and Drug therapy in pregnancy and breastfeeding Kari

and Drug therapy in pregnancy and breastfeeding Kari Laine, MD, Ph. D Tuomas Korhonen, MD University of Turku & medbase Ltd

Drug use in pregnancy • In Finland, approx. 55, 000 deliveries and more than 70, 000 pregnancies (25% spontaneous/induced abortions) are carried out per year • Approx. 50% of women have used prescription drugs during pregnancy or during one month prior to conception (Paldan et al. 2008) • > 30, 000 exposures to prescription drugs • > 20%, i. e. , more than 10, 000 exposures in early pregnancy • Difficult to get reliable figures on over-the-counter drugs – the figure can be as high as 70% Am J Perinatol. 2005; 22: 321 -4.

The most commonly used drugs used in pregnancy in Finland - Antibiotics for systemic use (27%) >> Penicillins, cefalosporins, macrolides - Antimicrobial drugs for gynecological use (9%) - Topical preparations for blocked nose (6%) - Cough and cold preparations (5%) - Sex hormones (oral contraceptives) (4%) - Asthma medication (4%) - NSAIDs and antirheumatic products (4%)

• In roughly 30% of the cases, it is possible that prescription therapy had adverse fetal effects • Estimated number of exposures per year 20, 000 • In 5% of the cases, exposure to a prescription drug was shown to have adverse fetal effects • Estimated number of exposures per year 3, 000

Factors affecting transplacental transfer • Molecular size, p. Ka value – ionized or nonionized, lipophilicity, drug-protein binding • Factors governing diffusion/osmosis • Metabolites can also play a role (codein, aripiprazole) • Exposure via placenta • Most drugs cross the placenta • Both anatomic (cell structure) and functional (transporters) barrier • Exposure via amniotic fluid • Maternal drugs are excreted also in amniotic fluid • The fetus swallows amniotic fluid and urinates in it • For many drugs, concentration levels in maternal and fetal circulations are the same

Maternal-fetal transfer of saquinavir normally (○) and after placental prehandling with P-glykoprotein inhibitors, PSC 833 (●) or GG 918 (■). 5 - to 6 -fold difference in fetal exposure

Possible adverse effects of drugs in pregnancy • Congenital malformations (first-trimester exposure) • General prevalence 3% • At least 5% (possibly underestimated) of these are caused by drugs or other xenobiotics – in 60 -70% of the cases the cause is unidentified • Spontaneous miscarriages and fetal deaths • Amphetamins, other illicit drugs • Prematurity – low birth weight • Reduced placental circulation– systemic sympathomimetics, diuretics • Perinatal problems (late pregnancy) • NSAIDs, antidepressants, benzodiazepines, opioids, etc. • Long-term adverse effects – learning, etc.

Adverse effects of drugs on the developing embryo/fetus Embryonic age (weeks) Fetal age (weeks) Central nervous system Heart Upper limb Lower limb Upper lip Ears Eyes Teeth Extremely susceptible period Oral cleft Less susceptible period Genital organs

However, it should be remembered that: • diabetes mellitus • infections (such as toxoplasmosis, malaria, herpes) • epilepsy • psychosis, depression, etc. , if not appropriately treated, will often lead to greater risks for the fetus than correctly planned effective therapy – drug therapy cannot be avoided

Medication in breastfeeding • During the postpartum period, approx. 30% of mothers use at least one prescription drug – about 20, 000 exposures/year • 4% of the mothers use three or more prescription drugs • The most commonly used prescription drug groups are: - antibacterials for systemic use (21%) - NSAIDs (4%) - antidepressants (1%) • No information is available on OTC drugs Malm et al. 2003, Malm H. , 2008

Medication in breastfeeding • Therapeutic benefit for the mother has to be clear • The risk/benefit ratio of drug effects vs. breastfeeding must be assessed • The benefits of breastfeeding are indisputable: - complete nutrition for the infant, - protection against infections, DM, allergies - improved postpartum uterine involution and reduced risk of hemorrhage (oxytocin) - possible protection for the mother against breast cancer, ovarian cancer and osteoporosis - mother-baby bonding • Breastfeeding should be stopped only when there is a clear contraindication Agency for Health Research and Quality 2007, Malm 2008

Risks of drug use in breastfeeding • The drug inhibits milk secretion - prolactin secretion inhibited – dopamine agonists, amantadine • The drug dyes breast milk (minocycline) • Essential factors affecting the risk for the nursing infant: 1. The dose transferred to the infant - maternal and child genetic factors may cause unexpected problems (azathioprine, codeine) - high levels of excretion in breast milk (lithium) - the amount of milk consumption and the time of breastfeeding in relation to the time of drug intake 2. Toxicity of the drug - the drug causes adverse effects even with a low dose - antineoplastic drugs, immunosuppressive drugs

