Medication Use in Pregnancy; Treating the Mother: Protecting the Unborn

Medicines For Women

4. Medication Use in Pregnancy; Treating the Mother: Protecting the Unborn

Yifat Gadot¹ and Gideon Koren¹

(1)

The Motherisk Program, Clinical Pharmacology & Toxicology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Gideon Koren

Email: gidiup_2000@yahoo.com

Introduction

Each year, numerous new medications enter the market. The formal labeling for most of these drugs does not contain safety data related to exposure during gestation. However, millions of pregnant women have conditions that need to be treated such as diabetes, urinary tract infections and nausea and vomiting. The paucity of knowledge in regard to fetal safety of medications introduces significant challenges for practitioners, and situates the mother at risk of insufficient therapy for her disease, and her unborn baby at a potential risk of toxicity (McBride 1978; Koren 2013).

Since thalidomide was demonstrated to be a major human teratogen, many practitioners practice as if any medication is hazardous to the fetus, leading physicians and pregnant women to refrain from the use of medications, even for the management of serious conditions. Presently, we must change the climate whereby pregnant women and their unborn babies become therapeutic orphans. Ultimately, this knowledge gap may prevent the mother from obtaining needed therapeutics, or make her decide not to treat serious conditions, or even to terminate otherwise wanted pregnancies.

For the vast majority of drugs which have been evaluated in pregnancy, including first trimester exposure to ACE inhibitors, oral contraceptives and benzodiazepines, large amounts of data have failed to show fetal risks in humans (Koren et al. 1998). Before considering potential fetal risks of drugs, it is imperative to note that all pregnancies have a birth defect baseline risk of 1–3 %, by chance alone (Heinonen et al. 1977). Hence, any attempt to prove fetal safety/risk must compare exposure to a given drug to this baseline risk.

Overall 80–90 % of pregnant women take at least one medication during pregnancy, commonly before they realized they have conceived. During the last 30 years, there has been a 60 % increase in first trimester use of prescription drugs, while use of four or more drugs tripled (Mitchell et al. 2011). Moreover, 12 million prescriptions for potentially teratogenic medications are prescribed annually in the U.S. for women in their reproductive years (Schwarz et al. 2005). Contraceptive counseling is given in less than 50 % of women prescribed potentially teratogenic medications (Schwarz et al. 2005) and approximately 6 % of US pregnancies are exposed to potentially teratogenic medications (Andrade et al. 2004; Lee et al. 2006).

Timing of Fetal Exposure to Medicines

All-or-None Period

The “all-or-none” period is the period of time between fertilization and implantation. At this time the embryo is not yet in contact with the maternal circulation, and any injuries sustained by the conceptus are likely to result in either recovery, repair or death (Fabro and Scialli 1986). It is improbable that exposure to teratogens in the “all-or-none” period will result in malformations.

The timing of implantation is approximately 14 days post-ovulation, although recent information suggests that it may occur several days prior (Wilcox et al. 1999). Implantation in the uterus lining induces the production of human chorionic gonadotropin (hCG) which enters the maternal circulation, creating a connection between the mother and the conceptus (Wilcox et al. 1999).

Period of Organogenesis/First Trimester

The period of organogenesis (menstrual weeks 5–10) is the period of time when the differentiation of fetal tissues takes place and thus in this period the fetus is susceptible to the impact of teratogens. The organ systems that are most influenced by the effects of teratogens are those developing at the time of teratogenic exposure. For example, limb development has a relatively short duration of susceptibility to teratogenicity, while the fetus is susceptible to central nervous system defects over a period of months (Brent 1986).

Further Fetal Development in Second and Third Trimesters

The second and third trimesters of pregnancy are characterized by cell growth and differentiation. Exposure to teratogenic agents at this period may cause cell growth retardation, decrease the cell population by cell death, or inhibit differentiation. For example, chronic exposure to antenatal corticosteroids may decrease birth weight (French et al. 1999).

Estimating the Risk of Drugs in Maternal Milk

There are serious concerns among mothers and health professionals regarding neonatal exposure to drugs through breast milk. In order to confirm the safety of use of drugs during breastfeeding one needs to estimate the extent of infant’s exposure to the drug through breast milk, by calculating the infant’s weight-adjusted dose ( referred to as” relative infant dose”). The calculation of infant’s weight- adjusted dose is based on maternal weight and dose, concentration of the drug in breast milk, and an estimation of infant’s daily milk consumption of 150 ml/kg. If an infant’s weight adjusted dose is less than 10 % of the maternal weight adjusted dose, it is unlikely that it would elevate the risk for adverse neonatal effects above baseline risk (Bennett 1996).

Medicines with Safety Concerns During Pregnancy and Lactation

In this chapter we will discuss selected medications for which there are potential or proven concerns for fetal safety.

The reader is referred to Table 4.1, where we summarize drugs which are apparently safe to the developing fetus when used in therapeutic doses. Table 4.2 summarises data related to neonatal safety of drug exposure through breastfeeding.

