e-Therapeutics+ Complete : Therapeutic Choices : Drug Use during Pre...

1 5


Print

http://www.e-therapeutics.ca/tc.showPrintableChapter.action?chapterId...

Close

Drug Use during Pregnancy

Date of revision: June 2014
Orna Diav-Citrin MD Gideon Koren MD FRCPC FACMT FAACT
The following is an overview of drug use during pregnancy. This information is not intended to be a comprehensive review; the reader is therefore encouraged to seek
additional and confirmatory information.

Principles of Prescribing in Pregnancy

Many pregnant women are exposed to a variety of medications that may exert therapeutic, toxic or teratogenic effects on the fetus. Since the thalidomide disaster,
many physicians and pregnant women tend to withhold any medication during pregnancy, although the risk of teratogenic effect from most drugs in therapeutic doses
is nonexistent. Major congenital defects occur in 13% of the general population at birth.1 Of the major defects, about 25% are of genetic origin (genetically inherited
diseases, new mutations and chromosomal abnormalities) and 65% are of unknown etiology (multifactorial, polygenic, spontaneous errors of development and
synergistic interactions of teratogens). Only 23% of malformations are thought to be associated with drug treatment. The remaining defects are related to other
environmental exposures including infectious agents, maternal disease states, mechanical problems and irradiation.2 , 3
Optimal prescribing in pregnancy is a challenge and should provide maximal safety to the fetus as well as therapeutic benefit to the mother. To date, very few drugs
are proven teratogens in humans. However, drug-induced malformations are important because they are potentially preventable.
Maternal physiologic changes during pregnancy may alter the pharmacokinetics of drugs. Clearance rates of many drugs increase during late pregnancy due to
increases in both renal and hepatic elimination (e.g., digoxin, phenytoin), while for other drugs the clearance rate decreases (e.g., theophylline). Generally, little is
known about the relationship between maternal serum drug concentration and risk of teratogenicity.
The importance of timing of drug exposure is better understood; the effect produced by a teratogenic agent depends upon the developmental stage in which the
conceptus is exposed. Several important phases in human development are recognized:3
The all or none period, the time from conception until somite formation, corresponds to the first 17 days after conception. Insults to the embryo in this phase
are likely to result in either death and miscarriage or intact survival. The embryo is undifferentiated, and repair and recovery are possible through multiplication of
the still totipotential cells. Consider that exposure to teratogens during the presomitic stage usually does not cause congenital malformations unless the agent
persists in the body beyond this period.3 , 4
The embryonic period, from 1860 days after conception when the basic steps in organogenesis occur. This is the period of maximum sensitivity to
teratogenicity since tissues are differentiating rapidly and damage becomes irreparable. Exposure to teratogenic agents during this period has the greatest
likelihood of causing a structural anomaly. The pattern of anomalies produced depends on which systems are differentiating at the time of teratogenic exposure.
The fetal phase, from the end of the embryonic stage to term, when growth and functional maturation of formed organs and systems occurs. Teratogen exposure
in this period will affect fetal growth (e.g., intrauterine growth restriction) and the size or function of an organ, rather than cause gross structural anomalies. The
term fetal toxicity is commonly used to describe such an effect.
The potential effect of psychoactive agents (e.g., antidepressants, antiepileptics, alcohol and other drugs of abuse) on the developing central nervous system has
led to the new field of behavioural teratology.
Many organ systems continue structural and functional maturation long after birth. Most of the adenocarcinomas associated with 1st trimester exposure to
diethylstilbestrol occurred many years later.
Teratogens must reach the developing conceptus in sufficient amounts to cause their effects. Large molecules with a molecular weight greater than 1000 (e.g.,
heparin) do not easily cross the placenta into the embryonic-fetal bloodstream. Other factors influencing the rate and extent of placental transfer of drugs include
polarity, lipid solubility and the existence of a specific carrier protein (e.g., P-glycoprotein).
In an attempt to provide the practitioner with a better assessment of fetal risk, the US Food and Drug Administration (FDA) developed a classification of fetal risk in
19795 (see Glossary). These categories initially appeared logical but are not helpful in counselling individual patients. Drug manufacturers may have legal rather
than scientific reasons for assigning particular designations. The classification frequently results in ambiguity and even false alarm. For example, oral contraceptives
are denoted as X (contraindicated in pregnancy), despite failure of 2 meta-analyses to show increased teratogenic risk. In 1994 the Teratology Society stated that the
FDA ratings are inappropriate and should be replaced by narrative statements that summarize and interpret available data regarding hazards of developmental toxicity
and provide estimates of teratogenic risk.6 During the last few years the FDA has begun a process to change the present system.

