DRUG

INDUCED
BIRTH
DEFECTS
P R E SE NTE D B Y – F A U Z IA K H A N

C OUR SE – P HARM.D 5 T H Y E AR
INTRODUCTION

Birth defects is an abnormality of structure, function or metabolism present at birth that

results in physical or mental disabilities or death
Birth defects are part of the human condition having been observed throughout history.
Major birth defects, typically defined as those that are life threatening, requires major
surgery, or present a significant ability, affect appx. 3-4% of live born infants.
WHAT CAUSES BIRTH DEFECTS
• Genetic problems- one or more genes might have a change or mutation that results in them not
working properly, such as in Fragile X syndrome. Similarly, a gene or part of the gene might be
missing.
• Chromosomal problems- In some cases, a chromosome or part of a chromosome might be missing,
such as in Turner syndrome, when a female is missing an X chromosome. Other birth defects result
from having an extra chromosome, such as in Klinefelter syndrome and Down syndrome.
• Infections- Women who get certain infections during pregnancy are at higher risk for having a child
with birth defects. For example, infection with Zika virus during pregnancy is linked with the birth
defect called microcephaly, in which the brain and skull are smaller than normal
• Exposure to medications, chemicals, or other agents during pregnancy- The infants whose mothers
took thalidomide are examples of an exposure leading to birth defects. Other examples include
exposure to rubella (also called German measles) and toxic chemicals, such as hydrocarbons.
BIRTH About 90% of women take medication during
DEFECT DUE pregnancy. Pregnant women take prescribed or
non-prescribed drugs .
TO DRUGS Some women suffer from chronic health
conditions such as high blood pressure
,diabetes, asthma and thyroid conditions.
Some women suffer from acute illness during
pregnancy such as respiratory infection like
pneumonia.
 Act directly on fetus which causes birth defects.

EFFECT OF
DRUGS ON During the first 2 weeks of development, teratogenic
agents usually kill the embryo or have no effect.

FETUS
During the organogenesis period (3rd-8th
weeks),teratogenic agent may cause major congenital
anomalies.congenital anomalies means a structural or
functional abnormality that occur during intrauterine life
During the fetal period(9th week-9th months)
teratogens may produce morphological and functional
abnormalities particularly of the brain and eyes.

Reduces the supply of nutrients and oxygen to the

fetus which leads to underweight or under
development of fetus.

The muscles in uterus contract forcefully which

injured the fetus by reducing the blood supply to
the fetus or preterm labor and delivery
RISKS OF DRUGS DURING
PREGNANCY
• More than 80% of pregnant women take OTC or prescription drugs during pregnancy,
with only 60% of these patients consulting a health care professional for associated
conditions including cough, cold, allergies, gastrointestinal disorders, infections and
pain. Among the most frequently used medications in pregnancy are antiemetics,
antacids, antihistamines, analgesics, antimicrobials, diuretics, hypnotics, and
tranquilizers.
• Drug use during pregnancy continues to remain a major concern due to the unknown
effects on mother and fetus. Physicians are faced with difficult situations as they
have very little information to help them decide whether the potential benefits to the
mother outweigh the risks to the unborn fetus.
• To help guide physicians, the FDA introduced a drug classification system in 1979
•All new FDA-approved medications are classified as Category C

•Approximately 20 to 30 of the most commonly used drugs are identified as teratogens, with 7% of the more than
1,000 medications listed in the classified as Category X. Some commonly used drugs with proven teratogenic
effects in humans are warfarin, isotretinoin, valproic acid, and tetracycline antibiotics
VARIOUS DRUGS Thalidomide
INCLUDES
Retinoids (isotretinoin)
Ace inhibitor
Anticonvulsant
Tetracyclines
Alcohol
Oral hypoglycemic agents (sulfonylureas )
SSRI
Warfarin
Misoprostol
Ondansetron
Cocaine
THALIDOMIDE
• It was prescribed as a sedative and claimed to cure
anxiety, insomnia, gastritis and tension
• it was used against nausea and to alleviate morning
sickness in pregnant women
• Exposure to the drug in pregnancy resulted in severe limb
defects known as phocomelia and heart malformations
• Throughout the world 10,000 cases were reported out of
which only 50% of the 10,000 survived.
• The antiangiogenic action of drug that causes
limb defects through preventing blood vessels migration
into developing limb
CASE STUDIES OF THE PEOPLE
AFFECTED BY THALIDOMIDE
RETINOIC ACID

