Drug Use in Pregnancy and Lactation

PHYSIOLOGICAL CHANGES IN PREGNANCY

Pregnancy occurs when a sperm penetrates an egg. This is called fertilization and usually takes place in the woman’s fallopian tube. The fertilized egg immediately begins to divide into a growing cluster of cells. Between 5-7 days after ovulation the fertilized egg implants into the wall of uterus and starts forming the placenta.

The placenta maintains and nourishes the baby by enabling the transfer of O₂, CO₂, amino acids, fats, vitamins and minerals from the mother’s blood. It also allows transfer of waste substances from the growing baby.

From the time of implantation into the wall of uterus until approximately eighth week of life, the baby is known as embryo. Development is rapid during this stage as the specialized cells begin to form the vital organs, nervous system, bones, muscles and blood. After the eighth week of pregnancy the developing baby is called a fetus. It is 2.4 cm long with most of internal organs formed and external features such as eyes, nose, mouth and ears start to appear.

The most obvious physical changes are weight gain and altered body shape. Weight gain is due to increase in breast tissue, blood and water volume in the form of extra vascular and extra cellular fluid. Deposition of fat and protein and increased cellular water are added to maternal stores.

The average weight gain during pregnancy is 12.5 kg. During normal pregnancy 1 kg weight gain is due to protein. Also plasma albumin levels are decreased and fibrinogen levels are increased. Total body fat increases during pregnancy.

During second half of pregnancy plasma lipids increase but triglycerides, cholesterol and lipoproteins decrease soon after delivery. The ratio of LDL to HDL increases during pregnancy.

How a drug affects the fetus depends on the fetus’s stage of development and the strength and dose of the drug. Certain drugs taken early in pregnancy (15-21 days after fertilization) during the period of blastogenesis may act in an all or nothing fashion; killing the foetus or not affecting it at all. During this early stage, the fetus is highly resistant to birth defects. The fetus is highly vulnerable to birth defects between 3rd week and 8th week after fertilization; which is the period of organogenesis.

All major organs start developing during this period. Drugs reaching the fetus during this stage may cause a miscarriage, an obvious birth defect, or a permanent but subtle defect, that is noticed later in life. At 9th week, the embryo is referred to as a fetus. Development during this time is primarily maturation and growth. Exposure to drugs during this period is not associated with major congenital malformations but they may alter the growth and function of normally formed organs and tissues. The effect of a medication also depends on the dose that reaches the fetus. This dose is affected by the maternal dose, distribution of the drug in maternal blood stream, placental function, maternal and fetal genetic and physiologic status as well as exposure to other drugs, chemicals or environmental hazards.

PHARMACOKINETICS IN PREGNANCY

During pregnancy, a woman’s plasma volume increases by 30-50% and cardiac output and glomerular filtration rate also increase in similar proportion. Also there is increase in body fat during pregnancy; which increases the volume of distribution of fat soluble drugs. A decrease in plasma albumin concentration during pregnancy increases the volume of distribution for highly protein bound drugs e.g. anticonvulsants. But the unbound drugs are excreted out more rapidly by the kidney and liver; and this offsets the effect of increased volume of distribution.

Due to the effect of progesterone, gastric emptying time is decreased particularly in the third trimester thus delaying the onset of effect of the drug. Lastly estrogen and progesterone alter hepatic enzyme activity; which can increase drug accumulation or decrease elimination of some drugs.

PLACENTAL TRANSFER OF DRUGS

The placenta; the product of conception is the functional unit between fetal blood and maternal blood. The functions of the placenta include nutrition, respiration, metabolism, excretion and endocrine activity to maintain fetal and maternal well-being.

In order for a drug to cause a teratogenic or pharmacological effect on the fetus, it must cross from maternal circulation to fetal circulation through the placenta by diffusion. The rate of transfer depends on the chemical properties of the drug such as protein binding, pH difference, lipid solubility and molecular weight of the drug. Only free unbound drug crosses the placenta.

During pregnancy maternal plasma albumin decreases while fetal albumin increases. As a result the concentration of free drug increases which crosses the placenta to reach the fetus.

Fetal pH is slightly more acidic than maternal pH and so weak bases are more likely to cross the placenta. Moderately lipid soluble drugs can easily diffuse across the placental membrane. Drugs with low molecular weight (<500 g/mol) diffuse freely across the placenta. Drugs with a higher molecular weight (between 500-1000 g/mol) cross the placenta less easily, while a few drugs with a high molecular weight (>1000 g/mol) do not cross the placental membrane.

Transplacental transfer of drugs increases in the third trimester due to increased maternal and placental blood flow, decreased thickness and increased surface area of the placenta.

