Medications during pregnancy

Dr. Farzana BalouchOB/GY SPECIALIST

• Introduction•  • Majority of pregnant women (40 – 90%) are exposed to

medications during pregnancy• Many medications are taken without physicians advice or

before recognition of the pregnancy• Maternal and embryofetal effects of most of the

therapeutic agents are unknown for about one-half of medications.

• In general drugs ,unless absolutely necessary ,should not be used during pregnancy because many can harm fetus .

• About 2 to 3 % of all birth defects result from the use of drugs other then alcohol.

• Medications are sometime essential therapy for serious life threatening medical conditions that are superimposed on pregnancy.

• Medications frequently used by pregnant women

• Vitamins• Iron• Analgesics• Diuretics• Anti emetics.• Antimicrobials.• Antihistamine• Hypnotic or sedatives• Laxatives.

Drugs taken by a pregnant woman reach the fetus primarily by crossing the placenta, the same route taken by oxygen and nutrients, which are needed for the fetus's growth and development. Drugs that a pregnant woman takes during pregnancy can affect the fetus in several ways:

• They can act directly on the fetus, causing damage, abnormal development (leading to birth defects), or death.

• They can alter the function of the placenta, usually by causing blood vessels to narrow (constrict) and thus reducing the supply of oxygen and nutrients to the fetus from the mother. Sometimes the result is a baby that is underweight and underdeveloped.

• They can cause the muscles of the uterus to contract forcefully, indirectly injuring the fetus by reducing its blood supply or triggering preterm labor and delivery.

How Drugs Cross the Placental

Some of the fetus's blood vessels are contained in tiny hairlike projections (villi) of the placenta that extend into the wall of the uterus. The mother's blood passes through the space surrounding the villi (intervillous space). Only a thin membrane (placental membrane) separates the mother's blood in the intervillous space from the fetus's blood in the villi. Drugs in the mother's blood can cross this membrane into blood vessels in the villi and pass through the umbilical cord to the fetus.

How a drug affects a fetus depends on the fetus's stage of development and the strength and dose of the drug. Certain drugs taken early in pregnancy (within 20 days after fertilization) may act in an all-or-nothing fashion, killing the fetus or not affecting it at all. During this early stage, the fetus is highly resistant to birth defects. However, the fetus is particularly vulnerable to birth defects between 3rd and 8th week after fertilization .

• Medications may harm the unborn child via either teratogenic effect or “fetal effects”.

• Teratogenic effect occurs during the period of organogenesis. (2-8) weeks post conception.

• A teratogen will cause a malformation in unborn child when given during the period of embryo (organogenesis)

• The period of fetus is from week nine post conception to delivery.

• Fetal effects are alterations in structure or function of organ system

• Often, a safer drug can be substituted for one that is likely to cause harm during pregnancy. For an overactive thyroid gland, propylthiouracil is usually preferred. For prevention of blood clots, the anticoagulant heparin is preferred. Several safe antibiotics, such as penicillin, are available.

• Some drugs can have effects after they are stopped. For example, isotretinoin a drug used to treat skin disorders, is stored in fat beneath the skin and is released slowly. Isotretinoin can cause birth defects if women become pregnant within 2 weeks after the drug is stopped. Therefore, women are advised to wait at least 3 to 4 weeks after the drug is stopped before they become pregnant.

• Vaccines made with a live virus (such as the rubella and varicella vaccines) are not given to women who are or might be pregnant. Other vaccines (such as those for cholera, hepatitis A and B, plague, rabies, tetanus, diphtheria, and typhoid) are given to pregnant women only if they are at substantial risk of developing that particular infection. However, all pregnant women who are in the 2nd or 3rd trimester during the influenza (flu) season should be vaccinated against the influenza virus.

