INTRODUCTION



The safety of approximately 50 % of medications for the mother and fetus remains unknown



Pharmacokinetics are profoundly affected by pregnancy associated physiologic changes and dose adjustments are sometimes necessary for optimal clinical outcome

Teratogens



A substance, organism, physical agents or deficiency state capable of inducing abnormal structure or function such as:



Gross structural abnormalities



Functional deficiencies



Intrauterine growth restriction



Behavioral aberrations



Demis e

Current Categories for Drug Use in Pregnancy



Category A : Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities.

Examples:



Magnesium sulphate



Levotyroxine



vitamins

 

Current Categories for Drug Use in Pregnancy

Category B : Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well controlled studies in pregnant women.

or Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus

Examples:



Amoxiciliin



Amoxicillin + Clavulanic acid



Cefotaxime



Methyl dopa



Metronidazole



Erythromycin

Current Categories for Drug Use in Pregnancy

 

Category C: Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women.

or No animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women

Examples:



Diclofenac



Rifampicin



Fluoroquinolones



Aminoglycosides



Glyburide



Beta blocker



Calcium channel blocker

Current Categories for Drug Use in Pregnancy

Category D:



Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential harm

Examples:



Tetracyclines



Phenytoin



Valproic acid

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Carbamazepine



ACE inhibitors



Litium



azothioporine

Current Categories for Drug Use in Pregnancy Category X:



Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. The use of the product is contraindicated in women who are or may become pregnant.

Examples:



Thalidomide



Oral contraceptive pills



Misoprostol

DRUGS USED COMMONLY IN PREGNANCY



ANTIBIOTICS:



Cephalosporins



Fluoroquinolones



Macrolides



Aminoglycosides



Miscellaneous

CEPHALOSPORINS

(Eg: Ceftriaxone, Cefixime, Cefotaxime) Category B in pregnancy



Cross the placenta during pregnancy

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Some reports of increased anomalies with specific cephalosporins (cefaclor, cephalexin, cephradrine)



Primarily cardiac and oral cleft defects

 

Lactation Excreted into breastmilk in low concentrations Considered compatible with breastfeeding

  

FLUOROQUINOLONES

(Eg: Ciprofloxacin, Norfloxacin) Pregnancy Category C Not recommended in pregnancy Cartilage damage in animals Safer alternatives usually exist

  

Lactation Excreted into breastmilk Limited human data compatible with breastfeeding

MACROLIDES

(Eg: Azithromycin, Clarithromycin, Erythromycin) Pregnancy Categories B/C/B



Cross the placenta in low amounts



Limited data with azithromycin and clarithromycin Lactation



Erythromycin compatible



Others probably compatible

AMINOGLYCOSIDES

(Gentamicin, Amikacin)



Pregnancy Category C

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Rapidly cross placenta



Enter amniotic fluid through fetal circulation

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Lactation



Compatible with breastfeeding



Not absorbed through GI tract

Tetracyclines

(doxycycline, minocycline, tetracycline)



Pregnancy Category D

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Can cause problems with teeth and bone and other defects/effects



Have been linked to maternal liver toxicity



Lactation



Compatible with breastfeeding

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Serum levels in infants undetectable

MISCELLANEOUS ANTIBIOTICS



Clindamycin



Pregnancy Category B, commonly used

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Lactation – Compatible

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Metronidazole

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Pregnancy Category B, carcinogenic in animals, avoid in 1 st trimester if possible



Lactation – hold feeds for 12-24hrs afterward

MISCELLANEOUS ANTIBIOTICS



Vancomycin



Pregnancy Category B, compatible

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Lactation – likely compatible, not absorbed



Nitrofurantoin

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Pregnancy Category B, possible hemolytic anemia with use at term



Lactation – Compatible, avoid with G-6-PD deficiency

MISCELLANEOUS ANTIBIOTICS



Trimethoprim



Pregnancy Category C, potentially problematic early in pregnancy



Lactation – Compatible as combination drug

Antivirals

(acyclovir, famciclovir, valacyclovir)



Pregnancy Category B



Acyclovir and valacyclovir readily cross the placenta



Can be used for HSV treatment and suppression

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Lactation



Acyclovir and valacyclovir are compatible



Famciclovir should be avoided

Antiretrovirals/NRTI

(abacavir, didanosine (ddI), emtricitabine (FTC))



Pregnancy Categories C/B/B



Maternal benefit usually outweighs fetal risk



Cross the placenta



Limited data with each do not show increased risk of anomalies



Didanosine has been associated with severe lactic acidosis w/ or w/o pancreatitis

Antiretrovirals/NRTI

(lamuvidine (3TC), stavudine (d4T))



