Company LOGO Principles of drug use in pregnancy Maulana A. Empitu Department of Pharmacology Airlangga University – School of Medicine

History  Thalidomide: probably the most notorious human teratogen  Marketed as a sedative in late 1950’s  Associated with up to 12,000 birth defects, primarily phocomelias  Other effects included:  facial hemangiomata, oesophageal & duodenal atresia, teratology of Fallot, renal agenesis & anomalies of the external ear

Thalidomide  No malformations if taken before the 34 th day after last menstruation & usually no malformations if taken after the 50 th day  Sensitive time period: day 35 to day 49  Day 35 – 37: absence of ears & deafness  Day 39 – 41: absence of arms  Day 43 – 44: phocomelia with three fingers  Day 46 – 48: thumbs with three joints  If taken throughout the sensitive period: severe defects of the ears, arms & legs & internal malformations often leading to early death (40% died before their 1 st birthday)

Thalidomide  20% of pregnancies exposed during this period resulted in anomalies  Administration to female rabbits did not show any adverse effects on fertility  There was an increase in early pregnancy loss (equivalent to miscarriage)  There were no thalidomide-associated malformations in surviving foetuses

Overview  All drugs should be avoided in pregnancy unless they are ‘essential’  In practice, it may not be easy to know what treatment is really necessary or whether a particular medicine is an appropriate choice  Requires a balanced approach:  Being over-cautious may deny a beneficial therapy  Lack of due caution might harm babies as a consequence of drug exposure  Benefits of treatment need to be weighed against the risks of giving no medication  Note: while the benefits of Tx may be clear, the risks may be largely unknown or unquantifiable  For minor conditions, the risks almost always outweigh the (often trivial) benefits

The problem  80% of women use prescribed or OTC drugs during pregnancy  3 – 8 different drugs (partly prescribed and partly self-medication)  The risks of drug use in pregnancy has lagged far behind advances in other areas of pharmacotherapy  Main reasons: epidemiological difficulties in establishing causality and ethical barriers to prospective RCTs

Treatment Goals  Utilize appropriate resources to determine teratogenic risk and excretion in breast milk  Assess the risk: benefit ratio of pharmacotherapy  Utilize drug regimen that is safe, effective and minimizes risk to fetus or infant  Minimize drug exposure to neonate/infant during lactation

Teratogenicity and drugs  In the UK, the spontaneous malformation rate at birth is 2-3% i.e. approximately 1 in 40 babies will be born with a malformation  The incidence of malformations increases to approximately 5% by 4-5 years of age  Drugs are thought to cause less than 1% of malformations  Therapeutic drugs do not appear to be a significant cause of birth defects  However, most birth defects have no known cause and exposure to drugs may play a part in some of these

Causes of developmental disorders Unknown:- Spontaneous development disorders; multigenetic conditions; combination and interactions of exogenic and endogenic factors (65%) Genetic diseases:- (20%) Chromosomal disorders:- (5%) Anatomical factors:- Uterus anomalies; twin pregnancy; oligohydramy (2%) Maternal conditions:- Diabetes mellitus; hypothyroidism; phenylketonuria; cytomegaly; listeriosis; lues; rubella; toxoplasmosis; Varicella (4%) Chemical and physical agents:- Medicinal products; drugs of abuse (especially alcohol); ionizing radiation; hyperthermia; environmental chemicals (4%)

Some teratogenic drugs ACE inhibitorsRenal dysfunction and hypotension in the newborn, decreased skull ossification, hypocalvaria and renal tubular dysgenesis AlcoholFetal alcohol syndrome AminoglycosidesDeafness, vestibular damage Androgens (e.g. danazol)Masculinisation of female fetus Anti-cancer drugsMultiple defects, abortion Anti-thyroid drugsFetal goitre CarbamazepineNeural tube defects CocaineCardiovascular, central nervous system defects DiethylstilboestrolVaginal carcinoma after in utero exposure LithiumCardiovascular defects (Ebstein’s anomaly) PhenytoinFetal hydantoin syndrome RetinoidsCraniofacial, cardiac, central nervous system defects Sodium valproateNeural tube defects ThalidomideLimb-shortening defects, renal malformations, congenital heart disease WarfarinFetal warfarin syndrome

Embryo/fetotoxic risk assessment  Generally accepted that the predictive value of animal studies for predicting safety in humans is less than adequate  With the exception of androgens, several antimitotic drugs, sodium valproate and vitamin A derivatives, all human teratogens were discovered earlier in man than in animals  Most were case studies from alert clinicians rather than epidemiological studies