Table 4.1

Summary of safety of medicines in pregnancy

Drug	Overall assessment	Existing evidence
ACE inhibitors	In 1st trimester-no relation to congenital malformations	Meta-analysis, prospective and retrospective cohort studies, case reports
ACE inhibitors	In 2nd and 3rd trimesters- fetal hypotension and renal failure
Acetaminophen	Safe for use in pregnancy	Large retrospective cohort studies, prospective cohort studies
Acetazolamide	Limited data on first trimester is reassuring	Cohort studies, case reports, case series
Acetylcysteine	Limited data on first trimester is reassuring	Case reports, case series
Biological therapies	Safe for use in pregnancy- avoid live vaccine in baby up to 6 months	Cohort studies, case reports, case series
CA channel blockers	Limited data on first trimester is reassuring	Cohort studies
Cephalosporins	Safe for use in pregnancy	Cohort studies
Chloroquine	Safe for use in pregnancy	Prospective and retrospective cohort studies, reviews, case reports
Chloroquine	Long half life
Clavulonic acid	Safe for use in pregnancy	Cohort studies
Clindamycin	Limited data on first trimester is reassuring	Randomized case-control, Cohort studies
Codeine	Safe for use in pregnancy	Case-control studies, cohort studies
Codeine	Withdrawal may occur in neonates	Case-control studies, cohort studies
Dextromethorphan	Safe for use in pregnancy	Case-control study, cohort studies
Digoxin	Safe for use in pregnancy	Cohort studies, case series, case reports
Digoxin	Monitor maternal drug levels	Cohort studies, case series, case reports
Flecainide	Limited data of no malformations, should only be used if potential benefit justifies potential fetal risk	Case series, case reports
Furosemide	Limited data of no malformations	Meta-analysis, cohort study, review
Gabapentin	Limited data on first trimester is reassuring	Cohort studies
Heparin	Safe for use in pregnancy	Review, cohort studies, case reports
Heparin	Maternal osteopenia in prolonged use	Review, cohort studies, case reports
Hydralazine	Limited data on first trimester is reassuring	Cohort study, case series
Isoniazid	Limited data on first trimester is reassuring. Vitamin K recommended ( to prevent haemorrhage), Vit B6 supplementation	Case-control study, prospective and retrospective cohort studies, case reports
Lamotrigine	Safe for use in pregnancy	Prospective and retrospective cohort studies
Levetiracetam	Safe for use in pregnancy	Cohort studies, case series
Low molecular weight heparin	Safe for use in pregnancy	Cohort studies
	Does not cross the placenta
	Might be related to increase in maternal osteoporosis
Macrolides	Safe for use in pregnancy	Cohort studies
Mesalamine	Safe for use in pregnancy	Meta-analysis, cohort studies
Methyldopa	Safe for use in pregnancy	Meta-analysis, cohort studies
Metronidazole	Safe for use in pregnancy	Meta-analyses, cohort studies, review
Montelukast	Safe for use in pregnancy	Cohort studies
Nitrofurantoin	Safe for use in pregnancy	Meta-analysis, cohort studies
Nitrofurantoin	Hemolytic anemia of fetus/newborn-discontinue >37 weeks	Meta-analysis, cohort studies
NSAIDS	Safe for use in 1st and 2nd trimesters, not recommended in 3rd trimester-premature closure of ductus arteriosus	Case-control study, cohort studies, case reports
Oral contraceptives	Safe for use in pregnancy	Meta-analysis, case-control studies, cohort studies
Oseltamivir	Relatively safe for use in pregnancy	Cohort studies
Penicillins	Safe for use in pregnancy	Case-control study, prospective and retrospective cohort studies
Propafenone	Very limited data	Case report
Quinolones	Safe for use in pregnancy	Meta-analysis, prospective and retrospective cohort studies
Rifampin	Limited data on first trimester is reassuring. Vitamin K recommended (to prevent hemorrhage)	Cohort study, case reports
Salbutamol	Safe for use in pregnancy	Cohort studies
Salmeterol	Safe for use in pregnancy	Cohort studies
Spironolactone	Limited data on first trimester is reassuring	Cohort study, case reports
Sulfasalazine	Safe for use in pregnancy	Cohort studies, case reports
Sulfasalazine	Folic acid supplementation advised to reduce toxicity	Cohort studies, case reports
Tetracyclin	Bone growth suppression, teeth discoloration>mainly after 4 months of gestation	Cohort studies
Theophylline	Limited data on first trimester is reassuring	Prospective and retrospective cohort studies
Thiazide	Limited data on first trimester is reassuring	Meta-analysis, case reports, review
Trimethoprim-sulfonamide	1st trimester-increased risk of neural tube defects	Case-control studies, cohort studies
Trimethoprim-sulfonamide	Not recommended >32 weeks due to risk for kernicterus	Case-control studies, cohort studies
Triptans	Safe for use in pregnancy	Systematic review, prospective and retrospective cohort studies
Vancomycin	Limited data on first trimester is reassuring	Small cohort studies

Table 4.2

Summary of safety of medicines during breast feeding

Drug	Compatibility	Pharmacokinetics	Evidence
ACE Inhibitors	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case series, case reports
Acetaminophen	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case reports, case series, review, prospective cohort study
Acetazolamide	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case reports
Acetylcysteine	No information		No studies or reports
Acyclovir	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case series, case reports
Aminoglycoside	Compatible with breastfeeding	Excreted in breast milk in very low concentrations	Case series, case reports
Aminoglycoside	Observe for diarrhea, candidiasis	Excreted in breast milk in very low concentrations	Case series, case reports
Amiodarone	Careful breastfeeding because of large proportion of iodine in the drug	Excreted in breast milk in low concentrations, stays in breast milk days-weeks after stopping to breastfeed	Case reports
Amiodarone	Monitor cardiac and thyroid function		Case reports
Angiotensin II-AT1 Receptor Blockers	No information		No studies or reports
Aspirin-high dose	Not recommended	Excreted in breast milk in high concentrations	Case series, case reports
Aspirin-high dose	Metabolic acidosis, Reye synd with viral infections	Excreted in breast milk in high concentrations	Case series, case reports
Aspirin-low dose	May be considered	Excreted in breast milk in high concentrations	Case series, case reports
Atenolol	Contraindicated	Accumulates in potentially high levels in breast milk	Case series, case reports
Atenolol	Adverse effects such as bradycardia	Accumulates in potentially high levels in breast milk	Case series, case reports
Biological therapies	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case reports
Biological therapies	Live vaccines are contraindicated	Excreted in breast milk in low concentrations	Case reports
β blockers (labetolol, metoprolol, nadolol)	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case series, case reports
CA channel blockers	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case series, case reports
Cephalosporins	Limited information	Excreted in breast milk in low concentrations	Case series, case reports
	Compatible with breastfeeding
	Observe for diarrhea
Chloroquine	When given once a week-might be safe, no information in breastfeeding	Excreted in breast milk in low concentrations	Case series, case reports
	Other drug may be preferred
	Long half life-over a month
Clavulonic acid	Compatible with breastfeeding	Excreted in breast milk in very low concentrations	Two small, controlled, prospective studies, case series, case report
Clavulonic acid	Observe for diarrhea, rash, restlessness	Excreted in breast milk in very low concentrations
Clindamycin	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case series, case reports
Codeine	Other agents are preferred. Max 4 days treatment is recommended	Variability in excretion to breast milk (due to maternal polymorphism of CYP2D6)	Guidelines, retrospective cohort studies, case series, case reports
	Can cause drowsiness, central nervous system depression and even death
	Newborn infants particularly sensitive
	Monitor mother and infant
Dextromethorphan	No reported adverse events		No reports
Dextromethorphan	Probably compatible with breastfeeding		No reports
Digoxin	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case series, case reports
Flecainide	Limited data, no adverse effects	Monitor breastfed infants, including serum levels	Case series, case report
Furosemide	No information	Increased diuresis might decrease lactation	Case report
Gabapentin	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case series, case reports
Gabapentin	Surveillance infant	Excreted in breast milk in low concentrations	Case series, case reports
Heparin	Compatible with breastfeeding	Estimated Excretion in breast milk in low concentrations	No reports
Heparin	Compatible with breastfeeding	Estimated Excretion in breast milk in low concentrations	Data related on low molecular weight heparins data (case series)
Hydralazine	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case series, case reports
Isoniazid	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case series, case reports
Lamotrigine	Surveillance infant carefully	Excreted in breast milk in high concentrations-30 % of maternal plasma level	Small cohort studies, case series, case reports
Levetiracetam	Limited data	Excreted in breast milk in low concentrations	Case series, case reports
	Compatible with breastfeeding
	Surveillance infant
Low molecular weight heparin	compatible with breastfeeding	Excreted in breast milk in negligible -very low concentrations	Case series
Macrolides	Compatible with breastfeeding monitor infant GI symptoms, related to pyloric stenosis?	Excreted in breast milk in low concentrations	Cohort study, case series, case reports
Mesalamine	Monitor for diarrhea	Excreted in breast milk in low concentrations	Case series, case reports
Methyldopa	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case reports
Metronidazole	Compatible with breastfeeding, with caution	Excreted in breast milk in very low concentrations	Case-control study, case series
Montelukast	No information		No reports
Nitrofurantoin	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case series, case reports
Nitrofurantoin	Under 1 month or infants with G6PD- not recommended, risk of hemolysis	Excreted in breast milk in low concentrations	Case series, case reports
NSAIDS	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case series, case reports
NSAIDS	COX 2-exposure small, risk expected to be minimal	Excreted in breast milk in low concentrations	Case series, case reports
Oral contraceptives	Affect growth negatively in first month of life, may suppress breastfeeding		Cohort studies, case series, case reports
	Not recommended in the first 4 weeks postpartum
	Generally, progesterone only pills are preferred
Oseltamivir	Limited data compatible with breastfeeding	Excreted in breast milk in low concentrations	Case series, case report
Penicillins	Compatible with breastfeeding	Excreted in breast milk in very low concentrations	Case series, case reports
Penicillins	Monitor infant GI symptoms	Excreted in breast milk in very low concentrations	Case series, case reports
Phenobarbital	Compatible with breastfeeding with caution	Variability in excretion in breast milk, in some cases very high- dosage is 72 % of the maternal adjusted dose	Case series, case reports
	Can cause drowsiness
	Monitor the infant
	If suspected toxicity- check levels in infant
Propafenone	Compatible with breastfeeding, especially after 2 months of age	Doses up to 900 mg produce very low levels in milk	Case reports
Quinolones	Short-term use is acceptable	Excreted in breast milk in low concentrations	Case series, case reports
Quinolones	Avoid breastfeeding 4–6 h after the dose	Excreted in breast milk in low concentrations	Case series, case reports
Radionuclides	Guidelines vary with the specific agent and the test performed	Variability in excretion in breast milk between the different kinds, the dosage is between 0.01 % and 70 % of the maternal adjusted dose	Reviews, guidelines
	Elective diagnostic nuclear medicine procedures should be delayed until the patient has interrupted breastfeeding (hours-weeks-depending on substance)
	In some cases there is a need to refrain from close contact with the infants
Rifampin	Limited data	Excreted in breast milk in very low concentrations	Case series, case reports
Rifampin	Compatible with breastfeeding	Excreted in breast milk in very low concentrations	Case series, case reports
Salbutamol	Compatible with breastfeeding	Excreted in breast milk in very low concentrations	No reports
Salbutamol	Compatible with breastfeeding	Excreted in breast milk in very low concentrations	Data related on terbutaline data (case series, case reports)
Salmeterol	Compatible with breastfeeding	Excreted in breast milk in very low concentrations	No reports
Salmeterol	Compatible with breastfeeding	Excreted in breast milk in very low concentrations	Data related on terbutaline data (case series, case reports)
Spironolactone	Usually compatible with breastfeeding	Excreted in breast milk in low concentrations	Case report
Sulfasalazine	Other drug without sulfonamide may be preferred	Excreted in breast milk in low concentrations	Case series, case reports
Sulfasalazine	Monitor for diarrhea	Excreted in breast milk in low concentrations	Case series, case reports
Tetracyclins	Short-term use is accepted, refrain from long or repeat treatments	Excreted in breast milk in low concentrations	Cohort study, case series
Theophylline	Toxic effects of infant	Excreted in breast milk in high concentrations	Case series, case reports
Theophylline	Avoid breastfeeding a few hours after drug given	Excreted in breast milk in high concentrations	Case series, case reports
Thiazide	Scarce data	Low doses are acceptable Increased diuresis might decrease lactation	Case reports
Trimethoprim-sulfonamide	Acceptable for healthy, term babies		Systematic review, prospective controlled study, cohort study, case series
Trimethoprim-sulfonamide	Avoided in G6PD, preterm, ill, jaundiced (risk for kernicterus)
Triptans	Compatible with breastfeeding	Excreted in breast milk in low concentrations	Case series
Vancomycin	Limited data compatible with breastfeeding	Excreted in breast milk in low concentrations	Case report