• Drugs to lower high blood pressure (antihypertensives) may be needed by pregnant women who have had high blood pressure before pregnancy or who develop it during pregnancy. Either type of high blood pressure increases the risk of problems for the woman and the fetus (see Pregnancy Complications: Preeclampsia and Pregnancy Complicated by Disease: High Blood Pressure During Pregnancy). However, antihypertensives can markedly reduce blood flow to the placenta if they lower blood pressure too rapidly in pregnant women. So pregnant women who have to take these drugs are closely monitored.

• Digoxin used to treat heart failure and some abnormal heart rhythms, readily crosses the placenta. But it typically has little effect on the baby before or after birth.

• The Food and Drug (FDA)classifies drugs according to the degree of risk they pose for the fetus if they are used during pregnancy. Some drugs are highly toxic and should never be used by pregnant women because they cause severe birth defects.

• In general every medication is assigned to a category. (A,B, C, D or X) based on how safe or risky it is to use during pregnancy.

• CATEGORY A

• Only few medications fall into category A. which means human studies have shown no evidence of felet harm in the first trimester or later pregnancy.

• For all practical purposes there are no Category A drugs • CATEGORY B

• Most of the antibiotics are category B, which means there is no known association with birth defects or other pregnancy related complications and the drug is probably safe.

• Studies in animals show no risk to fetus ,and no well designed studies in humans have been done or studies in animals show a risk to fetus , but well designed studies in humans do not.

• These include:• Ampicilin• Dicloxicin• Macrobid (Nitrofurantoin) • Amoxicillin• All prenatal vitamins• Acitamenophen• Flagyl• Cephlosporins e.g cephalaxin, ceclor (cefaclor)• Duricef (Cefadroxil)• Erythromycin• Azithromycin• Zorivx (acyclovir)• Clotrimazole Vaginal

CATEGORY C

Category C means either there isn’t enough information or there are some concerns arising from animal studies, but no confirmation, of problems like birth defects in humans, but are some what more likely to have some complications for mother or fetus.

• These include.

• Bactrin, • Trimethoperin,• Ciprofloxacin, • Flucanazole, • Terconazolle • Isoniazid, Rifampin • Mebendezole• Diclofenic, • Vaccine Hepa A, B, influenza.,Meningococcus,

Pneumonia polio, Vaccines, Measles, Mumps, Rusells (in ther category but no proof that MMR vaccines cause birth defects.

• Category D:

• Category D medications have clean cut problem or health risk in pregnancy evidence show risk to human fetus and should not be used unless there are no better alternatives.sometimes benefit of the drug may overweigh risk in certain situations eg:mother may have life threatening disorder or a serious disorder that cannot be treated with safer drugs,

• Category D include.• Tetracycline• Phenytoin• Sulfa drugs• Anticonvulsants

Category X: Drugs have been showed to cause birth

defects and are not used in pregnancy under any circumstances. The risk to the fetus has been proved to outweigh any possible benefit. This include, Isotretinoin, Thalidomide, Ribaverin, Diethylstillbestrol.

Medicines with known teratogenic effects

• Retinoids

• Vitamin A – essential nutrients is prototype retinoic acid

• APP 10,000 IU Vitamin A is recommended in pregnant women

• High doses, beginning at 15, 000 IU per day are associated with risk of malformation.

• Both isotretinoin and itretinoin are derivatives of vitamin A.

• Isotretinoin is utilized for cystic acne• And etretinate is used primarly for psoriasis

• Table 3• Fetal amamolies reported to be associated with

maternal isotretinoin use.• Microtia• Anotia• Micrognathia• Cleft palate• Heart defects• Eye anomalies • Brain anomalies• Hydrocephalus• Thymic agenesis• Limb reduction anomalies

• In review of more than 80 pregnancies exposed to isotretinoin during early pregnancy 1/3 were associated with bad out come. Brain anomalies

• About 19% spontaneous abortion• 28% had malformation• Ettretinate has been reported to be

associated with CNS, craniofacail and skeletal anomalies

ANTINEOPLASTICS Folate antagonist (aminopterin, methotrexate)

are well known human teratogens.