Drugs and the fetus  Nearly all drugs, except those with a very high molecular weight e.g. insulin and heparin, cross the placenta to the fetus  Lipid-soluble un-ionised drugs cross the placenta more rapidly than polar drugs  In practice, all drugs should be regarded as having the potential to affect the unborn child  The effect of drug exposure will depend upon:  Timing of exposure  Dosage  Concomitant maternal disease  Genetic susceptibility

Drugs and the fetus  However, it should be remembered that:  Teratogens do not cause defects in all fetuses exposed at the critical period of gestation  A drug that harms a baby in one pregnancy may have no effect in a subsequent pregnancy in the same woman

Timing of drug exposure  Exposure during the pre-embryonic period (until 14 days post-conception)  the ‘all or nothing effect’  Damage to all or most cells  death  If only a few cells are injured  normal development  Women with a history of drug use in the month following their last menstrual period can often be reassured  Limitations  Drug must be completely eliminated before this time (not useful for drugs with long half-life)  Dates of conception uncertain

Timing of drug exposure  Fetus most vulnerable to teratogens from week 3 to week 8 after conception (embryonic phase) when major organ systems formed  For some drugs there is a period of greatest risk  Exposure to sodium valproate at the time the neural tube closes (between day 17 & 30 post-conception) may result in spina bifida  Cleft palate develops at about 36 days post- conception & so a drug exposure outside this period is unlikely to be implicated in any a/e

Timing of drug exposure  During the fetal period (week 9  birth) the fetus is less susceptible to toxic insults, although some organs (cerebellum & urogenital structures) continue to be formed  Exposure is more likely to cause growth retardation or interfere with functional development within specific organ systems  Danazol can cause virilisation of a female fetus after 8 weeks gestation  Warfarin may cause intracranial haemorrhage in the second & third trimesters

Timing of drug exposure  Drugs taken close to term cause predictable pharmacological effects  Beta-blockers can cause neonatal hypoglycaemia  SSRIs can cause withdrawal effects after regular in utero exposure  Rarely, exposure can have delayed effects  Diethylstilboestrol – synthetic oestrogen used for threatened spontaneous abortion  Many female fetuses exposed before the 9 th week developed vaginal or cervical cancer later in life

Dose & polypharmacy  In general teratogenicity is dose dependent  Neural tube defects & sodium valproate have shown a correlation with:  Total daily dose  Dose per administration  Peak level achieved  Dose is only a relative risk factor  Normal babies have been born to women who have received high doses of valproate & vice versa

Dose & polypharmacy  Risk of malformations increases with exposure to multiple drugs  e.g. anti-epileptics  4% incidence of defects for 1 drug  23% incidence for 4+ drugs  Potential for confounding with disease severity can be discounted as epilepsy is not thought to be associated with an increase in malformation rate  Avoid polypharmacy whenever possible

 Where to look up? FDA Category of drug in pregnancy

FDA Categories  Category A: Safest Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities  Category B: Use as necessary 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.

FDA Categories  Category C: Avoid 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  Category D: Never use, unless extremely needed 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 risk.

FDA Categories  Category X: Contraindicated Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities.  The use of the drug is contraindicated in women who are or may become pregnant.

Pregnancy alters the Pharmacokinetics  Increase in total body water (~8L)  Increase in total body fat  Increase in GFR  Decrease in gastrointestinal motility and changes in absorption and gastric acidity  Increase in CO, blood volume and plasma proteins  Decrease in plasma albumin concentration  Changes in serum albumin effect the bioavailability of protein-binding

Pregnancy and Pharmacokinetics  Pregnancy often accompanied by nausea and vomiting, which may prevent absorption of the medication, but…  Increased plasma volume, fetal growth, and increased interstitial tissue result in a wider distribution of medications

Bottom Line  Every woman requires thorough history of pregnancy complaints prior to pharmacologic treatment  Dosages may need to be considered based on the stage of pregnancy  Prescribing in pregnant patient requires more than just attention to FDA drug categories

In Translation…  Absorption affected by decreased GI tone  Drug remains in stomach longer leading to increase in absorption through stomach and delayed in absorption of drugs  Distribution affected by increased plasma volume causing prolonged half lives  Fat soluble drugs stay longer in the body  Drugs with high protein binding and lower lipid solubility (such as anticonvulsants) have longer half lives  Hormones (strongly protein bound) compete for available binding sites-resulting in wide distribution of free, unbound drug in the body