Drug excretion in breast milk Concentration in maternal blood concentratio n Concentration in milk pause? Diffusion Maternal circulation -molecular size -plasma protein bonding -lipophilicity -p. Ka value (ionization) Active excretion -transporter proteins -the role is poorly known -ranitinide, nitrofurantoine Breast milk time

Drug excretion in breast milk • The most reliable method to assess drug exposure in an infant is to calculate Relative Infant Dose, RID: RID= concentration in milk (mg/ml) x amount of milk ingested (ml/kg/day ) x mother’s weight (kg) / maternal dose (mg/day) x 100%. The amount of milk ingested approx. 150 ml/kg/day • A RID value < 10% is generally considered to be safe • Most drugs have RID <1% • The problem is lack of studies; information is often based on case reports and variation between individuals is not taken into consideration

Factors affecting drug exposure in a nursing infant • Drug absorption from the gastrointestinal tract - chelation by calcium and other cations in milk – tetracyclines - stomach acidity destroys the drug – PPI therapies - adverse events in the intestinal tract (antibiotic-associated diarrhea, hypersensitivity reaction) - poorly known in neonates • Metabolic activity and renal excretion in the infant - slow metabolism in the neonate (conjugation reactions, in particular) • Genome of the mother and the infant - genetic polymorphism of enzymes associated with target receptors , transporter proteins and drug metabolism (e. g. , codeine and CYP 2 D 6 polymorphism) Blake et al. 2005; Bartelink et al. 2006

Guidelines for breastfeeding mothers • Once daily administration: take the drug immediately after (or immediately before) breastfeeding followed by the longest time between feedings (usually the night). • More than once-a-day administration: take the drug immediately before or (immediately after) breastfeeding. • In most cases, avoiding breastfeeding for 4 -6 hours after drug ingestion significantly reduces drug exposure in the infant. • Appropriate dosing intervals are beneficial especially for drugs for which a maximum drug concentration (Cmax) is reached quickly after ingestion and ones with a short half-life (t ½). • contains instructions on appropriate dosing intervals.

Medication in breastfeeding; summary • Maternal drug therapy is rarely contraindicative to breastfeeding. - For most drugs, less than 1% of the maternal dose is excreted in the infant. - Differences between drugs – there are safe and well-documented alternatives – professional challenge for health care personnel • Severe adverse effects are rare, but long-term effects of neonatal exposure to drugs are poorly known. • Follow-up of the infant at child health clinics (acute adverse effects, weight and other development)

Why use a database? • Gestational and lactational drug exposures are common • Safety profiles of different drugs vary • Documentation of safety profiles of different drugs vary Appropriate choice of drug and treatment strategy helps to improve maternal/infant safety • Information is abundantly available, but it is not being updated. Additionally, it is hidden in scientific journals and books – poor penetration into clinical work • Making independent information available to doctors, dentists and pharmacists improves suitability and safety of drugs and guidance concerning their use • Effective drug therapy should not be contraindicated on false grounds

How is information gathered for the safety of drugs in pregnancy and breastfeeding ? • Accidental exposure to drugs during early pregnancy (oral contraceptives) • Chronic diseases require medication also in pregnancy/lactation (approx. 6% of mothers receive reimbursement) – Epilepsy, depression, rheumatic diseases, asthma, psychoses, migraine, HIV • Acute illnesses during pregnancy/lactation - infections • Animal experiments during drug development - precondition for PMA – Excretion in the fetus, in breast milk – Difficult to interpret – in most cases, significant teratogens are detected – For pharmaceutical industry, pregnant/breastfeeding women represent a small market but a big risk for image – overly withdrawn attitude

A Ursodeoxycholic acid (ursodiol) is a naturally occurring bile-acid. Its efficacy has been well shown in treatment of intrahepatic cholestasis during pregnancy, for which it is considered as the first-choice treatment. The safety of ursodeoxycholic acid has been proved during the 2 nd and 3 rd trimesters of pregnancy, when cholestasis symptoms typically occur. There is very little information on the fetal safety of ursodeoxycholic acid during the 1 st trimester of pregnancy. Adursal Summary of Product Characteristics Adursal tablets are contraindicated during pregnancy and for women of childbearing age unless reliable contraception is being used.