Teratology Counselling7
Ascertain the clinical facts regarding the nature of the exposure: the length, dosage and timing during pregnancy, as well as other exposures of concern (e.g.,
alcohol, cigarette smoking, herbal remedies).
Collect all available current data regarding the agent and the risk of exposure.
Counselling should include background human baseline risk for major malformations, whether the fetus is at increased risk, which anomaly has been associated
with the agent in question, a risk assessment, methods of prenatal detection when available, limitations in our knowledge and limitations of prenatal diagnostic
capabilities.
Additional considerations include the potential risk of the medical condition for which a drug is prescribed, known interactions between the disease state and the
pregnancy, and preventive measures when applicable (e.g., folic acid supplementation in carbamazepine exposure).
Because more than 50% of pregnancies are unplanned, teratogenic risk assessment should be started prior to pregnancy.
Table 1 lists drugs with sufficient evidence to prove their teratogenic effect in humans. Use an alternative in pregnancy when possible. Table 2 lists possible
teratogenic drugs with insufficient evidence as yet for teratogenicity in humans.

Drugs of Choice during Pregnancy

Table 3 presents drugs of choice during gestation for common maternal conditions.

Note: Antenatal drug/chemical risk counselling or information on safety of drug use during breastfeeding is available from the Motherisk Program, Hospital for Sick
Children, Toronto, Ontario. Tel.: 416-813-6780; email: momrisk@sickkids.ca; Web site: www.motherisk.org.

Table 1: Proven Teratogenic Drugs in Humans7

21/09/2014 04:02

e-Therapeutics+ Complete : Therapeutic Choices : Drug Use during Pre...

2 5


http://www.e-therapeutics.ca/tc.showPrintableChapter.action?chapterId...

Drug

Adverse Effects

Angiotensin-converting
enzyme inhibitors
(ACEIs) and
Angiotensin II
antagonists

Adverse effects relate to hemodynamic effects of ACEIs and angiotensin II antagonists on the fetus. In late pregnancy, ACEI fetopathy:
intrauterine renal insufficiency, neonatal hypotension, oliguria with renal failure, hyperkalemia, complications of oligohydramnios (fetal
limb contractures, lung hypoplasia and craniofacial anomalies), prematurity, intrauterine growth restriction and fetal death. 1st trimester
exposure: questionable teratogenic risk of cardiovascular and CNS malformations.8 Several cohort studies and meta-analyses suggest the
observed risk is associated with the underlying maternal conditions.9 , 10 , 11 , 12 , 13 , 14

Antineoplastic agents

A significant increase in the incidence of various fetal malformations and early miscarriages following 1st trimester exposure.15

Carbamazepine

1st trimester exposure: 1% risk of neural tube defects (10 baseline risk) and an increased risk of cardiovascular malformations. A
pattern of malformations similar to the fetal hydantoin syndrome has also been associated.16

Cocaine

Abruptio placenta, prematurity, fetal loss, decreased birth weight, microcephaly, limb defects, urinary tract malformations and poorer
neurodevelopmental performance. Methodological problems make the findings difficult to interpret. Cocaine abuse is often associated with
poly-drug abuse, alcohol consumption, smoking, malnutrition and poor prenatal care. Human epidemiology indicates the risk of major
malformation from cocaine is probably low, but the anomalies may be severe.17

Corticosteroids
(systemic)

1st trimester exposure: <1% increased risk of oral clefts.18

Coumarin
anticoagulants
(e.g., nicoumalone,
warfarin)

1st trimester exposure (69 wk gestation): fetal warfarin syndrome (nasal hypoplasia and calcific stippling of the epiphyses). Intrauterine
growth restriction and developmental delay (CNS damage), eye defects and hearing loss. Warfarin embryopathy is found in up to of the
cases where a coumarin derivative was given throughout pregnancy. Associated with high rate of miscarriage. Risk of CNS damage due to
hemorrhage after the 1st trimester.19 , 20

Diethylstilbestrol

Vaginal clear cell adenocarcinoma in offspring exposed in utero before 18th wk (>90% of the cancers occurred after 14 y of age). High
incidence of benign vaginal adenosis. Increased miscarriage rate and preterm delivery. In males exposed in utero: no signs of malignancy
but genital lesions in 27% and pathologic changes in spermatozoa in 29%. The drug is not currently available in Canada.21