Pregnancy and Pharmacokinetics  Metabolism of drugs in liver relatively unchanged  Drugs cleared through liver eliminated similar to non pregnant women  Excretion-increased rates of clearance  Renal blood flow increases by 25-50%  GFR increases by 50%  Serum level of drug must fall to allow diffusion of drug from the fetus’s circulation

Placental Transfer  Simple diffusion: molecular size may/not permit transfer  Active transport: where concentration of substances are higher in fetus and transported back to the mother  Pinocytosis: where soluble molecules (such as viruses) cross membrane in small vesicles and are released  Facilitated diffusion: glucose is rapidly transferred to fetus  Leakage: fetal cells enter mother’s circulation through small membrane breaks

Properties of Medications that easily cross the placenta  Small molecular size and weight ( d)  Most drugs have weights < 600d  Non-protein bound  Non-ionized  Lipophilic

Selecting a Drug for a Pregnant or Nursing Mother  Principles of teratology:  Timing of exposure  Timing of exposure in fetal development  Based on fetal developmental stage when insult is applied can help predict the possible defect all or nothing effect)  Exposure at time of conception and implantation may kill the fetus (all or nothing effect)  If exposure occurs in first 14 days after conception when the cells can assume another cell’s function (totipotential), the fetus may not be damaged  Most sensitive period: time from implantation to the end of organogenesis (days )  Damage to developing organs  heart is most sensitive during the 3rd and 4th weeks of gestation, external genitalia are most sensitive during the 8 th and 9 th weeks  brain and skeleton are sensitive from the beginning of the 3 rd week to the end of pregnancy and into the neonatal period.

Factors that Influence Teratogenicity of a drug  Genotypes of the mother and fetus  Embryonic stage at exposure  Drug dose  Duration of exposure  Nature of the agent and mechanism by which it causes a defect  Simultaneous exposure to other drugs and environmental agents that potentiate a drug  Maternal and fetal metabolism of the drug  Extent to which the drug crosses the placenta

The safest pregnancy-related pharmacy is as little pharmacy as possible  However, women with a history of psychiatric, seizure-related, or hematologic illnesses frequently require medication throughout pregnancy.  In such patients, care must to be taken to select the safest drug from the necessary class of medication.  Misri and Kendrick noted that prescribing drugs for women during the antenatal and postnatal period is a balancing act and that no risk-free alternatives exist  Misri S, Kendrick K. Treatment of perinatal mood and anxiety disorders: a review. Can J Psychiatry. Aug 2007

Overview of Frequently Used Drug

Drug Exposure Options for Pregnant and Lactating women 1. Withhold the drug (e.g., headache medications) E.g., Ergotamine: Pregnancy category - X E.g., Ergotamine: Pregnancy category - X Trimesters of risk - all Trimesters of risk - all Associated defects and complications: LBW, and preterm birth, ergotamine-induced vasoconstriction in the placenta of pregnant women. Associated defects and complications: LBW, and preterm birth, ergotamine-induced vasoconstriction in the placenta of pregnant women. The effect of ergotamine most obvious in male newborn infants, particularly after treatment in the third trimester. The effect of ergotamine most obvious in male newborn infants, particularly after treatment in the third trimester. 2. Delay drug therapy (if woman is close to end of lactation)

Options  Choose drugs that pass poorly into placenta or breast milk- (e.g., some variations even within same class of drug)  e.g., Benzodiazepines-Pregnancy category - D or X  Trimesters of risk: The first, second, and third trimesters are times or risk for flurazepam (dalmane), temazepam (restoril), and triazolam (Halcion) (category X).  Avoid alprazolam (Xanax-cat D) during pregnancy  Chlordiazepoxide(Librium) appears to be safest choice during pregnancy.