A Only limited clinical data is available on the use of ursodeoxycholic acid during breastfeeding. Ursodeoxycholic acid is excreted in breast milk in small amounts, but it seems to reduce the total bile acid concentration in patients with cholestasis. No adverse effects have been reported in infants of mothers who have used ursodeoxycholic acid while breastfeeding. The use of ursodeoxycholic acid is not contraindicated during breastfeeding. Adursal Summary of Product Characteristics Information is not available whether ursodeoxycholic acid is excreted in breast milk. Therefore, the product should not be used while breastfeeding.

Reference sources on drug safety in pregnancy and lactation: • National registers (e. g. , Motherrisk, Finland, Sweden) • Academic research • Golbal vigilance registers held by the pharmaceutical industry (new medicinal products)

and development process – Standardised procedural models for data searches – Reference sources • Other databases and text books • Registers (Scandinavian Medical Birth Registers, Mother risk, Medicaid) • Medical literature (Pubmed) • Manufacturer given information published in Europe and in the United States – Coding of data with standardised methods • Dosage form, classification, standard sentences – Scientific evaluation/inspection – Heli Malm, MD, Ph. D

• Dosage form taken into account: – Systemic (per oral, intravenous, intramuscular, subcutaneous) – Topical (cutaneous, ocular, vagitories, local anesthetic) • Effective and safe therapy is not needlessly contraindicated; on the contrary, it is enhanced – Different classification for different dosage forms – E. g. , antifungals for topical use and vagitories

Pregnancy classification – colour code system A No increased risk for congenital malformation or direct or indirect fetal defects have been detected in controlled clinical studies or large epidemiological data on first-trimester exposures. Furthermore, no increased risk has been associated with use during the 2 nd or 3 rd trimesters. B Only limited clinical data is available on human use in gestation and no controlled studies have been conducted. There is no evidence of congenital malformations or direct or indirect fetal defects in clinical trials or animal experiments. Alarm threshold C 1 Only limited clinical data is available on human use in gestation and no controlled studies have been conducted or the results are conflicting. Congenital malformations or direct or indirect fetal defects have been reported in animal experiments or no animal experiments have been conducted. C 2 No increased incidence of congenital malformations has been reported, but use during (late) pregnancy can cause adverse effects during the neonatal phase or later on in childhood. D There is reason to suspect or there is evidence that the drug causes congenital malformations or direct or indirect fetal defects. As the main rule, its use is contraindicated during pregnancy. In certain cases, benefits may outweigh adverse effects.

Lactation classification – colour code system A The drug is not excreted in breast milk in clinically significant amounts or the drug is not expected to cause adverse effects in the breastfed infant when taken at therapeutic doses. B No clinical data is available on the excretion of the drug in breast milk. The safety profile on human use includes only a limited amount of data or no data at all. Alarm threshold C Based on currently available information, the drug is excreted in breast milk in clinically significant amounts. The drug can cause adverse effects in the breastfed infant when taken in therapeutic doses. Breastfeeding should be based on an assessment of benefits of breastfeeding and possible adverse effects of the drug. D Breastfeeding is contraindicated during the drug therapy. The drug can cause serious adverse effects in the breastfed infant.

Recommendation (in end-user native language) No malformations due to omeprazole have been reported from preclinical animal studies. Based on roughly 4, 000 cases of fetal exposure to omeprazole during early pregnancy described in clinical records and reference data, omeprazole is not considered to increase the risk of congenital malformations or fetal death. No indication of preterm delivery or growth retardation has been reported. Omeprazole has been proved more effective than ranitidine in the treatment of gastroesophageal reflux disease and prevention of aspiration of gastric contents in conjunction with Cesarean section (or vaginal delivery).

Background (in English) Studies in rats and rabbits at doses up to 56 times the maximum recommended human dose in relation to the body surface area indicate that omeprazole does not produce congenital malformations, but dose-dependent embryotoxicity was noted with the dose range of 5. 6 to 56 times the maximum recommended human dose [(1)]. Similar results have been published by other investigators [(2)], [(3)]. In a clinical study with 20 women, omeprazole 80 mg single dose given 14 hours prior to cesarean section crossed the term human placenta, though producing a low exposure of the infant [(4)]. The birth and neonatal outcome up to 7 days of age were uneventful in all 20 infants. Omeprazole has been proved effective in the treatment of gastroesophageal reflux disease and prevention of aspiration of gastric contents; omeprazole has been shown to be safe but more effective in acid aspiration prophylaxis than ranitidine [(5)], [(6)], [(7)]. Overall, there is no indication that proton pump inhibitors (PPI) would increase the risk for malformations. A recent meta-analysis with almost 600 exposures to PPIs during early pregnancy reported an overall relative risk of 1. 18 with a 95% CI of 0. 72 -1. 94 for malformations [(8)]. A later follow-up study with 233 pregnancies of 1 st trimester exposure to omeprazole, 55 to lansoprazole and 47 to pantoprazole as well as 868 controls, found similar rates of major congenital anomalies in the exposed (range for rate 2. 1% to 3. 9%) and control groups (3. 8%) [(9)]. Three published studies with over 1, 000 exposures to omeprazole in early pregnancy, consistently report that the prevalence of birth defects is not increased (rate 3. 2% to 4. 0%) due to exposure to this drug [(10)], [(11)], [(12)]. Moreover, no relation was found between exposure to omeprazole and preterm delivery or growth retardation in these studies. In the Swedish Medical Birth Registry, there are 3, 703 pregnancies with early pregnancy exposures to omeprazole, of which 117 infants (3. 2%) were diagnosed with a malformation, which equals the expected number. No specific malformation was overrepresented [(13)].

