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Drugs in pregnancy

DR SUHAIR QUDSIEH

FETO-MATERNAL
CONSULTANT
Drug Epidemiology
 More than 50% of pregnant women take prescribed or non-
prescribed (OTC) drugs or use social drugs (such as tobacco
and alcohol) or illicit drugs at some time during pregnancy.
 In general, drugs should NOT be used during pregnancy
unless absolutely necessary because many can harm the
fetus.
 About 2-3% of all birth defects result from drugs that are
taken to treat a disorder or symptom.
Drug Disposition In The Maternal-fetal
Unit
Maternal Pharmacokinetics
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Changes in body fluid volume
Changes in CVS parameters
Changes in pulmonary function
Alterations in gastric activity
Changes in serum binding protein concentrations and
occupancy
Alterations in kidney function
Fetal Pharmacokinetics

Plasma binding proteins differ from maternal.
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Drugs transferred across placenta undergo 1st pass
through the fetal liver.
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Liver expresses metabolizing enzymes, but capacity less
than mother.
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Fetal kidney immature.
Placental Pharmacokinetics
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Blood flow through the placenta (maternal side) increases during
gestation
Transfer of flow-limited drugs affected by placental flow
Compounds that alter blood flow alter maternal drug disposition and
placental transfer
Placental metabolism (dealkylation, hydroxylation, demethylation)
affects drug transfer across the placenta
At term, the surface area of the placenta is at its maximum and nearly
all substances can reach the fetus
Drug Transfer
 Most drugs have a molecular weight below 1000 daltons (D)
 Drugs  1000 D cross the placenta ( 500 D cross easily)
 Main determinant of the drug concentration in the
embryo/fetus is the mother's blood concentration
 Other factors: lipid solubility & protein binding
 degree of ionization at physiologic pH
 placental blood flow & surface area available for transfer
The Processes That Govern The Passage Of A Drug Into
Milk Are Similar To The Placenta

Maternal serum concentration is the main determinant

The milk pH is slightly acidic in comparison to serum pH;
so weak bases could become trapped in milk (ion
trapping).
Fetal Age Affects The Type Of Drug Effect:

Before the 20th day after fertilization :

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During organogenesis (between 20 and 56 days after fertilization):


(all-or-nothing effect), Teratogenesis is unlikely during this stage.
Teratogenesis is most likely at this stage, spontaneous abortion, gross
anatomic defect (true teratogenic effect), or the drugs may have no
measurable effect.
After organogenesis (in the 2nd and 3rd trimesters):

Teratogenesis is unlikely, but drugs may alter growth and function of
normally formed fetal organs and tissues
Timing Of The Development Of Major Body
Structures In The Embryo And Fetus
Type Of Effects


Teratogenicity (e.g. thalidomide) - detected at, or shortly after,
birth .
Long term latency (e.g. DES - increased risk of vaginal
adenocarcinoma after puberty, or abnormalities in testicular
function and semen production) .

Predisposition to metabolic diseases (e.g. Barker hypothesis -

low birth weight associated with increased risk of diabetes,
hypertension, heart disease in adulthood).
Impaired intellectual or social development (e.g. exposure to
phenobarbitone- alters programming of brain)
Teratogenesis
Teratogenesis
 It is defined as structural or functional dysgenesis of the fetal
organs.
 Typical manifestations include
 congenital malformations with varying severity
 intrauterine growth restriction
 carcinogenesis
 fetal demise
 In humans, the critical time for drug-induced congenital
malformations is in the first trimester
Malformations

The overall incidence of
 major congenital malformations is around 2-3%
 minor malformations is 9%
 25% are due to genetic or chromosomal abnormalities
 10% due to environmental causes including drugs
 65% of unknown aetiology

The part played by drugs is probably small
Organogenesis

The critical time for drug-induced congenital malformations is
usually the period of organogenesis
 about 20 to 55 days after conception
 about 34 to 69 days (5-10 weeks) after the first day of the LMP

If a drug is given after this time it will not produce a major
anatomical defect, but more of a functional one
Pregnancy Risk Categories - FDA

Category |A| Safety has been established using human studies, no
fetal risk.

Category |B| Presumed safety based on animal studies, but no wellcontrolled human studies.

Category |C| Uncertain safety. Animal studies show an adverse
effect, no human studies.