• Isotretinoin a widely used treatment for acne causes severe

malformations of the face, heart, CNS and thymus if taken during
early pregnancy
• In a prospective study of pregnancies exposed accidentally to
isotretinoin during the 1st trimester 23% developed malformation.
The critical period for exposure appears to be 2-5 weeks post
conception
• Follow up studies of children exposed to isotretinoin during the 1st
trimester indicated that 47% of 5 year old had intellectual defects.
The safety of retinoids in the second and third trimesters has not
been established
• Dermally applied retinoids are unlikely to be teratogenic as they
result in low systemic exposure.
ACE INHIBITOR
• ACE inhibitor are perhaps the least appropriate antihypertensive drug to use in
pregnancy. Their use in 2nd and 3rd trimester has been associated with reduced
amounts of amniotic fluid leading to compression of the fetus and neonatal death
from renal failure.
• The presumed mechanism is fetal hypotension causing reduced renal blood
flow leading to anuria (no urine)and reduced amniotic fluid production. Normally the
fetus swallows amniotic fluid and the kidneys excrete it back into the amnion cavity
via the urine
• It was thought that ACE inhibitors were safe in the 1st trimester which was good
since accidental use in pregnancy could be corrected by changing to another anti-
hypertensive drug before the start of the 2nd trimester.
ANTICONVULSANTS

• About 0.2-0.5% of women have epilepsy and most take

anticonvulsant during pregnancy
• Phenytoin- appears to double the risk of birth defects particularly
cleft lip, cleft palate and heart malformations. Also increases risk
of minor defects such as short fingers and flat midface. Mental
retardation is also associated.
• Carbamazepine- appears to double the risk of birth defects
particularly cleft lip and heart malformations 5-10 times increase
in spina bifida , increased risk of growth retardation and
microcephaly
• Valproic acid- appears to increase the risk of birth defects 3-4
times particularly malformation of the heart and spina bifida(5-10
times) increases , IQ may be reduced ,
• Phenobarbital- increases the risk of birth defect 2-3 times (heart and facial clefting) also increased the risk of
microcephaly ,growth retardation and mental retardation

• There is optimum that the newer anticonvulsants such as lamotrigine, gabapentin and topiramate are not
teratogenic but at this stage there is insufficient data.
TETRACYCLINES
• Tetracyclines deposit in calcifying teeth and bone . As little as 1g/day for 3 days at
any time after the end of 4th month of gestation can cause permanent yellow staining
of the deciduous teeth. Tetracyclines chelate with calcium and deposit in calcifying
teeth and bone
ALCOHOL
• Alcohol causes fetal alcohol
syndrome (FAS)
• FAS is a pattern of mental and
physical birth defects that is common
in babies of mothers who drink
heavily during pregnancy
ORAL HYPOGLYCEMIC DRUGS
• About 1% of women of child bearing age have diabetes before pregnancy (preexisting
diabetes)and another is 2-5% develop diabetes during pregnancy (gestational
diabetes)
• Poorly controlled diabetes in 1st trimester is associated with an increased incidence
of birth defects by 2-4 times including neural tube defects
• In the 2nd and 3rd trimester the extra transfer of glucose to the fetus can result in
increased fat storage in the fetus (macrosomia) and neonatal problems
• When the drug therapy is required insulin is the drug of choice as it does not
cross placenta
SSRI MEDICATIONS