Pregnancy Category C



Maternal benefit usually outweighs fetal risk



Cross the placenta by simple diffusion



Data with lamivudine show no increased risk of anomalies



Stavudine has been associated with severe lactic acidosis w/ or w/o pancreatitis

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All NRTIs have been possibly linked to mitochondrial dysfunction postnatally

Antifungals/Azoles

(fluconazole, itraconazole, ketoconazole, posaconazole,



voriconazole) Pregnancy Categories C/C/C/D



Likely cross placenta

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Fluconazole > 400mg/day seems to be associated with cranio-facial abnormalities

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Itraconazole appears to have low risk

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Ketoconazole can impair testosterone and cortisol synthesis

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No data in humans is available for voriconazole, increased risk in animals

Antifungals/Azoles

(fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)



Lactation



Fluconazole is compatible



Itraconazole could concentrate in milk and body tissues, not recommended



Ketoconazole is compatible



No data with voriconazole, not recommended

Migraine Headache Therapy



Triptans

 

Ergots Caffeine

Triptans (5-HT1 agonists)



Pregnancy Category C



Limited human data exists, sumatriptan has been associated with VSDs in several cases



No data available in humans for almotriptan, eletriptan, frovatriptan, or zolmitriptan

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Limited human data exists with naratriptan and rizatriptan, although animal data indicates moderate risks



Pregnancy registry available for exposures

Triptans (5-HT1 agonists)



Lactation



Cross into breastmilk and may concentrate



No reports of human lactation with almotriptan, frovotriptan, naratriptan, rizatriptan, or zolmitriptan



Sumatriptan is compatible



Eletriptan is likely compatible with low concentrations

Ergots

(Dihydroergotamine, ergotamine)



Pregnancy Category X

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Oxytocic properties could cause IUGR by vascular disruption or increased uterine tone

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Early exposure appears safe, not teratogens

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Chronic exposure is contraindicated

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Lactation

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Contraindicated

ANTICONVULSANTS

HYDANTOIN AGENTS Category D

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Hydantoin agents (Phenytoin) are teratogens long recognised for constellation of congenital anomalies known as fetal hydantoin syndrome

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The syndrome consists of craniofacial abnormalities , mental deficiency , hypoplasia of phalanges

ANTICONVULSANTS

CARBAMAZEPINE: Category D



Was considered relatively safe for use during pregnancy but recent FDA reports suggest increased risk of neural tube defects with carbamazepine too and a pattern of malformations similar to phenytoin

 Increases the risk facial dysmorphology, neural tube defects, cardiovascular defects, and urinary tract defects.

ANTICONVULSANTS

VALPROIC ACID: Category D

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It is commonly used for petit mal seizures

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1 to 2 % risk of neural tube defects with use in pregnancy

 atrial septal defect, cleft palate, hypospadias, polydactyly, and craniosynostosis.

Antidepressants

 Recent publications have implicated some of the SSRIs administered in the last trimester with postnatal neurobehavioral effects that are transient and whose long-term effects have not been determined. First trimester exposures to some SSRIs have been reported to increase the risk of some congenital malformations, predominantly congenital heart disease. The results have not been consistent, but warnings have been issued.

Antituberculous therapy

 Isoniazid and paraaminosalicylic acid have an increased risk for some CNS abnormalities.

Corticosteroids

 High exposures administered systemically have a low risk for cleft palate in some studies, but the epidemiologic studies are not consistent.

Methimazole

 Aplasia cutis has been reported to be increased in mothers administered this drug during pregnancy*

Warfarin and warfarin derivatives

 Early exposure during pregnancy can result in nasal hypoplasia, stippling of secondary epiphysis, intrauterine growth restriction. Central nervous system malformations can occur in late pregnancy exposure because of bleeding.

NSAIDs and aspirin

  Aspirin has been used for years in patients requiring NSAID therapy during pregnancy. Salicylates readily cross the placenta, but a 2002 meta-analysis did not find evidence of an overall increase in risk of congenital defects associated with first trimester use of aspirin .Although some case-control studies have reported associations between human congenital malformations and aspirin use early in gestation, no consistent adverse outcome attributable to drug use has been observed.

The NSAIDs and salicylates are considered by the FDA as category C drugs in terms of the risks associated with their use during the first two trimesters .A number of the NSAIDs are labeled as category D drugs from week 30 onwards, and high-dose aspirin is considered a category D medication during the third trimester

 However, third trimester use of these agents may pose greater risk. The inhibition of prostaglandin synthesis by NSAIDs or by high-dose aspirin therapy in the third trimester has the potential for causing premature closure of the ductus arteriosus; indomethacin and ibuprofen appear to have much stronger ductal effects than aspirin .High-dose aspirin near delivery may increase the risk of fetal or neonatal bleeding or bruising although data are inconsistent

PROSTAGLANDINS

    

