Congenital anomalies – WHO defines congenital anomalies as…

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Proven teratogenic drugs in humans – see the link to Table 1 below

OTC medication use during pregnancy & lactation – see the link to Table 2 below

Prescription drugs of choice during pregnancy and lactation – see the link to Table 3 below

Congenital anomalies

WHO (World Health Organization) defines congenital anomalies as structural or functional anomalies (e.g. metabolic disorders) that occur during intrauterine life and can be identified prenatally, at birth or later in life.

There are a variety of causes of congenital malformations namely:

Socioeconomic and demographic factors: Congenital anomalies are more frequent among resource-constrained families and countries. This may be associated with lack of access to sufficient, nutritious food and increased exposure to agents or factors such as infection and alcohol that induce or increase the incidence of abnormal prenatal development.

Genetic factors: Consanguinity (when parents are related by blood) increases the prevalence of rare genetic congenital anomalies and nearly doubles the risk for neonatal and childhood death, intellectual disability and other anomalies in first-cousin unions.

Infections: Maternal infections such as syphilis and rubella are a significant cause of congenital anomalies in low- and middle-income countries.

Maternal nutritional status: Iodine deficiency, folate insufficiency, obesity and diabetes mellitus are linked to some congenital anomalies. For example, folate insufficiency increases the risk of having a baby with a neural tube defect. Also, excessive vitamin A intake may affect the normal development of an embryo or fetus.

Environmental factors: Maternal exposure to certain pesticides and other chemicals, as well as certain medications, alcohol, tobacco, psychoactive drugs and radiation during pregnancy, may increase the risk of having a fetus or neonate affected by congenital anomalies.

Despite widespread concern about drug safety, it is estimated that only 2 to 3% of birth defects are related to medications, leaving 97% to 98% to other causes namely genetic, environmental, or unknown causes.

A drug’s effect on the fetus is determined largely by fetal age at exposure, drug potency, and drug dosage. Fetal age affects the type of drug effect:

Before the 20^th day after fertilization i.e., Week 1 to 2 or the period between the last menstrual period (LMP) and fertilization: Drugs given during this period typically have an “all-or-nothing effect.” That is, the effect of the teratogen is either to kill the embryo & cause spontaneous abortion or have no effect at all. Teratogenesis is unlikely during this stage.
During organogenesis (between 20 & 56 days after fertilization) i.e., Week 3 to 8 or the embryonic period: The developing embryo is most susceptible to teratogenic agents during this stage of rapid cell division and differentiation. Virtually all organs of the body are formed during this period. Each organ of an embryo has a critical period during which its development may be disrupted (see Figure 1 above).
After organogenesis (in the 2nd and 3rd trimesters) i.e., Week 9 to birth or the fetal period: Teratogenesis is unlikely, but drugs may alter growth and function of normally formed fetal organs and tissues. As placental metabolism increases, doses must be higher for fetal toxicity to occur.

From the foregoing, the damage caused by medications can be classified into 2 broad categories:

those that are teratogens, and
those that cause adverse fetal effects.

Teratogens cause alteration of tissue development or organ formation and occur approximately 2 to 8 weeks post conception i.e., during the embryonic period. It is therefore important for clinicians to ascertain the stage of pregnancy when considering medication use in pregnancy.

The most common teratogenic effects are neural tube defects, congenital heart abnormalities, cleft lip or palate, and fetal stillbirth.

Conversely, adverse fetal effects result in the dysfunction of an organ or tissue after that organ or tissue has been formed. Some examples include difficult postnatal adaptation, withdrawal, electrolyte abnormalities, and altered glucose metabolism.

Medications that may cause adverse fetal effects include some antipsychotics, antidepressants, and opioid medications.

Relatively few medications are known teratogens (see Table 1 below).

Although the number of medications associated with teratogenicity is small, it is important because many of the underlying causes of congenital anomalies cannot be affected or changed, whereas drug exposure can be controlled.

The placental “barrier”?

The placenta is the lifeline of the developing fetus. It is a semipermeable barrier through which all nutrients and waste products must pass. Teratogenicity depends upon the ability of the agent to cross the placenta.