• Selective serotonin reuptake inhibitors, more commonly known as SSRIs, are typically
prescribed for depression and anxiety. Physicians have been prescribing certain SSRI
medications to women for years, but in 2006, the U.S. Food and Drug Administration
(FDA) released a public warning stating that infants are at a higher risk of developing
persistent pulmonary hypertension of the newborn (PPHN) if exposed to certain SSRI
medications including:
• Lexapro , Celexa ,Zoloft ,Prozac ,Paxil ,Fluvoxamine
• In addition to PPHN, SSRI medications may also cause: Limb abnormalities, Cleft lip
and/or palate Heart defects , Spina Bifida, Neural tube defects
ANTICOAGULANTS - WARFARIN
• Anticoagulant in pregnancy may be needed for thromboembolic disorders and in
patients with artificial heart valves. Although heparins appears to be safe for the
fetus it is difficult for outpatients to administer them. since warfarin is administered
orally it is preferred drug for chronic administration
• A recent analysis of 979 pregnant women concluded warfarin exposure in the first
trimester was associated with 6% prevalence of the warfarin embryopathy. This is
characterized by midfacial hypoplasia(upper jaw cheekbone and eye socket not grown
much) and abnormal calcification in cartilage . The embryopathy can be avoided by
replacing warfarin with heparin during 6th and 12th gestational weeks
• Bleeding in 3rd trimester
MISOPROSTOL • Misoprostol is an analogue of prostaglandin
E1. It is used for the treatment of peptic ulcer
disease at doses of 200-400 μg.
• In some countries misoprostol has been used
at higher doses 600-1800 μg in an attempt to
induce 1st trimester abortions. If
the attempted abortion is unsuccessful there
is a considerable risk that the child will be
born with birth defects particularly limb
defects and brain abnormalities
• Birth defects have not been associated
with use of drug for the treatment of ulcers.
ZOFRAN

• Zofran (ondansetron) is a prescription medication that was used for years to treat
severe nausea and vomiting. Ondansetron works by blocking chemicals in the body
responsible for nausea and vomiting. Doctors most often prescribed Zofran to
individuals undergoing chemotherapy, who had recently undergone surgery or who
were suffering from nausea, including pregnant women.
• Pregnant women experiencing severe symptoms of morning sickness often take anti-
nausea medication during the first trimester.
• Studies indicate that it also comes with a risk of side effects to both mother and
infant , the U.S. Food and Drug Administration (FDA) has not approved this medication
for use during pregnancy.
Several studies suggest that taking Zofran while pregnant can potentially lead to birth defects. Since morning
sickness is most common during the first trimester of pregnancy, women taking Zofran do so during an infant’s most
crucial development period. The types of birth defects that may result from Zofran or ondansetron use include:

•Cleft Palate – Cleft lip and palate occur as a result of an incomplete formation of the front of the upper jaw and
upper portion of the roof of the mouth.

•Atrial Septal Defect (ASD) – ASD occurs when the wall between the two upper heart chambers fails to fully close.
Because of the incomplete closure between the two chambers, the infant is born with a gap in the heart. This
“hole” could take multiple surgeries to repair and can lead to long term effects due to poor pumping of the heart,
and thus, the heart working too hard.

•Ventricular Septal Defect (VSD) – VSD is similar to ASD except that the lower two heart chambers experience an
incomplete closure of the wall.

Because of the controversial side effects of Zofran , researchers continue to study and gather more substantial
results. Some research suggests that cardiac birth defects are not common if ondansetron is taken during the first
trimester. Research is ongoing.
COCAINE
• General population estimates of cocaine use
by pregnant women range from 3-15% in
USA
• Cocaine causes vasoconstriction of the
uterine vessels and reduces blood flow to the
embryo
• Cocaine use increases the probability of
intrauterine growth retardation, preterm
labor, premature rupture of membranes,
pregnancy induced hypertension, precipitous
delivery and for certain birth defects .
PHARMACISTS ROLE
• As pharmacists, we play a vital role in educating and counseling pregnant women on
the risks associated with a drug. Informing a pregnant woman of the risks and
possible fetal defects can reduce the number of complications. Furthermore, it is our
responsibility to ensure that other health care professionals are familiar with the
current literature available on the safety of drugs administered during pregnancy. The
various medications used to treat pregnancy-associated conditions, including cough,
cold, and allergies; pain; and gastrointestinal (GI) disorders; as well as provide an
update on the current immunization recommendations for pregnancy.
REFERENCE
• http://www.cdc.gov/features/MedicationsPregnancy/
• http://health.usnews.com/health-news/family-health/womens-
health/articles/2009/11/02/cdc-study-links-2-antibiotics-to-birth-defects
• http://www.medscape.com/viewarticle/760804
• https://www.cnn.com/2018/12/18/health/morning-sickness-pill-birth-defects-
study/index.html
• https://www.cdc.gov/ncbddd/birthdefects/features/kf-ondansetron-and-birth-defects.html
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669077/
• https://www.cidrap.umn.edu/news-perspective/2019/02/antifungal-drug-during-pregnancy-
tied-miscarriage-birth-defects
• https://onlinelibrary.wiley.com/doi/abs/10.1002/bdr2.1497
THANKYOU