The medications selected below are either known teratogens, or have been the center of much debate on their potential adverse effects on the child, and although they ultimately have been not shown to cause fetal damage, their use have been curtailed by misperception and anxiety by women and prescribers alike.

Antibiotics

Antibacterial drugs are among the most common medications used by pregnant women. Most antibiotics are safe for use in pregnancy (e.g. cephalosporins, clavulonic acid, macrolides, metronidazole, nitrofurantoin, penicillins and quinolones). Regarding nitrofurantoin, increased risk for hemolytic anemia of the newborn has been suggested, with the recommendation for discontinuation at >37 weeks gestation recommended.

Few antibiotics are considered not safe in pregnancy, such as tetracyclins and trimethoprim-sulfonamides. Tetracyclins are associated with bone growth suppression, teeth discoloration after 4 months of gestation. Trimethoprim-sulfonamides have been associated with first trimester-increased risk of neural tube defects and are not recommended after 32 weeks gestation due to risk of billirubin displacement and kernicterus. Some of the antibacterial medications have limited data, although the data are reassuring. (e.g. clindamycin, isoniazid, rifampin, vancomycin) (Nahum et al. 2006).

Trimethoprim-Sulphonamide (T-S) combinations (e.g., Septra®, Bactrim™) are commonly used for urinary tract infections in pregnant women. Some evidence suggests that when prescribed in pregnancy, these folic acid antagonists may elevate the risk for neural tube defects and possibly other congenital malformations (Briggs et al. 2011).

Biological Therapies

An increasing number of biological therapies are IgG monoclonal antibodies. There is limited information currently available on the use of biological therapies during pregnancy, but they do not appear to elevate the risk of congenital malformations above the baseline risk in the general population (Mahadevan et al. 2005; American Gastroenterological Association Institute 2007; Johnson et al. 2011; Association of Rheumatology Health Professionals 2008; Ojeda-Uribe et al. 2006; Food and Drug Administration Dermatologic and Ophthalmic Drugs Advisory Committee 2012; Mahadevan et al. 2013). The high molecular weight of biologicals does not allow them to cross the placenta in early pregnancy; however they do cross later on (as do other IgGs when the placenta develops higher levels of the Fc transporter, and many of them have neonatal levels exceeding maternal concentrations. Biologicals which are not IgG, (e.g. CIMZIA)- minimally cross the placenta even in late pregnancy (Mahadevan et al. 2011). A case of a neonate who succumbed to vaccinia after maternal use of infliximab highlighted a potential risk of immunological deficiency in exposed babies (Mahadevan et al. 2011).

Therefore it is now widely agreed that live vaccines should be contraindicated in patients treated by biological therapies. Because biological medicines were found in exposed infants up to 6 months after birth, The World Congress of Gastroenterology (WCOG) states that: “Vaccination of infants exposed to biological therapy in utero should be given at standard schedules, except for live-vaccines, which are best not given if circulating biological agents are detectable in the infant” (Mahadevan et al. 2011).

Breastfeeding

Only very small amounts of biological therapies are excreted into breast milk, which would be predicted due to their high molecular weight. Considering biological therapies are proteins, they are most likely not to be absorbed systemically.

The infants’ systemic circulation exposure to biological therapies in human milk appears to be minimal (Murashima et al. 2009). These data imply that biological therapies may be safe during breastfeeding, but long-term follow-up information is not available.