Ethanol

Fetal alcohol spectrum disorders include 4 diagnostic categories: fetal alcohol syndrome (FAS); partial FAS; alcohol-related
neurodevelopmental disorders; alcohol-related birth defects. FAS presents as growth impairment, developmental delay and dysmorphic
facies. Cleft palate and cardiac anomalies may occur. Full expression of the syndrome occurs with chronic daily ingestion of 2 g alcohol per
kg (8 drinks/day) in about one-third of offspring and partial effects in three-quarters of offspring.22 , 23 , 24 , 25 , 26 Alcohol-related
neurodevelopmental disorders are much more common than FAS.27

Folic acid antagonists:

aminopterin and
methotrexate

Fetal aminopterin-methotrexate syndrome: CNS defects, craniofacial anomalies, abnormal cranial ossification, abnormalities in first
branchial arch derivatives, intrauterine growth restriction and mental retardation after 1st trimester exposure. Maternal dose of

Hydantoins (phenytoin)

Fetal hydantoin syndrome: craniofacial dysmorphology, anomalies and hypoplasia of distal phalanges and nails, growth restriction, mental
deficiency and cardiac defects.29

Lithium

Small increase in risk for cardiac teratogenesis in early gestation (1%). The risk of Ebstein's anomaly (a congenital heart defect,
characterized by anterior displacement of the tricuspid valve, enlarged right chambers, often with atrial septal defect and arrhythmias)
exceeds spontaneous rate of occurrence. Fetal echocardiography if exposed in 1st trimester.30 , 31 , 32

Misoprostol

1st trimester exposure: limb defects. Moebius sequence (a congenital facial palsy with impairment of ocular abduction, as a result of
dysfunction of cranial nerves VI and VII) and CNS injuries. Absolute teratogenic risk: 12%. Uterine contraction inducing activity causing
vascular disruption defects.33 , 34 , 35

Mycophenolate mofetil

1st trimester exposure: ear, eye and craniofacial malformations, oral clefts, cardiac, finger, urogenital, gastrointestinal, CNS and skeletal
malformations.36 , 37 , 38

Retinoids (acitretin,
isotretinoin)
and megadoses of
Vitamin A

Systemic exposure: potent human general and behavioural teratogens. Risk of retinoic acid embryopathy: craniofacial anomalies, cardiac
defects, abnormalities in thymic development and alterations in CNS development (congenital anomalies in 28% of prospectively
ascertained pregnancies that resulted in births). Risk for associated miscarriage: 40%.39 , 40

Tetracyclines

Discolouration of the teeth after 17 wk gestation when deciduous teeth begin to calcify. Close to term: crowns of permanent teeth may be
stained. Oxytetracycline and doxycycline associated with a lower incidence of enamel staining.41 , 42

Thalidomide

methotrexate needed to induce defects is probably above 10 mg/wk.28

Malformations limited to tissues of mesodermal origin, primarily limbs (reduction defects), ears, cardiovascular system and gut
musculature. Critical period: 3450th day after the beginning of the last menstrual period. A single dose of <1 mg/kg has produced the
syndrome. Embryopathy found in about 20% of pregnancies exposed in the critical period.43

Valproic Acid

1st trimester exposure: neural tube defects with 12% risk of meningomyelocele, primarily lumbar or lumbosacral, cardiovascular
malformations and hypospadias. Fetal valproate syndrome: craniofacial dysmorphology, cardiovascular defects, long fingers and toes,
hyperconvex fingernails and cleft lip, has been delineated by some investigations. Neurobehavioural teratogen.44 , 45 , 46 , 47 , 48 , 49

Table 2: Possible Teratogenic Drugs in Humansa , 50

Drug

Adverse Effects

Diazepam

A questionable small increase in the incidence of cleft lip and palate (small studies). Larger studies did not confirm the
association.51

Fluconazole

High-dose treatment: multiple synostosis, congenital heart defects, skeletal anomalies and recognizable dysmorphic facial
features (case reports).52

HMG-CoA reductase Inhibitors

(statins)

A questionable increase in the risk of CNS and limb anomalies (retrospective data), not confirmed by several prospective cohort
studies.53 , 54 , 55

Methimazole

Scalp defects such as aplasia cutis congenita suggested through case reports and an epidemiological study in which
methimazole had been added to animal feeds as a weight enhancer; methimazole embryopathy (choanal and esophageal
atresia, scalp defects, minor facial anomalies and psychomotor delay).56 , 57

Paroxetine

A questionable increase in the risk of cardiac malformations, which may be associated with the underlying psychiatric
disorder.58 , 59

Penicillamine

High-dose treatment: connective tissue disorders (cutis laxa).60

Sulfamethoxazole/trimethoprim

Possible increased risk of neural tube and cardiovascular defects and oral clefts with 1st trimester exposure. Folic acid
supplementation may reduce these risks.61 , 62 , 63

a. This list is not exhaustive.