References (Pubmed – links) - more than 8, 000 references Prilosec. Product information. Astra Zeneca 2007. http: //www. astrazeneca-us. com/pi/Prilosec. pdf [1] Shimazu H, Ishida S, Ikeya M et al: Reproduction studies of omeprazole in rats. Oyo Yakuri 36: 189 -203, 1988. [2] Shimazu H, Matsuoka T, Ishikawa Y, et al: Reproductive and developmental toxicity study of omeprazole sodium in rats. Oyo Yakuri 1995; 49: 573 -92. [3] Moore J, Flynn RJ, Sampaio M, Wilson CM, Gillon KR. Effect of single-dose omeprazole on intragastric acidity and volume during obstetric anaesthesia. Anaesthesia 1989 Jul; 44(7): 559 -62 [4] (PMID: 2774120) Gin T, Ewart MC, Yau G, Oh TE. Effect of oral omeprazole on intragastric p. H and volume in women undergoing elective caesarean section. Br J Anaesth 1990 Nov; 65(5): 616 -9 [5] (PMID: 2248836) Ewart MC, Yau G, Gin T, Kotur CF, Oh TE. A comparison of the effects of omeprazole and ranitidine on gastric secretion in women undergoing elective caesarean section. Anaesthesia 1990 Jul; 45(7): 527 -30 [6] (PMID: 2386275) Tripathi A, Somwanshi M, Singh B, Bajaj P. A comparison of intravenous ranitidine and omeprazole on gastric volume and p. H in women undergoing emergency caesarean section. Can J Anaesth 1995 Sep; 42(9): 797 -800 [7] (PMID: 7497561) Nikfar S, Abdollahi M, Moretti ME, Magee LA, Koren G. Use of proton pump inhibitors during pregnancy and rates of major malformations: a meta-analysis. Dig Dis Sci 2002 Jul; 47(7): 1526 -9 [8] (PMID: 12141812) Diav-Citrin O, Arnon J, Shechtman S, Schaefer C, van Tonningen MR, Clementi M, De Santis M, Robert-Gnansia E, Valti E, Malm H, Ornoy A. The safety of proton pump inhibitors in pregnancy: a multicentre prospective controlled study. Aliment Pharmacol Ther 2005 Feb 1; 21(3): 269 -75 [9] (PMID: 15691301) Lalkin A, Loebstein R, Addis A, Ramezani-Namin F, Mastroiacovo P, Mazzone T, Vial T, Bonati M, Koren G. The safety of omeprazole during pregnancy: a multicenter prospective controlled study. Am J Obstet Gynecol 1998 Sep; 179(3 Pt 1): 727 -30 [10] (PMID: 9757979) Ruigómez A, García Rodríguez LA, Cattaruzzi C, Troncon MG, Agostinis L, Wallander MA, Johansson S. Use of cimetidine, omeprazole, and ranitidine in pregnant women and pregnancy outcomes. Am J Epidemiol 1999 Sep 1; 150(5): 476 -81 [11] (PMID: 10472947) Källén BA. Use of omeprazole during pregnancy--no hazard demonstrated in 955 infants exposed during pregnancy. Eur J Obstet Gynecol Reprod Biol 2001 May; 96(1): 63 -8 [12] (PMID: 11311763) Swedish Medical Birth Registry. http: //www. socialstyrelsen. se/Publicerat/2003/1697/2003 -112 -3. htm [13]

• Data on gestational and lactational exposures of almost 1, 200 drugs, including: • • Over-the counter drugs and vitamins Coffee, smoking and illicit drugs Vaccines Covers the modern drug therapy in Europe and the Middle East • Search options with generic names and trade names • Updated every 3 months

and user environments: • Portal use • Doctors, dentists, pharmacists • All units of healthcare who treat pregnant/ breastfeeding mothers • Integration into patient record systems • Doctors, dentists • Automatic warnings – decision support