Angiotensin-Converting Enzyme Inhibitors (ACEIs)

Angiotensin-converting enzyme (ACE) inhibitors are effective antihypertensive agents, with few adverse effects. They are often used in women of reproductive age. The use of ACE inhibitors in the first trimester only, does not appear to be related to an elevated risk of major congenital malformation above the average risk in hypertensive pregnant women (untreated or treated with other drugs) (Diav-Citrin et al. 2011; Moretti et al. 2012; Walfisch et al. 2011; Li et al. 2011; Kreft-Jais et al. 1988; From the Centers for Disease Control and Prevention 1997; Lip et al. 1997; Steffensen et al. 1998; Yip et al. 1998).

In contrast, exposure to ACE inhibitors in the second and third trimesters appears to be fetotoxic, inducing fetal hypotention and renal failure. Oligohydramnios (reflecting renal failure), reduced urine formation, neonatal anuria and fetal hypotension shown in published cases, are a direct consequence of these medications on the fetal renin-angiotensin system (Boutroy et al. 1984; Guignard et al. 1981; Rosa et al. 1989). The degree of fetal and neonatal morbidity correlated with ACE inhibitors exposure in the second and third trimesters is estimated to be significant (between 10 % and 20 %) (Al-Maawali et al. 2012).

The anuria related to oligohydramnios may result in pulmonary hypoplasia, fetal limb contractures and craniofacial deformities. Severe neonatal hypotension, intrauterine growth retardation, persistence of patent ductus arteriosus, prematurity, hypocalvaria, neonatal anuria, and neonatal or fetal death have also been shown with exposure to these drugs in the second and third trimesters of pregnancy (Barr 1994).

Therefore, cessation of ACE inhibitor medication before the second trimester of pregnancy is recommended and physicians should then offer the patient an alternative medication. In cases where exposure in the second or third trimester take place, patients should be surveyed by ultrasound for toxic signs including growth restriction, oligohydramnios and fetal distress (Barr 1994).

ACE-I and Breastfeeding

ACE-I are secreted into human breast milk in low amounts. The peak milk level is about 1 % of the peak plasma concentration, while average milk levels over 12 h following a dose is about 3 % of the average serum levels. Based on this information, the maximum daily dosage in milk is less than 0.014 % of the maternal weight-adjusted daily dose (Devlin and Fleiss 1981; Redman et al. 1990). There have been no observed adverse effects in breastfed infants (Devlin and Fleiss 1981; Huttunen et al. 1989; Rush et al. 1989).

Angiotensin II-AT1 Receptor Blockers

Another group of medication for hypertension are the angiotensin II-AT1 receptor blockers (ARBs), including losartan, valsartan, telmisartan, eprosartan and irbesartan. Based on limited data from first trimester exposure (Walfisch et al. 2011; Schaefer 2003; Gersak et al. 2009; Serreau et al. 2005; Chung et al. 2001; Biswas et al. 2002; Mann et al. 1999), there does not appear to be an elevated risk of major congenital malformations above the risk in pregnant hypertensive women, untreated or treated with other medications.

Similar to the ACE inhibitors, ARBs are fetotoxic when used in the second and third trimesters. They have been also reported to produce oligohydramnios, fetal anuria, limb contractures, pulmonary hypoplasia, fetal growth retardation and hypoplastic skull bones (Serreau et al. 2005; Kato et al. 2008; Simonetti et al. 2006; Vendemmia et al. 2005; Bald et al. 2005; Alwan et al. 2005; Lambot et al. 2001; Briggs and Nageotte 2001; Cox et al. 2003).

Antidepressants

The second leading cause of burden of disease for women in the United States is major depressive disorders (Michaud et al. 2006). Up to 20 % of women of reproductive age are afflicted by depression (Bennett et al. 2004) and between 1 % and 8 % of pregnant women are treated by antidepressants (Engeland et al. 2008). The selective serotonin reuptake inhibitors (SSRIs) have been in clinical use for the last two decades and are generally regarded as safe in pregnancy, in terms of dysmorphology and in neurodevelopmental measures (Koren and Nordeng 2012). The selective serotonin and norepinephrine reuptake inhibitors (SNRI) – for example: venlafaxine, duloxetine, desvenlafaxine – and Tricyclic antidepressants (TCA) are also considered safe (Einarson et al. 2012; Moses-Kolko et al. 2005; Santos and Pergolizzi 2004).

Importance of Treatment

Proper control of maternal psychiatric illness during pregnancy is necessary to provide optimal outcome for the infant and mother. Untreated depression in pregnancy has been related to increased risk of miscarriage, pre-eclampsia (pregnancy-induced hypertension), perinatal complications, bleeding during pregnancy and postpartum bleeding (Reis and Källén 2010), increased admissions to Neonatal Intensive care Unit (NICU) and increased risk of post-partum depression (PPD) (Bonari et al. 2004).

Abrupt Discontinuation

Abrupt discontinuation of these medications can have both physiological and psychological withdrawal symptoms (general somatic, gastrointestinal and affective symptoms, and sleep disturbances), including suicidal thoughts and relapse of the psychiatric illness (Einarson et al. 2009).

Spontaneous Abortions

Studies have reported an elevated risk for spontaneous abortions of 5.5–13.0 % with antidepressants use (compared to non use) with a relative risk/odds ratio of 1.63–2.09 (Einarson et al. 2009; Nakhai-Pour et al. 2010). However, it is not known whether this effect is induced by the antidepressant or the depression itself.

Poor Neonatal Adaptation Symptoms (PNAS)

Exposure to an SSRI or an SNRI during pregnancy has been associated with feeding and breathing difficulty, jitteriness, low blood sugar, and neurological symptoms (increased motor activity and sleep disturbances) (Costei et al. 2002; Levinson-Castiel et al. 2006). In most cases, symptoms subside within a week, but may continue up to 3 weeks (Moses-Kolko et al. 2005; Chambers et al. 2006). Most studies document that 10–30 % of infants exposed to SSRI’s prenatally exhibit PNAS with more than half having mild symptoms (Costei et al. 2002; Levinson-Castiel et al. 2006).

Infants exposed to SSRI’s or SNRI’s (mainly in the 3rd trimester) should be closely monitored for several days after birth. Symptoms tend to be self-limited with supportive care.

Persistent Pulmonary Hypertension of the Newborn (PPHN)

Several studies have associated late pregnancy SSRIs exposure with PPHN (Chambers et al. 2006; Källén and Olausson 2008; Kieler et al. 2012). However other studies have failed to show it (Kieler et al. 2012; Wichman et al. 2009; Andrade et al. 2009; Wilson et al. 2011). Kielers reported that women who did not use antidepressants in pregnancy but who were hospitalized for psychiatric reasons had an increased likelihood to deliver infants with pulmonary hypertension in the newborn with an OR 1.3 (CI 1.1–1.7) (compared to non psychiatric pregnant population) (Koren and Nordeng 2011). PPHN may occur in less than 1 % of babies exposed prenatally to SSRI (Koren and Nordeng 2011; Jong et al. 2012). Moreover, no mortality has been documented in any infants exposed to SSRIs prenatally that developed PPHN, compared to mortality rate of 10–15 % among other causes of PPHN (Occhiogrosso et al. 2012).