Category |D| Evidence of fetal risk, but benefits outweigh risks.
 Category |X| Highly unsafe. Risk outweighs any possible benefit.
Antibiotics
Category |B|
Penicillin | Cephalosporin | Macrolides | Nitrofurantoin |
Metronidazole | Vancomycin (oral)
Antibiotics … Cont.

Penicillin one of the safest antibiotics that could be used in pregnancy

Cephalosporin one of the safest antibiotics in pregnancy

Macrolides; erythromycin& azithromycin can be used.

Nitrofurantoin;Commonly used in pregnancy to treat UTI should not be
given to women in late pregnancy due to the potential risk of hemolytic
anemia in the newborn.

Metronidazole; not recommended for lactation

Vancomycin (oral); possible fetal ototoxic effect
Antibiotics… Cont.
Category |C|
Aminoglycoside [neomycin – tobramycin]| Quinolones |
Trimethoprim | Chloramphenicol
Quinolones [ciprofloxacin – levofloxacin]; There are safety
concerns of fluoroquinolone use during pregnancy and, as a
result, are contraindicated except for when no other safe
alternative antibiotic exists.
Trimethoprim; can affect folate metabolism, so; relatively
contraindicated during pregnancy, especially the 1st trimester.
Chloramphenicol; Gray Baby Syndrome
Antibiotics … Cont.
Category |D|
Tetracycline | Aminoglycosides [streptomycin –
gentamicin]
Tetracycline; use during tooth development can cause
permanent discoloration & enamel hypoplasia.
Aminoglycosides [streptomycin – gentamicin]; hearing
deficit & 8th cranial nerve damage
Antivirals
Acyclovir |B| recommended for treatment of Varicella during
pregnancy, especially during the 2nd and 3rd trimesters
Amantadine|C| CHD; tetralogy of Fallot / single ventricle with
pulmonary atresia
Anti-retroviral agents|B|
[Didanosine – Etravirine – Ritonavir – Enfuviritide – Maraviroc]
Anti-retroviral agents|C|
[Lamivudine – Delaviridine – Indinavir ]
Antifungals
Category |B|
Amphotericin b | remains the drug of choice for systemic
fungal infections in pregnancy despite its serious side
effects i.e. renal toxicity
Terbinafine; approved for the treatment of onychomycosis
Antifungals … Cont.
Category |C|
Ketoconazole; inhibits placental microsomal aromatase &
cytochrome P-450
Antifungals … Cont.
Category |C/D|
Fluconazole; depends on doses & duration of use
Antifungals … Cont.
Category |X|

Griseofulvin; contraindicated during pregnancy &
pregnancy should be avoided for 1 month after
treatment
Antimalarial

Chloroquine**; drug of choice for the prophylaxis and
treatment of sensitive malaria species during pregnancy.
Thalidomide***
Potent Teratogen |X|
was used against nausea and to alleviate
morning sickness in pregnant women.

Meromelia
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CHD
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Eye abnormalities
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Facial Palsy
Phocomelia
Cytotoxic Drugs

Methotrexate*** |X|; Potent teratogen that produces
major congenital anomalies.

Cyclophosphamide*** – Chlorambucil ***|D|;
Teratogenic:
- growth restriction
- ear and facial abnormalities
- absence of digits
- hypoplastic limbs
Cytotoxic Drugs … Cont.

Azathioprine** |D|; can cause birth defects

Cyclosporine***|C|; does not appear to be a major
human teratogen; but could cause complications like:
-
Preeclampsia
-
Eclampsia
-
Oligohydramnios
Anti-inflammatory Drugs
NSAIDs:

Aspirin*** |D| in 3rd trimester

Ibuprofen*** – diclofenac** - celecoxib* |D|; >30 weeks
could cause premature closure of DA
Anticonvulsants
Phenytoin** - Carbamazepine** |D|; Potent teratogen
Fetal Hydantoin Syndrome || 5-10%
-
IUGR
-
Craniofacial anomalies
-
Developmental delay
-
Mental retardation
Anticonvulsants … Cont.