Options  Choose alternate routes of administration when possible  Avoid long acting/medications with long half lives  Advise lactating women to time their medications before the infant’s longest sleep period  Temporarily withhold breast feeding  Can safely resume after 1-2 half lives (50%-75% elimination)  For drugs with high toxicity, must delay 4-5 half lives  Discontinue nursing if medication is for life threatening condition (e.g., chemotherapy)

Treatment for common condition: Asthma

 Asthma:  Asthma complicates approximately 4% of pregnancies  In some cases, asthma improves during pregnancy  Those with poorly controlled asthma are at risk for:  Hyperemesis, uterine hemorrhage, preeclampsia, placenta previa, hypertension and premature labor

IMPLICATIONS of Pregnancy on Asthma  Pregnancy has a significant effect on the respiratory physiology of a woman  Respiratory rate and vital capacity do not change in pregnancy, but there is an increase in tidal volume, minute ventilation (40%), and minute oxygen uptake (20%) with resultant decrease in functional residual capacity and residual volume of air due to elevation of the diaphragm  Airway conductance is increased and total pulmonary resistance is reduced, possibly as a result of progesterone

 Asthma:  Asthma complicates approximately 4% of pregnancies  In some cases, asthma improves during pregnancy  Those with poorly controlled asthma are at risk for:  Hyperemesis, uterine hemorrhage, preeclampsia, placenta previa, hypertension and premature labor

Improved Outcomes associated with controlled asthma  Current EVIDENCE Supports Treatment  Almost all anti-asthma drugs are safe to use in pregnancy and during breastfeeding.  Under-treating is a frequent occurrence for the pregnant patient because patients are worried about the medication effects on the fetus  With a few exceptions, the medications used to treat asthma during pregnancy are similar to the medications used to treat asthma at other times during a person's life.

Common Asthma medications  Inhaled B2 Agonists  Albuterol-Category C  Mild, infrequent episodic  May cause maternal hyperglycemia, tachycardia, hypotension or neonatal hypoglycemia  Briggs, et al., 2002: study of 1090 infants exposed to albuterol in 1 st trimester-possible association with polydactyly  No congential defects link in 2 nd, 3 rd trimester  No adverse effects during lactation  Possible B2Choice-Brethine (category B)

Other Asthma Drugs Theophylline (Cat C)  Crosses placenta in equal concentrations to mother  Not associated with congenital defects but can cause jitteriness, cardiac arrythmias, hypoglycemia, feeding difficulties in infants  Neonates more likely affected Corticosteroids (Cat C)  Spontaneous abortion, prematurity, cardiac abnormalities reported in one study  Prednisone <20mg/day safe in lactation  In larger doses, delay nursing 3-4hours after dose

The Common Cold  No value in treating with medications  If using medication, avoid combination products  Limit duration of treatment  Antihistamine of choice: Loratidine (cat B)  Avoid brompheniramine (Dimetapp-Bromfed)  Antihistamines excreted in breast milk  Nasal cromolyn, beclomethasone useful alternative  Clubfoot and inguinal hernias associated with first trimester use of decongestants (e.g., Sudafed)  Anti-tussives and expectorants: bromhexine, n- acetylcysteine  If necessary: codeine and dextromethorphane short term

Nausea and Vomiting  80% of women experience n/v during 1 st trimester  Hyperemesis gravidarum-intractable, causes lyte imbalances, weight loss, possible end organ damage  Cause unknown-tx focused on sx  Non pharmacologic measures not supported by evidence  OTC phosphorated carbohydrate (EMETROL) safe  Drug of choice: Doxylamine combined with vit.B6  Metocloperamide can be use in 1 st and 2 nd trimester. Use in 3 rd trimester associated with pre-term birth.  Domperidone: no sufficient data in human  Ondancentron: use if other fail

Nausea (Cont.)  Antacid: can be use in all stages of pregnancy, but no longterm use. magaldrate and sucralfate may be considered the drugs of choice  Ranitidine: use if antacid fails. Avoid use of cimetidine.  Proton-pump inhibitor: Omeprazole is a 3 rd line drug  Bismuth salt: contraindicated

Analgesic and antipiretic  Paracetamol: the first choice, the safest  Aspirin: 2 nd choice but, avoid in 3 rd trimester  Metamizole: do not use, cause PDO  Analgesic combination: not recommended

Hemorrhoids  OTC external preparations preferred, not supposituria.  Avoid suppositories d/t potential for systemic absorption across rectal mucosa

Principles of prescribing in pregnancy  Consider non-drug treatments  Avoid all drugs in 1 st trimester if possible  Avoid drugs known to have harmful effects  Avoid new drugs where possible  More experience with ‘older drugs’ – greater evidence of safety, but can’t assume they are necessarily safe  Avoid polypharmacy  Use the lowest effective dose for the shortest duration possible & review regularly  Consider the need for dosing changes & TDM due to the effect of pregnancy on drug handling  Changes in serum albumin & total body water

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