Transcript gravlactbase

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Drug therapy in pregnancy and breastfeeding
Kari Laine, MD, PhD
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, pKa 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, PSC833 (●) or GG918 (■).
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
concentration
Concentration in milk
pause?
Diffusion
Maternal
circulation
-molecular size
-plasma protein bonding
-lipophilicity
-pKa 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 CYP2D6
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 2nd and 3rd
trimesters of pregnancy, when cholestasis symptoms typically occur. There is
very little information on the fetal safety of ursodeoxycholic acid during the
1st 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, PhD
• 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 2nd or
3rd 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
C1
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.
C2
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 1st
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 pH 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 pH 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:
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