Features of fetal amiopterin syndrome are:

* Short stature* Calvarial ossification* Hydroceph

• Busulfan (myleran) is an alkylating agent to treat some leukemia it is associated with fetal growth retardation, cleft palate and eye defects.

• Cyclophosphamide, (used for ovarian, cervical, and endometrial and breast cancinos) is associated with cleft palate, absence of digits, imperforate anus and IUGR.

• ANTICONVULSANTS

• Increased risk of congenital anomalies has been reported to be associated with anti convulsants.

• e.g Phenytoin, trimethadiones carbamazepine and valproic acid.

• The hydantoin agents (phenytoin ethotoin, mephentoin) are associated with congenital anomalies called fetal hydantoin syndrome.

• FEATURES OF FETAL HYDRATION SYNDROME

• Craniofacial abnormalities• Cleft left palate• Hypertelorism• Broad nasal bridge• Hypoplasia of distal phalanges and nails.• Growth deficiency• Mental deficiency

• The dione anti convulsant, paramethadione, trimethadion consisted of abnormalities similar to fetal hydration syndrome.

 • Carbamazepine (tegretol) was thought be safe

for use in pregnancy for many years. It has been reported that it use during early pregnancy can cause malformation very similar caused by phenytoin.

• Valproic Acid – most commonly used agent for petit mal seizurs.

• This agent is associated with high risk 10-20% of neural tube defects.

ANTICOAGULANTS

Warfarin a coumarin anticoagulant is relatively small molecule and readily cross plants.

It causes distinct pattern of anomalies termed as warfarin embropathy occurring in 15-25% of offsprings of mother using warfarin in early pregnancy.

Characteristic features of warfarin syndrome are.

• Nasal hypoplasia• stippled bone epiphyses• Malformed vertebral bodies,• Hydrocephaly,• Microcephaly• Growth retardation.

• HORMONES

• Maternal androgen therapy (ie. Testosterone) may result virilization of the external genitelia of female fetus, including clitorial enlargement and labioscrotal fusion.

• The anti emdometriosis drug; danazol can cause same effect as testerone.

• DES non-steroidal synthetic estrogen is associated with clear cell adeno carcinoma of vagina, in the progeny of women exposed to it during late embrogenesis also can cause vaginal adenosis, T-shaped uterus, uterine hypoplasia, incomplete cervix.

• The other risks to this hormone are preterm labour, spontaneous abortion and ectopic pregnancy.

• In male offspring can cause epididymel cyst, hypoplastic tests

• Clearly DES is contraindicated for pregnancy.

• PSYCHOTROPICS

• Lithium is used primarily to treat affected mental disorders.

• This agent used in early gestation is associated with increased risk of cardiovascular anomalies in exposed offspring.

• 1% of lithium exposed pregnancies may have Ebstains anomaly.

• Polyhydramnios and fetal diabetes incipedus are possible secondary complication of lithium during 2nd & 3rd trimester.

• OTHERS

• Pencillamine – • is used to treat rheumatoid arthritics and

cystimures, also used as chelating agent for heavy metal poisoning (eg lead).

• This agent is reported to be associated with connective tissue disorders in the offspring of exposed mothers in pregnancy.

THALIDOMIDEThis hypnotic/sedaline is the best known of

the all human teratogen.Thalidomide taken between 27 to 42

postconception produse phocomelia(absence of long bones from upper and/or lower limbs),external ear and heart defects

Some Drugs That Can Cause Problems Dung Pregnancy*

• USE OF SOME COMMON MEDICATION DURING PREGNANCY

• Medications that are considered safe in pregnancy are those that have been used extensively in humans and not appear to cause any major birth defects with other problems

• The majority currently available medicine is not proven to be human teratogen,_although fewer than 40% have been adequately studied for use in human pregnancy.

•Important, absence of evidence is not evidence of absence.