Table 3: Drugs of Choice for Select Conditions during Pregnancy7

21/09/2014 04:02

e-Therapeutics+ Complete : Therapeutic Choices : Drug Use during Pre...

3 5


Condition

Drugs of Choice

http://www.e-therapeutics.ca/tc.showPrintableChapter.action?chapterId...

Alternative

Comments

Allergy64 , 65

Antihistamines: chlorpheniramine,
desloratadine, diphenhydramine,
dimenhydrinate, loratadine

Intranasal preparations of
sodium cromoglycate,
beclomethasone, budesonide,
fluticasone; cetirizine,
fexofenadine

Anticoagulation

Heparin and low molecular weight

heparins66 , 67

Anxiety

Short-term treatment: benzodiazepines51

Long-term treatment: citalopram,
fluoxetine, sertraline58 , 68 , 69 , 70

Asthma71

Inhaled bronchodilators (ipratropium

bromide, salbutamol or terbutaline) and
inhaled corticosteroids (beclomethasone,
budesonide, fluticasone)

Systemic corticosteroids and

theophylline

Bacterial
infections5

Cephalosporins, clindamycin,
erythromycin, penicillins

Aminoglycosides (amikacin,
gentamicin, tobramycin),
azithromycin, clarithromycin,
quinolones

Bipolar disorder

Lithium31 , 72

Carbamazepine, lamotrigine

Constipation73

Bulk-forming agents (e.g.,

methylcellulose, psyllium hydrophilic
mucilloid)

Docusate sodium, glycerin

suppository, lactulose,
mineral oil

Long-term use of mineral oil can decrease absorption of lipid

soluble vitamins A, D, E and K.

Cough74

Antihistamines (in the case of cough due

to rhinitis or allergy), codeine (when
indicated)

Dextromethorphan

Avoid high doses of codeine close to term (risk of neonatal opioid

withdrawal).

Depression

Citalopram, fluoxetine, sertraline,58 , 69 , Other selective serotonin

reuptake inhibitors,
70 , 75 tricyclic antidepressants
bupropion, venlafaxine

Neonatal withdrawal may occur when used in 3rd trimester.

There is a questionable association between paroxetine exposure in
pregnancy and cardiac malformations.

Diabetes mellitus

Human insulin76

Important to achieve strict glycemic control before conception and

during the 1st trimester.

Watch for possible transient neonatal effects when benzodiazepines

or SSRIs used close to term.
Short- or intermediate-acting benzodiazepines (e.g., lorazepam,
oxazepam) may be preferred if needed for regular use near term.
For diazepam, there is a questionable small increase in the
incidence of cleft lip and palate (small studies). Larger studies did
not confirm the association.

With lithium, monitor using fetal echocardiography. Avoid valproic

acid when possible, especially in the 1st trimester (if not possible to
avoid, limit dose to <6001000 mg/day). With carbamazepine and
valproic acid, prescribe periconceptional folate supplementation:
5 mg po daily, ideally starting 3 months before trying to conceive
and continuing at least until the end of the 1st trimester. Monitor
using level II ultrasound for prevention of neural tube defects.

Metformin77 in gestational
diabetes in 3rd trimester,
glyburide78

Diarrhea

Bulk-forming agents (e.g.,

methylcellulose,
psyllium hydrophilic mucilloid), kaolin
pectin79

Loperamide

Dyspepsia

Alginic acid compound, antacids (various

combinations of aluminum, calcium,
magnesium salts),
omeprazole,80 ranitidine

Famotidine

Epilepsy81 , 82 , 83 Carbamazepine, lamotrigine

Fever and pain

Acetaminophen84

Hemorrhoids (3rd
trimester)

Topical hydrocortisone/pramoxine,86
topical lidocaine, topical zinc oxide

Herpetic infections

Acyclovir, valacyclovir87 , 88

Hypertension89

Hydralazine, methyldopa

Benzodiazepines (e.g.,
clonazepam) (see Anxiety),
phenobarbital, phenytoin,
valproic acid (see
Comments).

The drug of choice for epilepsy in pregnancy should be the drug

that best controls the seizures; monotherapy should be favoured.
Use the lowest effective dose.
Avoid valproic acid when possible, especially in the 1st trimester (if

ASA, NSAIDs85

Avoid full anti-inflammatory doses of NSAIDs in 3rd trimester due

to the risk of oligohydramnios and premature closure of ductus
arteriosus.

Beta-blockers, calcium
channel blockers

With beta-blockers, reduced birth weight and persistent

beta-blockade possible in newborn. Monitor growth using serial
ultrasounds in the 3rd trimester. Monitor newborn for

not possible to avoid, limit dose to <6001000 mg/day).