Valproic Acid*|D|
-
neural tube defects
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cognitive impairment
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dysmorphic features
-
risk of autism
Diethylstilbestrol [Des]
Human teratogen |X|
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Vaginal adenosis
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Cervical erosions
-
Transverse vaginal ridges
-
Vaginal adenocarcinoma
Vitamin A Analogues

Isotretinoin*** |X|; Potent teratogenic
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Severe birth defects
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Neuropsychological impairment
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Spontaneous abortion
-
Premature birth
-
Fetal death
-
Internal abnormalities
ANTICOAGULANTS
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WARFARIN
ADVERSE EFFECTS WHEN GIVEN DURING THE 1ST TRIMESTER, FETAL
WARFARIN SYNDROME (E.G. NASAL HYPOPLASIA, EPIPHYSES STIPPLING,
BILATERAL OPTIC ATROPHY, VARIOUS DEGREES OF INTELLECTUAL
DISABILITY)
ADVERSE EFFECTS WHEN GIVEN DURING THE 2ND OR 3RD TRIMESTER,
OPTIC ATROPHY, CATARACTS, INTELLECTUAL DISABILITY,
MICROCEPHALY, MICROPHTHALMIA, AND FETAL AND MATERNAL
HEMORRHAGE.
FDA PREGNANCY CATEGORY |X/D| FOR WOMEN WITH MECHANICAL
HEART VALVES WHO ARE AT HIGH RISK FOR THROMBOEMBOLISM.
HEPARIN
HEPARINS ARE USED FOR THE MANAGEMENT OF VENOUS
THROMBOEMBOLISM IN PREGNANCY BECAUSE THEY DO NOT CROSS
THE PLACENTA.
FDA PREGNANCY CATEGORY: LOW MOLECULAR WEIGHT HEPARIN: |B|
UNFRACTIONATED HEPARIN: |C|
Cardiovascular drugs

ACE inhibitors, ARBs

Contraindicated in pregnancy. FDA pregnancy category |C| for the 1st trimester of
pregnancy and |D| during the 2nd and 3rd trimesters.

Prenatal exposure to an ACE inhibitor (e.g. enalapril) or to an angiotensin II receptor
antagonist (e.g. losartan) during the 2nd or 3rd trimester of pregnancy is associated
with an increased risk for fetal hypotension, renal failure, and oligohydramnios
leading to fetal growth restriction, joint contractures, pulmonary hypoplasia, &
stillbirth or neonatal death.

β-Blockers
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FDA Pregnancy category |C|
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Can cause Fetal bradycardia, hypoglycemia, & possibly fetal growth restriction

Amiodarone
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FDA pregnancy category |D|; should only be given during pregnancy when there are no
alternatives and benefit outweighs risk.

Ca channel blockers

When given during the 1st trimester, possibly phalangeal deformities

When given during the 2nd or 3rd trimester, fetal growth restriction

FDA Pregnancy Category |C|

Methyldopa
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FDA Pregnancy Category |B|
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Thiazide diuretics
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Can cause neonatal hyponatremia, hypokalemia, & thrombocytopenia

FDA Pregnancy Category |D|

Statins

FDA pregnancy category |X|

statins should be avoided during pregnancy
– congenital anomalies have been reported.
Insulin & Hypoglycemic Drugs

insulin is the treatment of choice for diabetes during pregnancy.

Neonates born to mothers with diabetes who are taking oral
hypoglycaemics in pregnancy may have hypoglycaemia.

Metformin is FDA pregnancy category |B|.
Progesterone

Danazol, Synthetic progestin (but not the low doses used in oral
contraceptives), when given during the first 14 wks., masculinization of a
female fetus's genitals. FDA pregnancy category |X|

progestin exposure is associated with an increased prevalence of
cardiovascular abnormalities.

Combined Oral contraceptive pills, when taken during the early stages of
an unrecognized pregnancy, are believed to be teratogenic agents.
Antithyroid drugs
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Carbimazole - Propylthiouracil (PTU)
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Both drugs cross the placenta and may cause fetal hypothyroidism in high doses. PTU is
preferred for new cases as there is less transfer across the placenta.
Corticosteroids
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When used during the 1st trimester, possibly orofacial clefts

FDA pregnancy category |B|

Hydrocortisone and prednisolone are largely (90%) metabolized by placental
dehydrogenase, but fluorinated corticosteroids (e.g. betamethasone) and dexamethasone
are not, thus making them the drugs of choice when treating the fetus is the aim of therapy,
such as for fetal lung maturation.
GI drugs
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Omeprazole does not seem to be teratogenic, but less is known about
other PPIs during pregnancy.