ANTI MICOBIALS

-Infections occur commonly during pregnancy-Antibacterial, antifungal, anti virals and

antiparasites are antimicrobial agents prescribed during pregnancy.

• All the Penicillin are apparently safe for use during pregnancy in patients not allergic to these drugs.

• All the Penicillin cross the placenta, resulting in significant fetal levels. This are drugs of choice treating Syphylis during pregnancy.

• Cephalosporins also cross placenta to similar degree like penicillin resulting in significant fetal levels similar to that in mother.

• There is no controlled scientific studies regarding cephalosporins use in pregnancy.

• Second and third generation cephalosporins contain N-methyl thio tetrazole (MTT) side chain that was reported to be associated with testicular hypoplasia in new born animals.

• Cefoxitin a commonly used 2nd generation have no MTT side chain, this apper to be rational choice when therapy with broad spectrum cephalosporins if indicated during pregnancy.

• Erythromycin a macrolide antibiotic is not associated with adverse fetal effects. This agent doest not cross placenta in appreciable quantity.

• All aminoglycosides cross the placenta to some degree and result in significant level.

• A drug is this class streptomycin, has been associated with 8th cranial nerve damage ( sensorineural deafness ) in fetus whose mothers received it for a significant time during pregnancy .

• Clindamycin is utilized primarily for anaerobic infections and known to cross placenta. There are no scientific studies regarding its use in pregnancy, it effects on the developing fetus are unknown.

• Sulfonamide and trimethoprim are often used in combination primarily to treat UTI.

• Sulfonamides is utilized during late gestation can cause neonatal hyperbilirubinemia.

• Trimetroprim is weak folate antagonist but is not associated with increased risk of anomalies

• Nitrofurantion also safe to use in pregnancy.• Fluoroquinilona ( cipro and norfloxacin) are also

used to treat UTI. There are no scientific studies ,but can cause irreversible arthopathy in dogs whose mothers were given drug during pregnancy.

• ANTIFUNGALS

• -Antifungals commonly used are clotrimazole, miconizole nestatin and Amphotericin B. The use of these drugs is not associated with increased risk of malformations .griseoflavin utilized for the treatment of mycotic infection of skin and nails has been repeates of increased central nervous system and skeletal anomalies inanimal studies.

• ANTIVIRALS

• Frequently prescribed antivirals agents include Zidovudine, acyclovir, amantadine. Ramantadine rebavirin, vidarabine.

• AZT (Zidovudine) is currently the primary agent for the treatment of HIV infection. Among 10 infants whose mothers took AZT in the first trimester there were no birth defects.

• Acyclovir is the drug of choice to treat herpes viruses and varicella, is currently recommended for routine use in pregnant women with genital herpes,

• Amantadine if taken early pregnancy can cause malfomatios in fetus..

• Ribavirin is administered as an aerosol in the treatment of respiratory syncytial viral infection in infants. It seems to be a potent teratogen therefore should not be used in pregnancy.

• ANTI PARASITIC AGENTS

• Commonly prescribed anti parasitics are metronidazole and nitromidazole.

• Metronidazole ia apparently safe for use during pregnancy.

• Lidane is a topical agent indicated for treatment of pediculosis pubis and scabies can cause CNC toxicity however topical preparation over limited surface area seems to result in minimal systems absorption.

• Chloroquine is first line antimaterial agent. There is no increased risk of congenital with its use.

• Quinine is the prototype antimaterial agent and used to treat chloroquine resistant plasmodium.

• Large doses may cause otolithic agenesis, eye defects and vestibular in infants born to mothers who took therapeutic large doses of this drug during first trimester.

• Pyrimethamine is an anti parasitic agent for treatment of malaria and toxoplasmosis. Two other agent spiramycin and sulfadiazine is also used to treat toxoplasmos, but no scientific studies of the effects of either agent have been and published.

• Mebendazole is an anti parasitic that is effective to treat helminthic infections , including enterobiasis (pinworm), tricluriasis (whipworms), nectoriasis (hookworm), mebendazole has been reported to be texatogenic in laboratory animals.