Preterm Birth

Numerous prospective observational studies with thousands of pregnant women reported a small increase in premature births among babies exposed to antidepressants in late pregnancy. However, it is unknown whether this is the result of the antidepressants or depression itself (Wisner et al. 2009; Einarson et al. 2010; Lewis et al. 2010).

Teratogenicity

Published information from 2004 and onward proposed, based on registries, that some SSRIs may be associated with increased risk of cardiovascular malformations, mainly ventricular septal defects (VSD). However, for each study postulating such risk there were two studies refuting such an association (Koren and Nordeng 2012). It should be taken into account that there is a substantial ascertainment bias because depressed women who use antidepressants undergo significantly more ultrasound and echocardiography. Therefore, their babies are much more likely to be diagnosed with congenital malformations (Bar-Oz et al. 2007). Outcomes of more than 20,000 women exposed to all classes of antidepressants documented no overall increased risk for congenital malformations (Koren and Nordeng 2013; Riggin et al. 2013).

The Risk Benefit ratio

of antidepressant use in pregnancy is strongly tilted toward use of the medication in symptomatic women, due to the high and serious risks of not treating depressed pregnant women, including hospitalization, suicide attempts, and increased risk of postpartum depression (Koren and Nordeng 2012).

Antidepressants and Breastfeeding

Typically SSRI’s, SNRIs and TCAs generate low levels in breast milk (Berle et al. 2004; Lanza di Scalea and Wisner 2009; Rampono et al. 2006; Newport et al. 2009). The average concentration of drug in breast milk is higher with fluoxetine (and its active metabolite) in comparison to most SSRIs. There have been reports of adverse effects such as colic, fussiness, and drowsiness in some breastfed infants. If fluoxetine is required by the mother, it is not a reason to discontinue breastfeeding. Otherwise, antidepressants with lower excretion into breast milk may be preferred, especially while breastfeeding a preterm infant (Kristensen et al. 1999; Moretti et al. 1999).

The breastfed SSRI/SNRI/TCA infant should be monitored for adverse events such as colic, fussiness or sedation and for inadequate weight gain (Newport et al. 2009; Kristensen et al. 1999; Moretti et al. 1999).

Lithium

Lithium is used in the management of bipolar disorder and has been on the market for more than 30 years. The malformation associated with lithium is the Ebstein anomaly which is characterized by apical displacement of the septal and posterior tricuspid valve leaflets. It may lead in severe cases to right heart failure and death and increased birth weight (Giles and Bannigan 2006; Schou 1976; Källén and Tandberg 1983; Pinelli et al. 2002; Abstracts of the Teratology Society 2012).

Higher lithium levels at delivery have been associated with an increased risk of perinatal complications, including cyanosis, disturbances of cardiac rhythm, hypotonia, nephrogenic diabetes insipidus, and hypothyroidism (Newport et al. 2005; Karlsson et al. 1975; Mizrahi et al. 1979; Krause et al. 1990).

A level II ultrasound and fetal echocardiogram are recommended. Toxic effects can be monitored by serum lithium levels and adjusting to minimally effective plasma levels, particularly in late pregnancy. Short withdrawal of lithium treatment may be considered peri-partum, if it does not compromise the mother. Importantly, neonatal symptoms are self-limited and can be treated effectively.

Lithium and Breast Feeding

Although there have been documentations of high levels of lithium in breast milk, more recent research has failed to document excessive exposure (Moretti 2003; Viguera 2007; Bogen et al. 2012). Based on available information, maternal lithium treatment should not be a contraindication for breastfeeding, and the decision needs to be made on an individual case basis. Monitoring drug levels in serum and breast milk can be performed as necessary.

Corticosteroids

Corticosteroids are used for various conditions during pregnancy, including arthritis, asthma, nephrotic syndrome and inflammatory bowel disease. The most common corticosteroid in use is prednisone but others include dexamethasone, cortisone and prednisolone. Betamethasone and dexamethasone can accelerate fetal lung maturity and are given to women at risk of preterm delivery, to decrease risk for prematurity complications (ACOG 2011).

Corticosteroids do not present a major teratogenic risk in humans, although there is an apparent elevated risk for oral cleft (Rodríguez-Pinilla and Martínez-Frías 1998; Czeizel and Rockenbauer 1997; Carmichael and Shaw 1999; Gur et al. 2004; Park-Wyllie et al. 2000) which is consistent with animal data (Walker 1971; Pinsky and Digeorge 1965). Both human and animal studies have documented an increased risk of low birth weight and stillbirth, but this may be related to the maternal underlying diseases (Gur et al. 2004; Reinisch et al. 1978; Scott 1977; Mercer et al. 2001; Thorp et al. 2002; Bloom et al. 2001).

Corticosteroids should be used based on specific indications without safe alternatives or to life threatening maternal illnesses. Since the formation of the lip and palate is completed by 12 weeks of gestation, therapy may be continued after that time. If exposure has occurred during the critical period in pregnancy, a level II ultrasound may detect some cases of oral cleft.

Corticosteroids (Inhaled)

Inhaled corticosteroids are used for the treatment of asthma or other respiratory conditions. Several studies including a meta-analysis on inhaled corticosteroids have not found an increased risk for congenital malformations (Greenberger and Patterson 1983; Rahimi et al. 2006; Källén and Otterblad 2007; Choi et al. 2007; Lim et al. 2011). No adverse fetal outcomes such as pregnancy-induced hypertension, preterm delivery or low birth weight were documented (Rahimi et al. 2006; Lim et al. 2011). Treatment during pregnancy with inhaled corticosteroids decreases the risk of an acute asthma attacks in the mother and therefore leads to more favorable fetal outcomes.

Thiopurines

The thiopurines azathioprine (AZA) and 6-mercaptopurine (6-MP) are effective medications for inflammatory bowel disease (IBD), generating a steroid-free, endoscopic and clinical remission (Mowat et al. 2011; Timmer et al. 2007). These drugs are being used more extensively in pregnancy (Goldstein et al. 2007; Kwan and Mahadevan 2010) and they have not been shown to cause increased malformation rates in observational studies and meta analyses (Mowat et al. 2011).

Based on recent studies, azathioprine exposure is not associated with increased risk of congenital malformations (Goldstein et al. 2007; Schramm et al. 2006; Moskovitz et al. 2004; Armenti et al. 2002; Cleary and Källén 2009), spontaneous abortions, stillbirth (Schramm et al. 2006) or neurocognitive impairment (Teratology Society 2011). Risks of other adverse pregnancy outcomes such as intrauterine growth retardation, prematurity (Goldstein et al. 2007; Armenti et al. 2002; Pirson et al. 1985), and immunosuppression (Alter 1985; Davison et al. 1985; DeWitte et al. 1984; Sahasranaman et al. 2008) have been reported, although these may be the results of the disease itself.