Ranitidine crosses the placenta. Although the manufacturer advises use should be
avoided during pregnancy, epidemiological study reveals no increased prevalence of adverse
fetal outcomes. Rodent teratogenicity studies are reassuring.

Metoclopramide has been assigned to pregnancy category B by the FDA
Dermatologic agents
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Based on large population-based follow-up studies, topical corticosteroids are generally
considered safe for use at any stage of pregnancy.
Benzodiazepines

FDA pregnancy category |D|

If benzodiazepines (especially those with a long half-life) are taken in late pregnancy,
they can cause neonatal respiratory depression, poor temperature regulation, poor
feeding and hypotonicity.
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There is a risk of neonatal withdrawal symptoms and craniofacial anomalies.
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Avoid regular use and use only if there is a clear indication such as seizure control.
Lithium
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FDA pregnancy category |D|
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Neonatal lethargy, hypotonia, poor feeding, hypothyroidism, goiter, and nephrogenic
diabetes insipidus
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Increased risk of Ebstein’s anomaly when it is used in early pregnancy.
SSRI
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Fluoxetine (category |C|) is the SSRI with lowest known risk in pregnancy.

Paroxetine is category |D|
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SSRIs should not be used during pregnancy unless the potential benefit
outweighs the risk.

There is a small increased risk of congenital heart defects when SSRIs are taken
during early pregnancy.

If SSRIs are used during the third trimester there is a risk of neonatal
withdrawal symptoms, and persistent pulmonary hypertension in the newborn
has been reported.
Opioids
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Codeine, Meperidine, Morphine

FDA pregnancy category |C|
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In neonates of women addicted to opioids, withdrawal symptoms possibly occurring
6 h to 8 days after birth
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With high doses given in the hour before delivery, possibly neonatal CNS depression
and bradycardia
Tricyclic antidepressants
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Tricyclic antidepressants (amitriptyline, imipramine, & nortriptyline) have lower known
risks than other newer antidepressants.

There is no convincing evidence that any
of the drugs commonly used to treat
respiratory disorders cause particular
problems during pregnancy.

Pseudoephedrine: possible risk of
gastroschisis. FDA pregnancy category |C|

Loratadine; Possible risk of hypospadias.
FDA pregnancy category |B|
Vaccines

Killed virus, toxoid, or recombinant vaccines
be given during pregnancy.

Live attenuated vaccines (varicella, measles, mumps, polio, and
rubella) should be given 3 months before pregnancy or postpartum.
Live virus vaccines are contra-indicated in pregnancy secondary to the
potential risk of fetal infection.
may
Caffeine
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Whether consuming caffeine in large amounts can increase perinatal
risk is unclear. Consuming caffeine in small amounts (e.g. 1 cup of
coffee/day) appears to pose little or no risk to the fetus.
Some data, which did not account for tobacco or alcohol use, suggest that consuming
large amounts increases risk of stillbirths, preterm deliveries, low birth weight, and
spontaneous abortions.
Aspartame (artificial sweetener)

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Use during pregnancy is often questioned.
The most common metabolite of aspartame, phenylalanine, is concentrated in the
fetus by active placental transport; toxic levels may cause intellectual disability.
However, when ingestion is within the usual range, fetal phenylalanine levels are far
below toxic levels. Thus, moderate ingestion of aspartame (e.g. no more than 1 liter of
diet soda per day) during pregnancy appears to pose little risk of fetal toxicity.
Smoking

Carbon monoxide and nicotine in cigarettes cause hypoxia and vasoconstriction,
increasing risk of spontaneous abortion, fetal growth restriction, abruptio
placentae, placenta previa, premature rupture of the membranes, preterm birth,
chorioamnionitis, and stillbirth.

Neonates whose mothers smoke are also more likely to have anencephaly, congenital
heart defects, orofacial clefts, sudden
infant death syndrome, deficiencies
in physical growth and intelligence,
and behavioral problems.

Smoking during pregnancy is linked
to childhood asthma.
Alcohol

Increases risk of spontaneous abortion.

Decreases birth weight by about 1 to 1.3 kg if regular drinking.

Binge drinking in particular can cause fetal alcohol syndrome. This
syndrome may include fetal growth restriction, facial and
cardiovascular defects, neurologic dysfunction, Vision or hearing
problems, behavioral, and intellectual disabilities.

It can cause neonatal death due to failure to thrive (FTT)