• Thiabendazole is another antihelminthic agent no studies available for its use in pregnancy.

• CARDIOVASCULAR DISEASES •  • The prevalence of cardiovascular diseases

among pregnant women is approximatly 3-5%. Most gravidas require these medications because these drugs are given to treat life threatening conditions.

• With few exceptions cardiovascular medicine may be given during pregnancy with minimal risk to unborn child.

•  • Cardiovascular Agent for which either there are

no epidemiological studies or are used frequently without adverse fetal effects include.

ANTIHYPERTENSIVE:Mellyldopa, (Aldomet), Clonidine ext.

ANTIARRYTHMICS Digoxin – also used to treat fetal cardiac erelythmias

since readily cross placenta. Quinidine – lidocaine Amiodazone.

ANTI ANGINAL• Nitroglycerine, amyl nitratye, can be used as

life safeing drugs.• Dipyramidole, not tevatogenic in animal studies•  DIURETICS• Thiazide diuretics are not associated with an

increased frequency of congenital anomalies among exposed infants.

• ASTHMA: • Asthma occurs among 1-3% gravidas.• Two major classes are used in asthma

bronchodilators and immunosuppressents. These are relativity safe in pregnancy.

• Theophylline, terbutaline, salbutamol, albuterol, have no significant teratogenic or fetal effects.

• Epinephrine is another bronchodilator. It is reserved for acute asthmatic attacks.

• An increased frequency of non major malformations is reported with its use.

• Immunosuppressant:

• Cromolyn sodium ( nasal crom)• Glucocorticoids ex: beclamethazone,

betamethazone• Dexamethazone• Acute asthmatic attack may be life threatening• These agents should be utilized because

potential risk clearly outweigh potential benefit.

• PSYCHOTROPICS

• Psychiatric illness occurs among 1-2% of gravidas.• Treatment of most Psychiatric disorders should continue

because abrupt discontinuation may have adverse effects ,includind suicie gestures.

• Numerous sedative, hypnotics and tranquilizers are commercially available.

• The most commonly used are, Phenobarbitol prescribed as sedative, secobarbitol short acting barbiterate for sleep medication, diazepam, chlordiazepoxide ( Librium, Librex, etc) are used as minor tranquilizer. Meprobamile is minor tranquilizer & muscle relaxant and chloral hydrate also minor sedatine frequency of malformations was not increased with use of these drugs.

• Initially diazepam was thought to be associated with increased risk of facial cleft but is not confirmed by large studies.

• Chlordiazepoxide also has been reported to be associated with congenital anomalies in one study, but not confirmed in other larger studies.

• Antidepressants: • The antidepressants are generally devided into tricyclic

and non tricyclic agent.• Commonly used tricyclic antidepressants are impramine ,

amitriphyline, anoxapine etc.• Only one tricyclic agent amitriphyline has been reported

to cause limb reduction defects, such association not confirmed by other studies.

• Fluoxetine ( Prozac) is currently one of the most frequently prescribed antideppressents, The frequency of congenital anomalies is not increased with its use.

Antihistamines:

Chlorphenaranine, Laratadine, doxylamine, bromphenerine diphenlydramine are low risk during pregnancy. It is best to avoid prendo ephedrine and pherylephrine during first trimester, there have been same reports of birth defects.

• ANALGESICS• Analgesics are the medications most commonly

prescribed to pregnant women with few exceptions, most analgesics can be given to pregnant women with relative safety.

• Some commonly used non-steroidal anti-inflammatory effects

• Indomethacin (indocin)• Ibuprofen (Advil, Brufen, Prof)• Fenaprofen (Nalfon)• Meclofenamide (Meclamin)• Naproxen (Anaprex, Proxen)• Diflunisel (Dolobid)• Diclofenac (Voltaren)

• The frequency of congenital anomalies is not increased if given during first trimester.