Thiopurines and Breastfeeding

Azathioprine exerts low risk to the breastfed infant and breastfeeding can continue during treatment. Studies reported low or unmeasurable concentrations of the active metabolites in breast milk and in infant serum (Christensen et al. 2008; Mahadevan et al. 2012). Mothers with reduced activity of the enzyme thiopurine methyltransferase (TPMT), involved in azathioprine metabolism, may excrete higher levels of drug. Cases of asymptomatic mild neutropenia have been documented (Coulam et al. 1982), thus it might be advisable to monitor breastfed infants. Refraining from breastfeeding for 4–6 h after a dose may reduce the dose received by the infant through breast milk (Sau 2007).

Leflunomide

Leflunomide (Arava®) is an inhibitor of pyrimidine biosynthesis with an antiproliferative activity. The drug is marketed for rheumatoid arthritis. The product label for Arava® contains a warning against treatment by this drug during pregnancy based on animal studies, which reported an elevation in congenital malformations. Leflunomide is transformed into an active metabolite which has a long elimination half-life of approximately 2 weeks. Due to concerns of leflunomide exposure in pregnancy, the label advises to treat with cholestyramine for 11 days (to increase drug elimination) with two plasma levels taken 14 days apart showing no detectable drug (Hajdyla-Banaś et al. 2009).

The organization of Teratology Information Specialists assessed the safety of leflunomide when used in early pregnancy. Of 64 leflunomide-exposed pregnancies there was no increased rate of major and or minor malformations. After adjustment for confounders, no increase in prematurity or small for gestational age babies were reported either (Chambers et al. 2010). Another study of 16 pregnant exposed women also did not find an elevated risk for malformations or other adverse events in pregnancy (Cassina et al. 2012). This is an example of an agent where, at equal serum concentrations, animal species are much more sensitive to teratogenicity than humans, due to higher affinity of the drug to the enzyme.

Methotrexate

Methotrexate (MTX) is in use for the treatment of rheumatoid arthritis, psoriasis and cancer. MTX and its congener aminopterin (AMPT) are structural analogues of folic acid, competitively impeding dihydrofolate reductase and hindering folinic acid formation.

Daily supplementation of folic acid with MTX decreases the toxicity but not the efficacy of MTX and will decrease the occurrence of neural tube defects (Morgan et al. 1990). The fetal aminopterin syndrome was illustrated in aborted fetuses (Thiersch 1952) and infants born after unsuccessful abortion (Shaw and Steinback 1968). Malformations include limb defects, intrauterine growth retardation, CNS defects and mental retardation. In older studies on rheumatoid patients treated by low-dose MTX, no malformations or apparent neurobehavioral defects were reported (Kozlowski et al. 1990; Lewden et al. 2004).

However, a recent large study showed increased risk of malformations when the mothers used the low weekly dose of MTX (Martín et al. 2014), and there is one prospective case of aminopterin embryopathy with this dose range (Martín et al. 2014).

Mycophenolate Mofetil

Mycophenolate mofetil (MMF) is a purine synthesis inhibitor in use as an immunosuppressant in rheumatoid arthritis and organ transplantation. There is a pattern of malformations associated with mycophenolate mofetil exposure during pregnancy (Hoeltzenbein et al. 2012; Coscia et al. 2010). The most common malformations include abnormal ear development, facial clefts, ocular, skeletal and heart defects (Merlob et al. 2009; Perez-Aytes et al. 2010). Increased risk for spontaneous abortions and preterm delivery have also been documented however those may be related to the maternal disorder rather than the exposure to the medication.

Anticonvulsants

Treatment of epilepsy cannot usually be discontinued during pregnancy since seizures may lead to falls, injury, and physical stress that can put the health of the woman and fetus at risk (Matlow and Koren 2012). Whereas earlier studies suggested an increased rate of malformations with untreated epilepsy, more recent studies refuted such association (Holmes et al. 2001; Pediatric Academic Societies’ annual meeting 2002; Holmes et al. 2000). The teratogenic risk increases as the number of antiepileptic drugs (AEDs) is increased (5 % with 2 drugs, 10 % with 3 and more than 20 % when 4 drugs are used) (Lindhout et al. 1984). Therefore, AEDs should be given at the lowest effective dose and as mono-therapy whenever possible. Essentially all first line AEDs are teratogenic in humans. Valproic acid and carbamazepine cause Neural Tube Defects (NTDs) which can be detected prenatally, with a recommendation of combination of a level II U/S and either maternal blood or amniotic fluid α-fetoprotein at 16–18 weeks of gestation.

Carbamazepine

Carbamazepine (CBZ) is used for various seizure disorders, as well as for bipolar manic-depressive disorder and for pain control of various etiologies. Carbamazepine has been regarded by many as the antiepileptic drug (AED) of choice in pregnancy. CBZ monotherapy is considered to have one of the lowest risks of teratogenicity among antiepileptic drugs (Matlow and Koren 2012). First trimester exposure carries a 0.2–1 % risk of NTDs (baseline risk is 0.1 %) (Rosa 1991; Matalon et al. 2002; Kaaja et al. 2003; Morrow et al. 2006). No adverse association between CBZ and neurobehavioral measures in humans has been reported (Meador et al. 2009; McVearry et al. 2009).

Carbamazepine and Breast Feeding

Carbamazepine is excreted in relatively high levels into breast milk and breastfed infants have measurable serum levels, but they are usually within the anticonvulsant therapeutic range (Kaneko et al. 1979). Most infants have no adverse effects (Meador et al. 2010; Froescher et al. 1984; Veiby et al. 2013), but poor sucking, sedation, withdrawal symptoms and a few cases of hepatic dysfunction have been documented (Kuhnz et al. 1983; Kaneko et al. 1982). If carbamazepine is essential for the mother, it is not necessary to discontinue breastfeeding. It is advised to monitor the breastfed infant for jaundice, adequate weight gain, lethargy and developmental milestones, especially in younger, exclusively breastfed infants and when the mother is treated by polytherapy of anticonvulsant or psychotropic drugs (Stowe 2007).

Phenytoin

Phenytoin is used for treatment of many types of epilepsy except for petit mal epilepsy. A pattern of malformations has been associated with prenatal phenytoin exposure, referred to as Fetal Hydantoin Syndrome which includes craniofacial abnormalities such as microcephaly, broad nasal bridge, metopic ridging, cleft lip/palate and ptosis, as well as hypoplasia and ossification of the distal phalanges (Briggs et al. 2008; Mountain et al. 1970; Artama et al. 2005; Harden et al. 2009). Congenital heart defects and impaired physical and mental growth frequently accompany the syndrome (Meador et al. 2009; Harden et al. 2009; Thomas et al. 2008; Scolnik et al. 1994). Furthermore, phenytoin may create hemorrhagic disease of the newborn (Briggs et al. 2008; Mountain et al. 1970).

Phenytoin and Breast Feeding

Due to low levels of phenytoin in breast milk (Bar-Oz et al. 2000), the concentrations infants will be exposed to are modest and are not anticipated to cause adverse events (Meador et al. 2010; Mirkin 1971; Livingston 1956). Combination therapy with sedating anticonvulsants may produce sedation or withdrawal symptoms in the infant (Kok et al. 1982; Finch and Lorber 1954). Since idiosyncratic reactions cannot be excluded for any drug, all infants should be monitored for adverse events.