They are synthesised from essential fatty acids PGF2a promotes myometrial contractility , is produced mainly from decidua PGE2 helps cervical maturation / ripening , is mainly produced from amnion They also sensitise myometrium to oxytocin Commonly used for induction of labour

PROSTAGLANDINS

PGE1 – Misoprostol: (Category X)

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PGE1 promotes cervical ripening and myometrial contractility is increased

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Transvaginally used for induction of labour

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Failure of induction is less



Can be used per rectally /orally also

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Incidence of tachysystole is high and thus should not be used in cases with previous ceasarean birth

ANTIHYPERTENSIVES

METHYL DOPA: Category B



It is the drug of first choice in pregnancy



Has central and peripheral anti adrenergic action



Safe for both mother and fetus

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Postural hypotension is a common side effect

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May be given orally or i.v

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Doses start from 25o mg bd to 500 mg four times a day

ANTIHYPERTENSIVES

NIFEDIPINE:



Cause direct arteriolar vasodilatation by inhibition of slow calcium channels

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Flushing , hypotension , headache , tachycardia are side effects noted

ANTIHYPERTENSIVES

LABETALOL:



Has combined alpha and beta adrenergic blocking actions

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Can be used orally and as iv infusion



Efficacy and safety appears to be equal to methyl dopa



Dose is 100 mg twice a day

ANTIHYPERTENSIVES

ACE INHIBITORS: Category C or D



Not used in pregnancy as studies show increased risk of oligohydramnios , neonatal anuria , renal anomalies and nephrotoxicity when used in 2 nd and 3 rd trimesters



Thus considered human teratogens

ANTIHYPERTENSIVES

SODIUM NITROPRUSSIDE:



It is used to treat serious , life threatening hypertension



Animal studies have shown fetal cyanide toxicity but human studies have not proved the same



Nonetheless , it is avoided in preganancy and is only used as last resort

ANTIHYPERTENSIVES

MAGNESIUM SULPHATE: Category A



Mechanism of action :



It decreases acetycholine release from nerve endings and reduces motor end plate sensitivity to acetylcholine



It blocks calcium channels and causes vasodilation

 

Can be given by Pritchard regime Zuspan regime or

Pritchard Regime:

4 gm iv slowly followed by 5 gm in each buttock deep im -- loading dose 5 gm deep im 4 hourly in alternate buttock

       

Indications:

In eclampsia , as an anticonvulsant As a tocolytic

Contraindications

In patients with renal impairment

Dosage:

For I.V infusion , 50% solution must be diluted to 20 % before administration 50% solution (undiluted) is given for intramuscular injections

  

It is relatively safe . Muscular paresis , respiratory failure and renal effects on mother are known side effects Thus deep tendon reflexes, respiratory rate and urine output monitoring is essential in a patient receiving Magnesium Sulpahate Has no harmful effects on fetus though neonatal respiratory depression may be seen

TOCOLYTICS



BETAMIMETICS:( Terbutaline , Isoxsuprine) Category C Mechanism of action:



They activate intracellular enzymes and reduce intracellular free calcium which leads to reduced interaction of actin and myosin

Dosage:



Terbutaline can be subcutaneously 0.25 mg 6 hourly or orally 0.5 mg 6 hourly



Isoxsuprine is given either as intravenous infusion drip or intramuscularly(10mg 6 hourly) or orally (10 mg 6/8 hourly)



Contraindications :

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Cardiac arrhythmias

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Poorly controlled diabetes mellitus

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Poorly controlled thyroid disorders

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Maternal side effects are headache , palpitations , pulmonary edema , hyperglycemia and hypotension

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Fetal tachycardia , heart failure may be seen

    

INDOMETHACIN AND CALCIUM CHANNEL BLOCKERS : They are also used commonly for tocolysis Indomethacin may cause gastric disturbances in mother Calcium channel blockers may cause headache , flushing Both cause no known fetal harm

OXYTOCIN



Mechanism of action:

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It acts through calcium channels to initiate myometrial contractions



Also stimulate amniotic and decidual prostaglandin production

OXYTOCIN

Routes of administration:



Can be given intramuscularly or by controlled intravenous infusion

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It is also available as nasal solution , buccal tablets

OXYTOCIN

Indications:



Induction of labour



Augmentation of labour

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In active management of third stage, as an alternative to methergin



To control postpartum hemorrhage

OXYTOCIN

Contraindications:



Obstructed labour



Malpresentations



Contracted pelvis



History of previous Caesarean section/hysterotomy (relative contraindication)

OXYTOCIN

Maternal side effects:



Uterine hyperstimulation (sometimes rupture)



Water intoxication due to its antidiuretic effect



Hypotension

OXYTOCIN

Fetal side effects:



Fetal distress , fetal hypoxia or even fetal death may occur due to hyperstimulation

ERGOT DERIVATIVES

METHERGIN: (Category X) Mechanism of action:



Acts directly on myometrium and cause tetanic uterine contractions

Route of administration:



Parenterally – 0.2 mg ampoules available



Orally – 0.5 or 1 mg tablets available

ERGOT DERIVATIVES

Indications:



Therapeutic:



To stop atonic uterine bleeding following delivery or abortion



Prophylactic :



Should be only used in second stage of labour after delivery of anterior shoulder or following delivery of baby

ERGOT DERIVATIVES

Contraindications:



In cardiac diseases



Rh negative pregnancies



Severe pre-eclampsia/eclampsia

IRON DEXTRAN

  

It is intramuscularly used iron preparation for treatment of iron deficiency anemia 1 ml of iron dextran contains 50 mg elemental iron Oral iron to be stopped 24 hour before therapy to avoid reactions

IRON DEXTRAN



Mode of administration:



Dose to be given is initially calculated



Initial test dose is given



This is followed by daily or alternate day injections given deep im by Z technique

IRON DEXTRAN

Drawbacks:



Injections are painful



May cause staining of skin



Allergic reactions , though rare , may occur



Abscess formation over injection site may occur

IRON DEXTRAN

Indications:



Iron deficiency anemia , when oral iron therapy is unsatisfactory or not tolerated

Contraindications:



Anemia other than iron deficiency



Hypersensitivity to the product

Ionizing radiationRadiation

 Ionizing radiationRadiation exposure above a threshold of 20 rad (0.2 Gy) can increase the risk for some fetal effects such as microcephaly or growth retardation, but the threshold for mental retardation is higher.

Some common teratogenic medications include:

   

Angiotensin converting enzyme inhibitors. Anticonvulsant agents Antineoplastic agents Thalidomide , retinoic acid, blue , misoprostol , methylene penicillamine , fluconazole , hium , isotretinoin , and acitretin lit

Some common teratogenic medications include:



Retinoic acid is highly teratogenic in the first trimester of pregnancy, leading to spontaneous abortions and fetal malformations, including microcephaly and cardiac anomalies . At doses of only several times the RDA , many animal models as well as human studies have shown high incidence of birth defects in mothers who ingested therapeutic doses of retinoic acid for dermatological uses . A safe upper limit for vitamin A intake has been recognized at about 800 to 10,000 IU/day .

Acitretin should not be used by women who want to become pregnant as conception is contraindicated for at least three years after discontinuation.

Some common teratogenic medications include:



Androgenic agents, such as testosterone or danazol , do not cause malformation, but can virilize a female fetus. Cocaine induced vasoconstriction of uterine vessels is one mechanism for fetal damage from this substance . Infants whose mothers consume alcohol during pregnancy can have fetal alcohol effects (FAE), alcohol related birth defects (ARBD), fetal alcohol syndrome, or they may be normal.

Some common teratogenic medications include:



Folicacid antagonists(eg, bamazepine , phenytoin , trimethoprim phenobarbital , , triamterene , primidone , car met hotrexate ) increase the risk of neural-tube defects and possibly cardiovascular defects, oral clefts, and urinary tract defects and placenta-mediated adverse pregnancy outcomes, including preeclampsia, placental abruption, fetal growth restriction, and fetal death .

       Specific information on the fetal and neonatal risks of maternal drug ingestion during pregnancy and lactation are available from several resources , including: www.perinatology.com/exposures/druglist.htm

www.reprotox.org/ (requires subscription) www.OTISpregnancy.org

file://depts.washington.edu/terisweb/teris/ (requires subscription) www.motherisk.org/women/drugs.jsp

UpToDate drug information database

Antibiotics in Pregnancy

          Penicillins Erythromycin Cephalosporins Nitrofurantoin Metronidazole Trimethoprim Sulpha drugs Chloramphenicol Tetracycline Gentamicin           A A A A B2 B3 C A D D

Anti-malarial drugs for Pregnancy

 Chloroquine  A  Quinine  D  Paludrine  B2  Maloprim, Daroprim  B3  Larium  B3  Fansidar  D  Doxycycline  D

HAART drugs for Pregnancy

     AZT Lamivudine Nevirapine 3TC Abacavir      B3 B3 B3 B3 B3

Anti-emetics for Pregnancy

       Pyridoxine Diphenhydramine Metoclopromide Hyoscine Ondansetron Promethazine Prochlorperazine        A A A B2 B1 C C

Antihypertensive drugs in Pregnancy

      Aldomet Hydralazine Beta blockers Ca channel blockers Thiazides ACE Inhibitors        A C C C C D ↑ risk of CNS & CHD defects 3 fold in 1 st trimester, ?cause

Analgesic Drugs for Pregnancy

 Paracetamol  A  Codeine  A  Aspirin  C  Narcotics  C  NSAIDs  C  Have the potential to cause in utero closure of the ductus arteriosus >34w

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