With carbamazepine and valproic acid, prescribe periconceptional
folate supplementation: 5 mg po daily, ideally starting 3 months
before trying to conceive and continuing at least until the end of
the 1st trimester. Monitor using level II ultrasound for prevention of
neural tube defects.

hypoglycemia, bradycardia, hypotension and respiratory problems

during the first 2448 h.
Hyperthyroidism90

Propylthiouracil

Perform fetal ultrasound near term for goitre detection.

Migraine
(abortive therapy)

Acetaminophen

ASA, NSAIDs, sumatriptan91

, 92 , 93

Nausea/Vomiting

Doxylamine/pyridoxine (Diclectin)94 , 95

Dimenhydrinate,

Avoid full anti-inflammatory dose of NSAIDs in 3rd trimester due to

the risk of oligohydramnios and premature closure of ductus
arteriosus.

metoclopramide,96 , 97
ondansetron98

Schizophrenia99

Phenothiazines

Haloperidol, risperidone

Watch neonate for possible adverse effects if taken close to term.

Continue present antipsychotic if the woman is stable and
unplanned pregnancy occurs. Monitor the woman for metabolic

21/09/2014 04:02

e-Therapeutics+ Complete : Therapeutic Choices : Drug Use during Pre...

4 5


Condition

Drugs of Choice

http://www.e-therapeutics.ca/tc.showPrintableChapter.action?chapterId...

Alternative

Comments
complications (weight gain, hyperglycemia, hyperlipidemia),
especially with second-generation antipsychotics.

Vaginal candidiasis

Vaginal: clotrimazole, miconazole,

nystatin
Topical azoles are preferred100 , 101

Fluconazole: single systemic

dose of 150 mg102

References
1.
2.
3.
4.

Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton (MA): Publishing Sciences Group; 1977.
Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998;338(16):1128-37.
Brent RL, Beckman DA. Environmental teratogens. Bull NY Acad Med 1990;66(2):123-63.
Adam MP. The all-or-none phenomenon revisited. Birth Defects Res A Clin Mol Teratol 2012;94(8):664-9.
5. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 9th ed. Philadelphia (PA): Lippincott Williams &
Wilkins; 2011.
6. FDA classification of drugs for teratogenic risk. Teratology Society Public Affairs Committee. Teratology 1994;49(6):446-7.
7. Koren G. Medication safety in pregnancy and breastfeeding. New York (NY): McGraw-Hill; 2007.
8. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med
2006;354(23):2443-51.
9. Malm H, Artama M, Gissler M et al. First trimester use of ACE-inhibitors and risk of major malformations. Reprod Toxicol 2008;26(1):67.
10. Lennestal R, Otterblad Olausson P, Kallen B. Maternal use of antihypertensive drugs in early pregnancy and delivery outcome, notably the presence of congenital
heart defects in the infants. Eur J Clin Pharmacol 2009;65(6):615-25.
11. Diav-Citrin O, Shechtman S, Halberstadt Y et al. Pregnancy outcome after in utero exposure to angiotensin converting enzyme inhibitors or angiotensin receptor
blockers. Reprod Toxicol 2011;31(4):540-5.
12. Li D, Yang C, Andrade S et al. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a
retrospective cohort study. BMJ 2011;343:d5931.
13. Moretti ME, Caprara D, Drehuta I et al. The fetal safety of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. Obstet Gynecol Int
2012;2012:658310.
14. Polifka JE. Is there an embryopathy associated with first-trimester exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists?
A critical review of the evidence. Birth Defects Res A Clin Mol Teratol 2012;94(8):576-98.
15. Selig BP, Furr JR, Huey RW et al. Cancer chemotherapeutic agents as human teratogens. Birth Defects Res A Clin Mol Teratol 2012;94(8):626-50.
16. Jones KL, Lacro RV, Johnson KA et al. Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med
1989;320(25):1661-6.
17. Addis A, Moretti ME, Ahmed-Syed F et al. Fetal effects of cocaine: an updated meta-analysis. Reprod Toxicol 2001;15(4):341-69.
18. Park-Wyllie L, Mazzotta P, Pastuszak A et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of
epidemiological studies. Teratology 2000;62(6):384-92.
19. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980;68(1):122-40.
20. Schaefer C, Hannemann D, Meister R et al. Vitamin K antagonists and pregnancy outcome. A multi-centre prospective study. Thromb Haemost
2006;95(6):949-57.
21. Mittendorf R. Teratogen update: carcinogenesis and teratogenesis associated with exposure to diethylstilbestrol (DES) in utero. Teratology 1995;51(6):435-45.
22. Lemoine P, Harousseau H, Borteyru JP et al. [Les enfants des parents alcoholiques: anomalies observes a propos de 127 cas]. Ouest Med 1968;21:476-82.
[French].
23. Ulleland CN. The offspring of alcoholic mothers. Ann N Y Acad Sci 1972;197:167-9.
24. Jones KL, Smith DW, Ulleland CN et al. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1973;1(7815):1267-71.
25. Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet 1973;2(7836):999-1001.
26. Rosett HL, Ouellette EM, Weiner L et al. Therapy of heavy drinking during pregnancy. Obstet Gynecol 1978;51(1):41-6.
27. Breiner P, Nulman I, Koren G. Identifying the neurobehavioral phenotype of fetal alcohol spectrum disorder in young children. J Popul Ther Clin Pharmacol
2013;20(3):e334-9.
28. Hyoun SC, Obican SG, Scialli AR. Teratogen update: methotrexate. Birth Defects Res A Clin Mol Teratol 2012;94(4):187-207.
29. Mercier-Parot L, Tuchmann-Duplessis H. The dysmorphogenic potential of phenytoin: experimental observations. Drugs 1974;8(5):340-53.
30. Congenital malformations. N Engl J Med 1983;309(5):311-2.
31. Jacobson SJ, Jones K, Johnson K et al. Prospective multicenter study of pregnancy outcome after lithium exposure during the first trimester. Lancet
1992;339(8792):530-3.
32. Diav-Citrin O, Shechtman S, Finkel-Pekarsky V et al. Pregnancy outcome following in utero exposure to lithium: a prospective, comparative, observational study.
Am J Psychiatry 2014;171(7):785-94.
33. Pastuszak AL, Schuler L, Speck-Martins CE et al. Use of misoprostol during pregnancy and Mbius' syndrome in infants. N Engl J Med 1998;338(26):1881-5.
34. Koren G, Schuler L. Taking drugs during pregnancy. How safe are the unsafe? Can Fam Physician 2001;47:951-3.
35. Vauzelle C, Beghin D, Cournot MP et al. Birth defects after exposure to misoprostol in the first trimester of pregnancy: prospective follow-up study. Reprod
Toxicol 2013;36:98-103.
36. Le Ray C, Coulomb A, Elefant E et al. Mycophenolate mofetil in pregnancy after renal transplantation: a case of major fetal malformations. Obstet Gynecol
2004;103(5 Pt 2):1091-4.
37. Anderka MT, Lin AE, Abuelo DN et al. Reviewing the evidence for mycophenolate mofetil as a new teratogen: case report and review of the literature. Am J Med
Genet A 2009;149A(6):1241-8.
38. Hoeltzenbein M, Elefant E, Vial T et al. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information
Services. Am J Med Genet A 2012;158A(3):588-96.
39. Lammer EJ, Chen DT, Hoar RM et al. Retinoic acid embryopathy. N Engl J Med 1985;313(14):837-41.
40. Dai WS, LaBraico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol 1992;26(4):599-606.
41. Forti G, Benincori C. Doxycycline and the teeth. Lancet 1969;1(7598):782.
42. Sanchez AR, Rogers RS, Sheridan PJ. Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity. Int J Dermatol 2004;43(10):709-15.
43. Newman CG. Teratogen update: clinical aspects of thalidomide embryopathya continuing preoccupation. Teratology 1985;32(1):133-44.
44. Bjerkedal T, Czeizel A, Goujard J et al. Valproic acid and spina bifida. Lancet 1982;2(8307):1096.
45. Robert E, Guibaud P. Maternal valproic acid and congenital neural tube defects. Lancet 1982;2(8304):937.
46. Centres for Disease Control (CDC).Valproate: a new cause of birth defectsreport from Italy and follow-up from France. MMWR Morb Mortal Wkly Rep
1983;32(33):438-9.
47. Christianson AL, Chesler N, Kromberg JG. Fetal valproate syndrome: clinical and neurodevelopmental features in two sibling pairs. Dev Med Child Neurol
1994;36(4):361-9.
48. Moore SJ, Turnpenny P, Quinn A et al. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet 2000;37(7):489-97.
49. Jentink J, Loane MA, Dolk H et al. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med 2010;362(23):2185-93.
50. Motherisk. Toronto (ON): Hospital for Sick Children. Available from: www.motherisk.orgwomen/index.jsp. Accessed November 2013.
51. Enato E, Moretti M, Koren G. The fetal safety of benzodiazepines: an updated meta-analysis. J Obstet Gynaecol Can 2011;33(1):46-8.
52. Lopez-Rangel E, Van Allen MI. Prenatal exposure to fluconazole: an identifiable dysmorphic phenotype. Birth Defects Res A Clin Mol Teratol
2005;73(11):919-23.
53. Godfrey LM, Erramouspe J, Cleveland KW. Teratogenic risk of statins in pregnancy. Ann Pharmacother 2012;46(10):1419-24.
54. Winterfeld U, Allignol A, Panchaud A et al. Pregnancy outcome following maternal exposure to statins: a multicentre prospective study. BJOG
2013;120(4):463-71.
55. Zarek J, Koren G. The fetal safety of statins: a systematic review and meta-analysis. J Obstet Gynaecol Can 2014;36(6):506-9.