Valproic Acid

Valproic acid was originally introduced for seizure control, however, over the last two decades it has gained large popularity in the treatment of psychiatric conditions such as bipolar disorder. In recent decades, extensive evidence has documented that prenatal exposure to valproic acid increase the risk for major congenital malformations, including NTD (in 1–2 %) (Gram and Bentsen 1985; Lammer et al. 1987; Lindhout and Omtzigt 1992; Wyszynski et al. 2005), limb and cardiac anomalies (Koren et al. 2006; Jentink et al. 2010), and cognitive deficiencies (Adab et al. 2004; Vinten et al. 2005; Eriksson et al. 2005; Gaily et al. 2004; Adab et al. 2001; Banach et al. 2010).

Codeine

Codeine is the pro-drug of morphine. Although the opioids have not been implicated as human teratogens, new concerns have arisen about their use during breastfeeding (see Table 4.2).

Codeine in Breastfeeding

Maternal treatment by oral opioids during breastfeeding can cause central nervous system depression and even death in the neonate, with mothers who are ultra rapid metabolizers of CYP 2D6 at higher risk (Willmann et al. 2009; Nauta et al. 2009). Newborn infants appear to be especially sensitive to the effects of even modest doses of narcotic analgesics. Once the mother’s milk starts to flow, it is best to provide non narcotic analgesic pain control and limit maternal codeine intake to 4 days at a low dose with close infant surveillance (Willmann et al. 2009; Madadi et al. 2009). If the neonate shows signs of increased drowsiness, breastfeeding difficulties, breathing difficulties, or limpness, a physician should be involved immediately (US Food and Drug Administration 2007). Maternal excessive sedation often is associated with excess sedation in the breastfed infant (Kelly et al. 2013; Sachs and The American Academy of Pediatrics committee on Drugs 2013).

Misoprostol

Misoprostol is a synthetic prostaglandin E1 (PGE1) analogue in use for the treatment of gastric and duodenal ulcers. It has the ability to induce uterine contractions and vaginal bleeding and is licensed for induction of labour, treatment of missed miscarriage and also therapeutic abortion in some countries. The use of misoprostol vaginally or orally during the first trimester of pregnancy is associated with an increased risk of pregnancy loss and of Möebius sequence (Gonzalez et al. 1993; Pastuszak et al. 1998; Vauzelle et al. 2013; da Silva Dal Pizzol et al. 2006). Limb defects were also proposed by some of the reports (Gonzalez et al. 1993).

In a case-control study (Pastuszak et al. 1998) 48.9 % (47/96) of infants with Möebius sequence had been exposed to misoprostol in the first trimester. A systemic review and meta-analysis on the data of 4,899 cases of congenital anomalies and 5,742 controls (da Silva Dal Pizzol et al. 2006) found a relationship between prenatal exposure to misoprostol and elevated risk of Möbius sequence (OR = 25.31; 95 % CI: 11.11–57.66) and terminal transverse limb defects (OR = 11.86; 95 % CI: 4.86–28.90).

While this odds ratio (OR) is extremely high, the incidence of Möebius sequence is very low in the general population (1:1,000–1:200,000) and hence the risk for developing the syndrome, after exposure to misoprostol during the first trimester is probably less than 1–2 %.

Warfarin (Coumadin)

Warfarin is an oral anticoagulant that impedes vitamin K dependent clotting factors. It is in use mainly for the prophylaxis or treatment of deep vein thrombosis, and thrombosis and embolism in patients with mechanical heart valves, atrial fibrillation and myocardial infarction.

Many case reports and case series linking warfarin with embryopathy have been published. The use of warfarin in the first trimester can result in the Fetal Warfarin Syndrome (FWS) (Hall et al. 1980; Harrod and Sherrod 1981; Wong et al. 1993). These malformations include skeletal defects, such as nasal hypoplasia and stippled epiphyses, intrauterine growth retardation, developmental delay, eye malformations and hearing loss. The critical period for malformations is between 6 and 12 weeks of gestation (Hall et al. 1980; Chan et al. 2000; Iturbe-Alessio et al. 1986). Exposure in the second and third trimesters may be associated with an increased risk of CNS damage and stillbirth due to fetal hemorrhage (Hall et al. 1980; Iturbe-Alessio et al. 1986; Ville et al. 1993; van Driel et al. 2002). There is also a reported increase in spontaneous abortions in women taking warfarin although this could be related to the underlying disease (Born et al. 1992).

Warfarin therapy after the first trimester induces a minor risk, if any, to a child’s skeletal development and neurobehavioral achievements (Van Driel et al. 2000, 2001). The effects of warfarin are probably dose dependent. The rates of minor neurological dysfunction are elevated with increasing dose (Wesseling et al. 2001). The risks of pregnancy and fetal complications are increased when warfarin doses exceed 5 mg/day (Cotrufo et al. 2002; Vitale et al. 1999).

The present guidelines state that warfarin should be avoided in pregnant women, except in those women considered especially high risk (e.g., maternal mechanical heart valve) [Guyatt et al. 2012]. High risk women should be advised to continue oral anticoagulation until they are pregnant because the risk of embryopathy is low in the first 6 weeks of pregnancy. As soon as pregnancy is achieved they should substitute to a treatment with low molecular weight heparin. If warfarin is used during pregnancy (after the first trimester), it should be discontinued after 34–36 weeks of gestation to prevent fetal intra-partum and postpartum bleeding, and substituted by an alternative anticoagulant. A dosage ≤5 mg should be maintained, if appropriate, to prevent fetal bleeding related complications (Guyatt et al. 2012).

Isotretinoin

Isotretinoin is a synthetic vitamin A derivative which is an effective treatment for severe acne. Isotretinoin (13-cis-retinoic acid; Accutane®) is a potent human teratogen at therapeutic doses. The highest risk for malformation is when exposure to the drug continues beyond day 15 after the last menstrual period. Exogenous isotretinoin is undetectable 1 week after a given dose. However, the main metabolite requires 10 days to be eliminated.

There is an estimated risk of 20–35 % for congenital malformations in infants exposed to isotretinoin prenatally (Lammer et al. 1985; Adams and Lammer 1993). The typical anomalies include cardiac (transposition of the great arteries, Tetralogy of Fallot), craniofacial (microtia/anotia, micrognathia), central nervous system (hydrocephalus) and thymic malformations (Lammer et al. 1985). Up to 30–60 % of prenatally isotretinoin- exposed children have been reported to exhibit neurocognitive impairment (Lammer et al. 1985; Adams and Lammer 1993).

The US and Canadian guidelines for preventing fetal exposure to isotretinoin include the following: awareness of the risks, ruling out pregnancy at the beginning of treatment; parallel use of two forms of contraception during treatment, monitoring for pregnancy throughout treatment and avoiding pregnancy 1–3 months after the drug has been cleared from the body (Choi et al. 2013; Pastuszak et al. 1994).