Teratogenic Effects of Drugs

  1. malformation
  2. growth retardation
  3. fetal death
  4. functional defects in newborn
  5. premature birth
  6. spontaneous abortion
  7. intrauterine growth retardation
  8. neuropsychological and behavioural abnormalities
  9. transplacental carcinogenesis

In general, drugs unless absolutely necessary should not be used during pregnancy because drugs taken by a pregnant woman can reach the fetus and harm it by crossing the placenta, the same route taken by oxygen and nutrients, which are needed for the growth and development of fetus.

While avoiding medications when pregnant may be desirable, it is often not possible and may be dangerous because some women enter pregnancy with medical conditions that require ongoing and episodic treatment (e.g. asthma, epilepsy, hypertension). Also during pregnancy new medical problems can develop and old ones can be exacerbated (e.g. migraine headache) requiring pharmacological therapy. Failure to manage conditions like these may affect the health of both the mother and her infant.

Use of drugs in pregnancy is not always wrong. Some examples:

  • High fever is harmful for the fetus in the first months. Use of paracetamol is better then no treatment
  • Diabetes during pregnancy needs intensive therapy with insulin
  • Some drugs like vitamins, minerals, iron and dietary supplements are essential for the health of pregnant woman and the fetus. Folic acid protects against spina bifida
  • Anti-epileptics are teratogenic. But an epileptic insult may provoke harmful anoxia for the fetus.
  • Drugs are also used for treatment of some common symptoms associated with pregnancy such as aches and pains, nausea and vomiting, and edema.
  • Medications may also be prescribed to treat conditions occurring during but unrelated to pregnancy such as upper respiratory infections, urinary tract infections and gastrointestinal upsets to name some.
  • Also pregnant woman may be using medications to treat pre existing chronic conditions such as epilepsy, hypertension or psychiatric disorders or to treat pregnancy related disorders such as pregnancy induced hypertension, to induce labor or to facilitate lung maturity in the fetus expected to be delivered preterm.

This patient population may be exposed to any other agents that may have an adverse effect on fetus. It therefore becomes important to examine the pattern of drug use in pregnancy to see to what extent there may be room for improvement in the light of current knowledge.

Before conception

Spermatozoa are continuously produced. Damaged spermatozoa are slower and arrive late when the oocytes is already fertilized. Use of some drugs by men may lead to infertility → paternal teratogenicity cannot fully be excluded.

Advice:

  • use of condoms when the man is taking products that are suspected to be harmful as termination of pregnancy because of paternal teratogenicity is not justified .
  • Toxic chemicals and irradiation can damage Oocytes
  • All female germ cells develop prenatally.
  • No germ cells are formed after birth
  • Oocytes are in situ and not multiplying.
  • teratogenic effects can become apparent after fertilization, maybe long after the presence of damage
  • EMEA does not allow women with childbearing potential to take part in first in man studies

The pre-implantation period (day 1-day 7)

  • Damage of fertilized oocyte→ death → complete recovery
  • Contact with toxic chemicals or irradiation does not increase the risk of fetal malformation

The first trimester (day 8- end of month 2)

  • Is the most important period for teratogenicity. It is period of formation of organs.

3rd – 9th month

  • Less risk for malformations except for urogenital tract, central nervous system
  • More functional effects i.e. aminoglycosides: nephro- & ototoxicity salicylates increased risk of bleeding

Delivery

Drugs have effects in newborn. Avoid CNS depressants during delivery as it can cause floppy infant syndrome. Avoid drugs with increased bleeding risk like anticoagulants, salicylates increased risk of cerebral hemorrhage during delivery. NSAIDS and salicylates decreases uterine contractility and can cause spontaneous malformations (=unknown origin).

You should always bear in mind that no drug is proven free from teratogenic effects

Risk classifications

Different risk classifications have been proposed. The FDA risk classification is widely used. Drug risks to the fetus runs from:

Category A (safest) → Category X (known danger–do not use!)

  1. Category A: Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote.
  2. Category B: Either animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).
  3. Category C: Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
  4. Category D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
  5. Category X: Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

Commonly Prescribed Teratogenic Drugs

  1. Antidepressants (paroxetine): Category D
  2. Antiepileptic drugs (valproic acid, carbamazepine, phenytoin): Category D
  3. Agents acting on renin-angiotensin system (captopril, lisinopril, enalapril): C (first trimester) D (second and third trimesters)
  4. Anxiolytics (diazepam): Category D
  5. Alkylating agents (cyclophosphamide): Category D
  6. Androgens (danazol): Category X
  7. Antimetabolites (methotrexate): Category D, X
  8. Carbimazole: Category D
  9. Coumarin derivatives (warfarin): Category X
  10. Estrogens (diethylstilbestrol): Category X
  11. Fluconazole: Category C
  12. Lithium: Category D
  13. Misoprostol: Category X
  14. Oral contraceptives: Category X
  15. Penicillamine: Category D
  16. Retinoids (isotretinoin): Category X
  17. Radioactive iodine (sodium iodide128): Category X
  18. Thalidomide: Category X

TERATOGENS

Teratogens are agents that act to irreversibly alter growth, structure, or function of the developing embryo or fetus.