• The major concern with NSAID’s possible association with premature closure of ductus artriosis when given during later half of pregnancy.

• These have also been reported to be associated with decreased liquor.

• NSAID’s generally not recommended after 34 weeks of gestation age because of theoretical risk of adverse effects.

• These agents are probably relatively safe before this gestation especially if given acutly.

• Large dose of asprin may also be associated with hemorrhagic disorders in both mother and fetus due to lower platelet activity.

• Acitamenophen is the preferred analgesic for use in pregnancy,it is apparently not associated with premature ductal closure or oligohydriamios.

• NARCOTIC ANALGESICS• The more frequently prescribed drug in this class

include codeine, meperidine, morphine, pentizocaine, sutophanol, nalbuphine, propoxyphene etc.

• Narcotic analgesics can cause a transient withdrawal syndrome in newborn when taken on chronic basis.

• None of these analgesics was associate increased frequency of malformations.

• Acute large doses near time of delivery especially morphine may be associated with newborn respiratory depression.

THYROID MEDICATIONSThyroxine does not cross the placenta to any

great extent so not associated with congenital anomalies.

ANTITHYROID MEDICATION• Agents used to treat hyperthyroidism are: Propyl-

thiouracil (PTU) methimezole, Potassium iodine and Propanolol.

• All three antithyroid drugs cross placenta • PTU may result in fetal hypothyroidism and goiter

formation, but unusual with therapeutic regimen.• No evidence that PTU is associated with malformation.• Methimezole was reportedly associated with scalp

defects but other investigation not confirm the association.

• Potassium iodide and sodium iodide block release of thyroid hormone. Prolonged use may result in fetal hypothyroidism and goiter formation.

• It is highly unlikely that iodide medications will result such adverse effect when given actually (thyroid storm)

•  • MANAGEMENT OF THE PREGNANT PATIENT WITH

MEDICATION EXPOSURE• Management of patient who has been exposed to

medication during pregnancy especially during critical period of organogenesis present challenge to clinical.

• There are several important questions that will arise:

• Is the medication was known taratogen?• Are there potential adverse effects or neonatal effects?• What is risk to mother with use of medications or if it is

withheld?• Are there other factors that may be important than

medication such as disease being treated?• How should the patient be counseled?

• INADVERENT EXPOSURE TO MEDICATION

• Obtain accurate details of exposure, especially gestational age.

• Check the confounding family history.• Get up-to-date information regarding

published risks of specific drug to known.• Emphasize background risks in conceiving• Be clear about what is known, do not assume

absence of date means no risk.

• CONSIDERATION OF COMMENCING/CONTINUING MEDICATION

• Medication should be used only if expected benefits ( to mother) are greater than risk (usually to fetus).

• Use drug which have been extensively used in mother rather than new/untried drugs.

• Use minimum dose for desired effect.• Absence of data does not imply safety.

• COUNSELLI NG THE PATIENT• Before counseling the patient and her family, it is

important to take detailed history and do physical examination.

• Establishing gestational age and timing of exposure is of importance.

• If it can be determined that medication was taken before conception or after period of organogenesis, counseling may simply consist of Reassurance.

• For known teratogens with reasonable established risk therapeutic option in exposed patients should include pregnancy termination.

• Al counseling should begin with explanation of ‘background’ risk of congenital anomalies in general population(i.e. 3-51).

• For certain medical illness (i.e. diabetes, seizure disorders) the risk of the condition itself, especially if untreated, generally for outweight may known or theoretical risk of medication to concepts such medication could not withheld from woman just because she is pregnant.

• Preconceptional counseling is preferred in such patients.• Finally when medications are being considered for

pregnant woman, it is important to consider whether the initiation of therapy can be delayed until after the completion of first trimester (i.e embrogenesis)

• But can not be delayed for example in leukemia patient, as chemotherapy should began as soon as diagnosis is confound regardless of gestational age.

Thank you