Health Canada requires that women treated by isotretinoin sign a written informed consent, receive information about the drug teratogenicity and use two contraceptive methods while on the medication. Similar measures in US were not effective in protecting fetuses (Koren et al. 2004; Andresen 2006). The SMART (System to Manage Accutane Related Teratogenicity) and iPLEDGE (an integrated isotretinoin risk management system for all isotretinoin compounds) systems, introduced by FDA were both disappointing (Koren et al. 2004; Andresen 2006).

Rubella Vaccine

While the Rubella virus is highly teratogenic, there are no reports in the literature to date, of any child that has been born with Congenital Rubella Syndrome (CRS) from the live attenuated vaccine. The Centre for Disease Control (CDC) assessed the fetal theoretical risk of CRS following rubella vaccination to be at 0.5–1.3 % and hence it is currently advised that the rubella vaccine and the combination MMR vaccine should not be administered during gestation and that women should be recommended to avoid becoming pregnant for 28 days after vaccination (Marin et al. 2010).

Alcohol

Alcohol (ethanol) consumption during gestation explains the etiology of fetal alcohol spectrum disorder (FASD), a principle cause of congenital handicap worldwide. Thereupon, any effort to avoid or manage FASD must begin from extensive understanding of women’s alcohol consumption in general, and specifically by women of reproductive years (Zelner and Koren 2013).

While women usually stop or reduce ethanol consumption once a pregnancy is confirmed, many fetuses are exposed to alcohol before pregnancy is detected, while other women simply continue drinking (Ethen et al. 2009). The Centers for Disease Control and Prevention estimated that 51.5 % of non-pregnant women in the reproductive age and 7.6 % of pregnant women used alcohol in 2006–2010 (Centers for Disease Control and Prevention 2012).

Fetal Alcohol Spectrum Disorder (FASD), is characterized by pre and post–natal growth retardation, microcephaly, developmental delay and neurobehavioral deficits, and dysmorphic facial features, including short palpebral fissures, poorly developed philtrum, and thin upper lip (Jones et al. 1973). Retarded growth in weight, length and head circumference both intrauterine and after birth is the most prevalent sign of FASD (Rossett and Weiner 1984). Full expression of the Syndrome generally arises only with chronic ingestion of at least 2 g/kg/day of alcohol. With full blown FAS, the rate of malformation is increased by 2–3 folds compared to moderate or rare drinkers (Rosett et al. 1978). Presently it is not apparent whether the rate of malformation of moderate drinkers is similar to that of non-drinkers.

Alcohol and Breast Feeding

Maternal alcohol consumption passes readily into the breast milk reaching comparable concentrations in the breast milk (Lawton 1985). Although the amount a breastfed infant is exposed to is only a portion of what the mother consumes (Mennella and Beauchamp 1991; Haastrup et al. 2014), an infant’s detoxifing alcohol rate in the first weeks of life is half of the adult’s rate (Abel 1984).

A study reported that at moderate amounts of alcohol in breast milk appears to influence the infant’s gross motor development in a dose-dependent manner (Little et al. 1989). Another study reported disrupted sleep-wake patterns amidst infants who exhaust milk containing alcohol at rates corresponding to maternal ingestion of 1.5 drinks (Mennella and Gerrish 1998). Such sleep pattern disruption may generate potential long-term effects because the brain is still developing in infancy. Another study showed elevated infant arousal after maternal and infant alcohol consumption (Schuetze et al. 2002).

As there are no recognized advantages of maternal alcohol consumption for the breastfed infant, mothers should be discouraged to expose their nursing babies to alcohol. A normogram published by the Motherisk Program illustrates the clearance time for a given alcohol consumption level to be extracted from the milk (Fig. 4.1).

Fig. 4.1

Alcohol and breastfeeding: time (h:min) until the zero level in milk is reached for women at different body weights (Ho et al. 2001)

Regulatory Guidance on Prescribing Medicines in Pregnancy

FDA Pregnancy Categories

The FDA-assigned pregnancy categories as used in the Drug Formulary are as follows:

Category A

Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).

Category B

Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Category C

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Category D

There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Category X

Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits (http://depts.washington.edu/druginfo/Formulary/Pregnancy.pdf).

However, this system has been heavily criticized as three quarters of the drugs are in Category C, and there are major ambiguity in translation these recommendation for clinical use. Over the last few years the FDA has approved moving into a new system that will be based on individual evidence-based narratives for each drug rather than on the ABC system.

The Australian Pregnancy Categorisation System

The Australian categorisation system and database for prescribing medicines in pregnancy have been developed by medical and scientific experts based on available evidence of risks associated with taking particular medicines while pregnant.

Definitions of the Australian Categories for Prescribing Medicines in Pregnancy

Category A

Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.

Category B1

Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.

Studies in animals have not shown evidence of an increased occurrence of fetal damage.

Category B2

Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.

Category B3

Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

Category C

Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.

Category D

Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

Category X

Drugs which have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy (http://www.tga.gov.au/hp/medicines-pregnancy-categorisation.htm).

Guidelines on Medicines During Lactation

The American Academy of Pediatrics committee on drugs has updated their guidelines on the transfer of medications into the breast milk. They state that the benefits of breastfeeding exceed the risk of exposure through breast milk for most medications. Most therapeutic agents do not pose a risk to the mother or breastfeeding infant however, certain medications should be handled with care, principally those that are concentrated in human milk or result in exposures in the infant that correlate to the relative infant dose. Caution is also recommended for medications with unproven benefits, drugs that may lead to drug accumulation through long half-lives or with known toxicity. Furthermore, specific infants may be more susceptible to adverse effects (e.g., preterm infants, neonates or infants with underlying medical conditions) (Sachs and Committee On Drugs 2013).

Pregnancy Registries and Other Monitoring Schemes

There are increasing numbers of registries linking prescription information with pregnancy outcome in an attempt to assess drug safety/risk in pregnancy in jurisdictions where prescription is covered by either governments or insurance companies. The main strength of such systems is their large sample sizes, however, prescription of a drug to a woman does not necessarily mean that she has chosen to take the medication in pregnancy.

The Motherisk Program

There are also a few registries collecting information directly from pregnant women, and we will describe here the Canadian Motherisk Program as an example. The Motherisk program is a counseling service offering a teratogen information phone line. Established in 1985, it provides information on the safety or risk of exposures to prescription and over-the-counter (OTC) drugs, radiation, chemicals, herbal products, chronic diseases and infections during gestation and while breastfeeding. Trained counselors answer calls from pregnant women or their partners as well as from health care professionals including physicians, nurses, midwives, pharmacists, genetic counselors, dietitians and nutritionists. Follow up of these calls after the expected date of confinement allow studying of safety/risk of medications, typically long before drug prescription registries can yield their safety signals. Detailed information about the program has been published (Moretti and Koren 2001).

Conclusions

While most women are exposed to medications in pregnancy, and quite few have been shown to be teratogenic in humans, high levels of anxiety, coupled with misinformation and misperception, lead women and their prescribers to commonly avoid drug therapy even in life threatening conditions.

It is critical for clinicians to always consider the risks of the untreated conditions in pregnancy and as needed, to empower women to use medications during gestation.

Take Home Message

· To ensure that women are counseled based on evidence based medicine and not emotionally based medicine

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