Recognized teratogens include:

  1. Viruses (eg, rubella, cytomegalovirus, congenital lymphocytic choriomeningitis virus),
  2. Environmental factors (eg, hyperthermia, irradiation)
  3. Chemicals (e.g, mercury, alcohol), and
  4. Therapeutic drugs (e.g, inhibitors of the renin angiotensin system, thalidomide, isotretinoin, warfarin, valproic acid, carbamazepine)

 

Factors Affecting Fetal Drug Exposure

Most drugs reach the fetus by the maternal bloodstream; thus embryonic and fetal exposure depends on several critical factors, such as

  1. Gestational age,
  2. route of administration,
  3. absorption of the drug,
  4. the dose of the drug medication,
  5. maternal serum levels, and
  6. the maternal and placental clearance system.

Placental passage to the embryo or fetus is necessary for a drug medication to exercise its specific teratogenic effect. In turn, placental transfer depends greatly on maternal metabolism, gestational age, protein binding and storage, charge, liposolubility of the drug, and molecular size

Molecular weight of a substance is an important regulator of its transplacental passage. Studies have shown that most substances with mass below 500 Da diffuse rapidly across the placental barrier, whereas agents of higher molecular weight demonstrate more variable transplacental migration rates. Ionization and high fat solubility (e.g, in anesthetic gases) assures rapid transfer of these drugs by simple diffusion. Lastly, variations in pH gradients between maternal and conceptal compartments play an important role as well

Very teratogenic drugs

  1. Thalidomide (Softenon)
    • for treatment of leprosy, in oncology focomelia (short extremities)
  2. Retinoids
    • multiple defects and malformations. Adequate birth control needed after isotretinoin for 1 month acitretin/etretinate for 2 years
    • Cytostatics
  3. DES (diethylstilboestrol):
    • adenocarcinoma of vagina during adolescence in daughters is the only proven example in human beings of prenatally-caused cancer
    • other: genital malformations in newborn (25%) if DES was given in first trimester
  4. Antiepileptics
    • harm from: epileptic  <-> drugs insult
      • advice
        • inform patient that chance of malformation increases 2-3 fold (is still ≤ 10%)
        • evaluation of treatment before pregnancy. Can treatment decreased or stopped? .
        • Valproic acid should be changed to another antiepileptic (very teratogenic [±15%]
        • many malformations like neural tube, spina bifida)
        • offer prenatal diagnosis
  5. ACE-inhibitors
    • malformations (oligohydramnion)
  6. Tetracyclins
    • caries, tooth coloration
  7. Coumarins
    • bone malformation
    • bleeding risk
  8. Alcohol
    • craniofacial skeletal abnormalities
    • growth retardation
    • mental disorders
  9. Smoking
    • orofacial clefts 1/500-1/183 • lower birth weight
    • premature birth

Frequently Used Teratogenic Agents

  1. Coffee: > 300 mg caffeine/day (>3-6 cups of coffee)
    • this increases the risk of fetal death
      • Advice: limit coffee to 3 cups/day
  2. Vitamin A
    • teratogenic in animal model, effect unknown in human beings
      • avoid > 3 mg = 10.000 IE
      • liver contains large amounts of vitamin A that will be enough for you
  3. Herbs not recommended or contraindicated
    • herbs that stimulate menstruation i.e. nettle root
    • alkaloid-containing herbs: coffee, mandrake
    • (podophyllin)
    • essential oils rosemary
    • anthraquinone laxatives senna
    • herbs with potential hormonal action: hops, ginseng, licorice

Drug Use in Lactation

Toxic effect of drug depends on:

  1. Free concentration of drug in maternal plasma transfer from plasma to milk
    • passive diffusion
    • non-ionized drugs pass more rapidly
    • lipophilicity
  2. amount ingested by the newborn
    • concentration in milk
    • milk volume
  3. kinetics in newborn
    • immature liver and renal function. This is hard to predict
      • advice
        • use the lowest possible dose
        • close observation of child
        • time of drug intake versus breast feeding
  4. avoid drugs like
    • aminoglycosides
    • thyrostatics
    • chloramphenicol
    • tetracyclins
    • immunosuppressants
    • cytostatics

Conclusions

Pregnancy

Some drugs have proven teratogenicity. No drug is proven free of teratogenicity. For some drugs there is enough evidence for a low risk of teratogenicity

Lactation

The amount of drug ingested by breastfeeding infant is difficult to assess. Careful observation of the baby is advised. Some drugs are absolutely contraindicated in breastfeeding mothers.

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