Drugs diffuse across the placenta similarly to the way they cross other epithelial barriers. Several factors affect a medication’s ability to cross the placenta, although the majority of drugs are transported by passive diffusion based on the concentration gradient. Medications most likely to cross are lipophilic, unionized in maternal blood, have low molecular weight (<600 Daltons), and are not highly protein bound. Conversely, if a medication is hydrophilic, ionized in maternal serum and highly protein bound, little to no medication will cross.

Not all maternal drugs cross the placenta to the fetus. Drugs that cross the placenta may have a direct toxic effect or a teratogenic effect. Drugs that do not cross the placenta may still harm the fetus by:

Constricting placental vessels and thus impairing gas and nutrient exchange
Producing severe uterine hypertonia that results in anoxic injury
Altering maternal physiology (e.g., causing hypotension)

In evaluating a medication for use during pregnancy, the clinician should:

first, consider the stage of pregnancy
second, review the information available regarding exposure of the fetus during that time.
finally, consider the risk to the mother and infant if the disease state is left untreated.

Principles of Safe Drug Prescribing in Pregnancy

All drugs carry some risk during pregnancy. It is important to balance the benefits and harms to both mother and fetus before recommending drug use during pregnancy.
Discuss the possible fetal effects of any medication prescribed to women of childbearing age and ask about their reproductive plans.
Avoid the use of nonessential medications (for relief of mild symptoms) in pregnancy.
Confirm the diagnostic indication for drug therapy during pregnancy and continue drugs which are essential for maternal health.
Consider the known risks of the medication and the consequences of withdrawing the medication during pregnancy.
Consult a reliable source of information about drug safety during pregnancy.
Consider non-drug alternatives and safer medications for the treatment of conditions during pregnancy.
Because drug metabolism and distribution may be altered during pregnancy, consider necessary dosing changes and follow drug levels when necessary.

Source: Powrie R, Hingle S. Drug prescribing in pregnancy. American College of Physicians; 2015 Jan. Available from: http://smartmedicine.acponline.org/

Quick reference tables

Click the links below to access the PDF Tables

Proven teratogenic drugs in humans (Table 1)

Table 1_Proven teratogenic drugs in humans

OTC medication use during pregnancy & lactation (Table 2)

Table 2_OTC medication use during pregnancy & lactation

Prescription drugs of choice during pregnancy and lactation (Table 3)

Table 3_Prescription drugs of choice during pregnancy and lactation

Important links

Drugs in Pregnancy and Breastfeeding – Perinatology.com. Collection of several resources and links

URL: https://www.perinatology.com/exposures/druglist.htm

MotherToBaby – Medications & More during Pregnancy & Breastfeeding. US-based site offers evidence-based information for mothers, health-care professionals and members of the general public

URL: https://mothertobaby.org/

Infant Risk Center – Texas Tech University Health Sciences Center

URL: https://www.infantrisk.com/categories/breastfeeding

References:

World Health Organization (WHO). Congenital anomalies. Fact sheet No. 370; 2015 Apr. Available from: http://www.who.int/mediacentre/factsheets/fs370/en/
Gunatilake R, Patil AS. Drugs in pregnancy. Merck Manual; 2013 Jan. Available from: http://www.merckmanuals.com/professional/gynecology-and-obstetrics/drugs-in-pregnancy/drugs-in-pregnancy
Burkey BW, Holmes AP. Evaluating medication use in pregnancy and lactation: what every pharmacist should know. J Pediatr Pharmacol Ther 2013;18(3):247–258
Chung W. Teratogens and their effects. Available from: http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt23-Teratogens.pdf
Kosar L. Peri‐pregnancy: drug treatment considerations. RxFiles; 2014 Oct. Available from: rxfiles.ca (login required).
Dutta S. Human teratogens and their effects: a critical evaluation. International Journal of Information Research and Review; 2015 Mar. Available from: http://www.ijirr.com/sites/default/files/issues/0296.pdf
Diav-Citrin O. Human teratogens: a critical evaluation. The Motherisk Program, the Hospital for Sick Children, Toronto, ON Canada. Available from: http://www.nvp-volumes.org/p2_4.htm
Koren G. Medication safety in pregnancy and breastfeeding. McGraw Hill Medical; 2007
Powrie R, Hingle S. Drug prescribing in pregnancy. American College of Physicians; 2015 Jan. Available from: http://smartmedicine.acponline.org/

Drug use in pregnancy