21/09/2014 04:02

e-Therapeutics+ Complete : Therapeutic Choices : Drug Use during Pre...

5 5


http://www.e-therapeutics.ca/tc.showPrintableChapter.action?chapterId...

56. Diav-Citrin O, Ornoy A. Teratogen update: antithyroid drugs-methimazole, carbimazole, and propylthiouracil. Teratology 2002;65(1):38-44.
57. Cassina M, Dona M, Di Gianantonio E et al. Pharmacologic treatment of hyperthyroidism during pregnancy. Birth Defects Res A Clin Mol Teratol
2012;94(8):612-9.
58. Diav-Citrin O, Ornoy A. Selective serotonin reuptake inhibitors in human pregnancy; to treat or not to treat? Obstet Gynecol Int 2012;2012:698947.
59. Huybrechts KF, Palmsten K, Avorn J et al. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med 2014;370(25):2397-407.
60. Rosa FW. Teratogen update: penicillamine. Teratology 1986;33(1):127-31.
61. Hernandez-Diaz S, Werler MM, Walker AM et al. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343(22):1608-14.
62. Hernandez-Diaz S, Werler MM, Walker AM et al. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol
2001;153(10):961-8.
63. Matok I, Gorodischer R, Koren G et al. Exposure to folic acid antagonists during the first trimester of pregnancy and the risk of major malformations. Br J Clin
Pharmacol 2009;68(6):956-62.
64. Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis. Am J Perinatol 1997;14(3):119-24.
65. Klln B. Use of antihistamine drugs in early pregnancy and delivery outcome. J Matern Fetal Neonatal Med 2002;11(3):146-52.
66. Fouda UM, Sayed AM, Ramadan DI et al. Efficacy and safety of two doses of low molecular weight heparin (enoxaparin) in pregnant women with a history of
recurrent abortion secondary to antiphospholipid syndrome. J Obstet Gynaecol 2010;30(8):842-6.
67. Romualdi E, Dentali F, Rancan E et al. Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the
literature. J Thromb Haemost 2013;11(2):270-81.
68. Ferreira E, Martin B, Morin C. Grossesse et allaitement: guide thrapeutique. 2nd ed. Montral (QC): CHU Sainte-Justine; 2013.
69. Koren G, Nordeng HM. Selective serotonin reuptake inhibitors and malformations: case closed? Semin Fetal Neonatal Med 2013;18(1):19-22.
70. Reis M, Klln B. Combined use of selective serotonin reuptake inhibitors and sedatives/hypnotics during pregnancy: risk of relatively severe congenital
malformations or cardiac defects. A register study. BMJ Open 2013;3(2). pii:e002166.
71. Lim A, Stewart K, Knig K et al. Systematic review of the safety of regular preventive asthma medications during pregnancy. Ann Pharmacother
2011;45(7-8):931-45.
72. Gentile S. Lithium in pregnancy: the need to treat, the duty to ensure safety. Expert Opin Drug Saf 2012;11(3):425-37.
73. Trottier M, Erebara A, Bozzo P. Treating constipation during pregnancy. Can Fam Physician 2012;58(8):836-8.
74. Gilbert C, Mazzotta P, Loebstein R, Koren G. Fetal safety of drugs used in the treatment of allergic rhinitis: a critical review. Drug Saf 2005;28(8):707-19.
75. Klln B. The safety of antidepressant drugs during pregnancy. Expert Opin Drug Saf 2007;6(4):357-70.
76. Lepercq J, Lin J, Hall GC et al. Meta-analysis of maternal and neonatal outcomes associated with the use of insulin glargine versus NPH insulin during pregnancy.
Obstet Gynecol Int 2012;2012:649070.
77. Gui J, Liu Q, Feng L. Metformin vs insulin in the management of gestational diabetes: a meta-analysis. PLoS One 2013;8(5):e64585.
78. Berggren EK, Boggess KA. Oral agents for the management of gestational diabetes. Clin Obstet Gynecol 2013;56(4):827-36.
79. Black RA, Hill DA. Over-the-counter medications in pregnancy. Am Fam Physician 2003;67(12):2517-24.
80. Pasternak B, Hviid A. Use of proton-pump inhibitors in early pregnancy and the risk of birth defects. N Engl J Med 2010;363(22):2114-23.
