placenta possesses multiple enzymes that are primarily involved with endogenous steroid
metabolism, but which may also contribute to drug metabolism and clearance.
The stage of gestation influences the effects of drugs on the fetus. It is convenient to divide pregnancy into four stages, namely fertilization and implantation (Ͻ17 days), the organogenesis/embryonic stage (17–57 days), the fetogenic stage and delivery.
FERTILIZATION AND IMPLANTATION
Animal studies suggest that interference with the fetus before 17 days gestation causes abortion, i.e. if pregnancy continues the fetus is unharmed.
ORGANOGENESIS/EMBRYONIC STAGE
At this stage, the fetus is differentiating to form major organs, and this is the critical period for teratogenesis. Teratogens cause deviations or abnormalities in the development of the embryo that are compatible with prenatal life and are observable postnatally. Drugs that interfere with this process can cause gross structural defects (e.g. thalidomide phocomelia).
Some drugs are confirmed teratogens, but for many the evidence is inconclusive. Thalidomide was unusual in the way in which a very small dose of the drug given on only one or two occasions between the fourth and seventh weeks of pregnancy predictably produced serious malformations.
DELIVERY
Some drugs given late in pregnancy or during delivery may cause particular problems. Pethidine, administered as an analgesic can cause fetal apnoea (which is reversed with naloxone). Anaesthetic agents given during Caesarean section may transiently depress neurological, respiratory and muscular functions. Warfarin given in late pregnancy causes a haemostasis defect in the baby, and predisposes to cerebral haemorrhage during delivery.
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