Drugs in pregnancy

SAMEER SALEH SAWAED

2016

Drug EpidemiologyMore 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

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. Drugs transferred across placenta

undergo 1st pass through the fetal liver.

Liver expresses metabolizing enzymes, but capacity less than mother.

Fetal kidney immature.

Placental Pharmacokinetics

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 TransferMost 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 bindingdegree of ionization at physiologic pHplacental 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 :

(all-or-nothing effect), Teratogenesis is unlikely during this stage.

During organogenesis (between 20 and 56 days after fertilization):  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 includecongenital malformations with varying

severityintrauterine growth restrictioncarcinogenesisfetal 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 organogenesisabout 20 to 55 days after conceptionabout 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 well-controlled 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 | ChloramphenicolQuinolones [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 trimestersAmantadine|C| CHD; tetralogy of Fallot / single ventricle with pulmonary atresiaAnti-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 toxicityTerbinafine; 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 CHD Eye abnormalities 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- cognitive impairment- dysmorphic features- risk of autism

Diethylstilbestrol [Des]

Human teratogen |X|- Vaginal adenosis- Cervical erosions- Transverse vaginal ridges- Vaginal adenocarcinoma

Vitamin A Analogues

Isotretinoin*** |X|; Potent teratogenic- Severe birth defects- Neuropsychological impairment- Spontaneous abortion- Premature birth- Fetal death- Internal abnormalities

ANTICOAGULANTS 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 FDA Pregnancy category |C| Can cause Fetal bradycardia, hypoglycemia, & possibly fetal

growth restriction

Amiodarone 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 FDA Pregnancy Category |B|

Thiazide diuretics 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 Carbimazole - Propylthiouracil (PTU) 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 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 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 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.

There is a risk of neonatal withdrawal symptoms and craniofacial anomalies.

Avoid regular use and use only if there is a clear indication such as seizure control.

Lithium FDA pregnancy category |D| Neonatal lethargy, hypotonia, poor feeding, hypothyroidism,

goiter, and nephrogenic diabetes insipidus Increased risk of Ebstein’s anomaly when it is used in early

pregnancy.

SSRI Fluoxetine (category |C|) is the SSRI with lowest

known risk in pregnancy. Paroxetine is category |D| 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 Codeine, Meperidine, Morphine FDA pregnancy category |C| In neonates of women addicted to opioids,

withdrawal symptoms possibly occurring 6 h to 8 days after birth

With high doses given in the hour before delivery, possibly neonatal CNS depression and bradycardia

Tricyclic antidepressants 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 may 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.

Caffeine 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) 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)