81. Battino D, Tomson T. Management of epilepsy during pregnancy. Drugs 2007;67(18):2727-46.
82. Harden CL, Meador KJ, Pennell PB et al. Management issues for women with epilepsyFocus on pregnancy (an evidence-based review): II. Teratogenesis and
perinatal outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and
the American Epilepsy Society. Epilepsia 2009;50(5):1237-46.
83. Holmes LB, Hernandez-Diaz S. Newer anticonvulsants: lamotrigine, topiramate and gabapentin. Birth Defects Res A Clin Mol Teratol 2012;94(8):599-606.
84. Niederhoff H, Zahradnik HP. Analgesics during pregnancy. Am J Med 1983;75(5A):117-20.
85. Daniel S, Matok I, Gorodischer R et al. Major malformations following exposure to nonsteroidal antiinflammatory drugs during the first trimester of pregnancy. J
Rheumatol 2012;39(11):2163-9.
86. Ebrahimi N, Vohra S, Gedeon C et al. The fetal safety of hydrocortisone-pramoxine (Proctofoam-HC) for the treatment of hemorrhoids in late pregnancy. J Obstet
Gynaecol Can 2011;33(2):153-8.
87. Stone KM, Reiff-Eldridge R, White AD et al. Pregnancy outcomes following systemic prenatal acyclovir exposure: conclusions from the international acyclovir
pregnancy registry, 1984-1999. Birth Defects Res A Clin Mol Teratol 2004;70(4):201-7.
88. Pasternak B, Hviid A. Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of birth defects. JAMA 2010;304(8):859-66.
89. Magee LA, Pels A, Helewa M et al. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary. J Obstet Gynaecol
Can 2014;36(5):416-41.
90. De Groot L, Abalovich M, Alexander EK et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice
guideline. J Clin Endocrinol Metab 2012;97(8):2543-65.
91. Klln B, Nilsson E, Otterblad Olausson P. Delivery outcome after maternal use of drugs for migraine: a register study in Sweden. Drug Saf
2011;34(8):691-703.
92. Hilaire ML, Cross LB, Eichner SF. Treatment of migraine headaches with sumatriptan in pregnancy. Ann Pharmacother 2004;38(10):1726-30.
93. Nezvalov-Henriksen K, Spigset O, Nordeng H. Triptan safety during pregnancy: a Norwegian population registry study. Eur J Epidemiol 2013;28(9):759-69.
94. McKeigue PM, Lamm SH, Linn S et al. Bendectin and birth defects: I. A meta-analysis of the epidemiologic studies. Teratology 1994;50(1):27-37.
95. Ashkenazi-Hoffnung L, Merlob P, Stahl B et al. Evaluation of the efficacy and safety of bi-daily combination therapy with pyridoxine and doxylamine for nausea
and vomiting of pregnancy. Isr Med Assoc J 2013;15(1):23-6.
96. Matok I, Gorodischer R, Koren G et al. The safety of metoclopramide use in the first trimester of pregnancy. N Engl J Med 2009;360(24):2528-35.
97. Pasternak B, Svanstrm H, Mlgaard-Nielsen D et al. Metoclopramide in pregnancy and risk of major congenital malformations and fetal death. JAMA
2013;310(15):1601-11.
98. Pasternak B, Svanstrm H, Hviid A. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med 2013;368(9):814-23.
99. Gentile S. Antipsychotic therapy during early and late pregnancy. A systematic review. Schizophr Bull 2010;36(3):518-44.
100. Public Health Agency of Canada. Canadian guidelines on sexually transmitted infections. Evergreen ed. Ottawa (ON): PHAC; updated January 2010. Available
from: www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/section-6-4-eng.php. Accessed November 13, 2013.
101. Young GL, Jewell D. Topical treatment for vaginal candidiasis (thrush) in pregnancy. Cochrane Database Syst Rev 2001;(4):CD000225.
102. Mlgaard-Nielsen D, Pasternak B, Hviid A. Use of oral fluconazole during pregnancy and the risk of birth defects. N Engl J Med 2013;369(9):830-9.

Therapeutic Choices. Canadian Pharmacists Association, 2014. All rights reserved.

21/09/2014 04:02