Perinatal Pharmacology

Perinatal

The time period around the birth. The World Health Organization (WHO) defines it as 22 completed weeks of gestation through 7 days post delivery.

Prenatal or Antenatal

Before birth.

Postnatal or Postpartum

After birth.

Post-Conceptional Age

A way to date pregnancy.

Post-LMP Age

A way to date pregnancy based on the last menstrual period.

Trimesters

Divisions of pregnancy.

Teratogen

An agent or factor that can cause congenital (i.e., detectable at birth) malformations. It is any agent that the pregnant mother is exposed to that causes or contributes to malformation or abnormal physiological function or mental development of the fetus or in the child after birth.

Congenital Malformations

Malformations detectable at birth.

Teratogenesis

The initiation of congenital defects.

Chemical Teratogenesis

Birth defects caused by exposure to chemicals (e.g., drugs, xenobiotics).

Teratology

The study of congenital defects.

Major Birth Defect

Something that affects the survival of the child, requires substantial medical care or surgery, or results in significant functional or psychological impairment.

Minor Anomalies

Less significant deviations from normal development.

Phocomelia

Poor development or absence of the proximal portion of the extremities, a type of limb reduction defect associated with Thalidomide exposure.

Critical period of exposure (for Thalidomide)

20-36 days post-fertilization is the period when exposure to Thalidomide is most likely to cause birth defects.

Interspecies variability in drug susceptibility

The fact that different animal species can show different responses to the same drug or teratogen. For example, rodents initially did not show the same effects as humans with Thalidomide until higher doses were used.

Embryo

The stage of development from the time of conception (day 0) until the end of the 8th week (day 56). During this time, tissues and organs develop.

Fetus

The stage of development from day 56 until birth. During this time, tissues and organs grow at a very rapid rate and differentiate.

"All or nothing" period

The first two weeks post-conception. If too many cells are damaged or killed during this period, the embryo will not survive.

Organogenesis

The period from weeks 3-8 post-conception. This is the period of greatest sensitivity to chemical insult.

Fetal death

Death of the fetus, a possible teratogenic consequence.

Mutations (teratogenic consequence)

Alterations in the genetic material, such as those potentially caused by diethylstilbestrol (DES).

Structural anomalies

Physical defects in the developing fetus, ranging from major to minor. Thalidomide is an example of a drug causing structural anomalies.

Functional anomalies

Abnormalities in the physiological function of the fetus or child, which can be sensitive indicators of prenatal damage. Alcohol exposure is an example that can lead to functional anomalies.

Placental blood flow

The rate of blood flow through the placenta, which can influence the transfer of drugs to the fetus.

Placental drug transport

The mechanisms by which drugs cross the placental barrier, including passive diffusion and active transport.

Placental drug biotransformation

The metabolism of drugs by placental enzymes, which can affect the amount of drug reaching the fetus.

Molecular weight (influencing placental transfer)

A drug property; lower molecular weight drugs tend to cross the placenta more readily.

Lipid solubility (influencing placental transfer)

A drug property; more lipophilic drugs tend to cross the placenta more easily.

Protein binding (influencing placental transfer)

A drug property; drugs with lower protein binding in the mother's plasma have a greater tendency to cross the placenta.

Ionization (influencing placental transfer)

A drug property; the degree to which a drug is ionized (charged) at physiological pH can affect its ability to cross lipid membranes of the placenta.

Receptor-mediated toxicity (fetal)

A direct effect of drugs on the fetus that is often predictable and proportional to drug concentrations, involving the drug interacting with fetal receptors.

Reactive intermediate-mediated toxicity (fetal)

A direct effect of drugs on the fetus where proteratogens are biotransformed to electrophiles and free radicals that can damage fetal DNA, proteins, and lipids.

Indirect maternal effects (on fetus)

Ways in which drugs can affect the fetus indirectly through the mother, such as by causing poor nutrition or altering blood supply to the fetus.

Fetal drug therapy

The treatment of the fetus in the womb, for example, using steroids for fetal lung immaturity or digoxin/sotalol for fetal tachycardia.

Neonatal Abstinence Syndrome (NAS)

Also called Neonatal Withdrawal, a condition that can occur in newborns exposed to certain drugs in utero. It generally occurs within days (or even hours) of delivery and often has similar features regardless of the drug withdrawn. Symptoms can include irritability, high-pitched cry, tremor, rapid breathing, increased muscle tone, and seizures.

Milk-to-plasma ratio (of a drug)

The ratio of the concentration of a drug in breast milk to its concentration in maternal plasma. It helps determine the extent of drug transfer into breast milk.

Relative Infant Dose (RID)

A measure used to assess the potential risk of infant drug exposure through breast milk, calculated as (Dose in the Infant (mg/kg/day) / Dose in the Mother (mg/kg/day)) * 100%. Infant Dose is often estimated as [Drug]milk * 150 mL/kg/day.

Thalidomide effects

Thalidomide is associated with a characteristic pattern of anomalies including limb reduction defects (phocomelia), facial hemangioma, small ears, eye abnormalities, kidney malformations, and congenital heart disease. The critical period of exposure for these birth defects is 20-36 days post-fertilization. The S-enantiomer is teratogenic.

Diethylstilbestrol (DES) effects

Diethylstilbestrol (DES), a synthetic estrogen used from 1938-1971, can cause a rare vaginal/cervical cancer called clear cell adenocarcinoma, genitourinary defects, and reproductive effects in both males and females. Notably, these effects may not be seen until the offspring reach puberty. DES is also listed as causing mutations.

Cyclophosphamide effects

Anticancer agents like cyclophosphamide can cause CNS malformations and secondary cancers.

Warfarin effects

Anticoagulants like warfarin can cause growth retardation and chondrodysplasia (abnormal growth of cartilage at the end of long bones), hypoplastic nasal bridge, CNS malformations, and congenital heart defects. The effects of warfarin depend on the timing of exposure.

Phenytoin effects

Antiseizure agents like phenytoin can cause craniofacial dysmorphology (including cleft lip or palate), growth retardation, CNS deficits, and other features of the fetal hydantoin syndrome.

Carbamazepine and valproic acid effects

Antiseizure agents like carbamazepine and valproic acid can cause neural tube defects.

Isotretinoin effects

Retinoids like isotretinoin are associated with a high risk of CNS, craniofacial, cardiovascular, and other malformations. This is also referred to as Retinoic Acid Embryopathy.

Fetal Alcohol Spectrum Disorder (FASD)

Heavy alcohol exposure can lead to Fetal Alcohol Spectrum Disorder (FASD), formerly called Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Effects (FAE). This can cause growth retardation, microcephaly, mental retardation, neurobehavioural deficits, and facial dysmorphology. The effects are dose-dependent.

vd during pregnancy (inc or dec)

increase

unbound fraction due to decrease in plasma protein during pregnancy (inc or dec)

decrease

Cmax and AUC during pregnancy increase or decrease

decrease

renal blood flow and GFR during preg inc or dec

inc

pgp and drug transporters during pregnancy, inc or dec

inc

clearance during pregnancy inc or dec

inc

half life during pregnancy inc or dec

dec

enzyme induction during pregnancy

CYP2D6 CYP3A4 CYP2C9 CYP2A6 UGTs

enzyme inhibition during pregnancy

CYP1A2 and CYP2C19