Gerald G. Briggs, BPharm, FCCP

A number of drugs are available for ophthalmic use. This review focuses on single drug products and, although combination drug products are not discussed, these formulations typically include the drugs reviewed here.

Since it appears that ophthalmic medications are commonly used for a wide range of conditions and ages, one would expect to see numerous reports of their use in the eyes of pregnant or breastfeeding patients. Unfortunately, the opposite is true. The majority of the drugs have no human pregnancy or lactation data. When there are human data, it invariably involves the systemic use of the drug for other indications, rather than its ophthalmic use. Moreover, the animal reproduction data are usually not relevant because they involve systemic drugs (e.g., IV or oral). Consequently, determining the level of risk an ophthalmic drug presents to an embryo and/or fetus is primarily based on time and dose, the two cardinal principles of teratology.

Avoiding exposure during organogenesis – the period when a drug can cause developmental toxicity (altered growth, structural anomalies, functional and/or behavioral deficits, or death) – is usually best, but may not be possible in some cases, including glaucoma, eye infections, and eye surgery. Fortunately, the systemic concentrations of drugs applied topically to the eye are typically thought to be low, even though the levels of most drugs have not been studied. Thus, the risk to the embryo and/or fetus in most cases can be considered low and the drug classified as compatible in pregnancy and breastfeeding.

If a topical eye drug must be used during pregnancy or lactation, teach the patient how to decrease the amount of drug reaching the systemic circulation. This involves placing pressure over the tear duct in the corner of the eye for 1 minute or more, then removing any excess solution with absorbent tissue.

In the sections below, drugs are shown by indication or by pharmacologic class. The term “human eye data” refers to the use of the drug in pregnancy and/or lactation.

Glaucoma

If you are caring for a pregnant patient who is being treated for glaucoma, two recent reviews may be helpful: Surv Ophthalmol. 2011 Jul-Aug;56(4):324-35 and Curr Opin Ophthalmol. 2014 Mar;25(2):93-7.

Sympathomimetics (alpha-adrenergic agonists) include apraclonidine (Iopidine), which has no human eye data, and brimonidine (Alphagan P), which has one case report in pregnancy and breastfeeding showing no fetal or nursing infant harm.

Four of the five beta-adrenergic blockers have no human eye data: betaxolol (Betoptic), carteolol (Ocupress), levobunolol (Betagan), and metipranolol, but there are two case reports for timolol (Betimol, Istalol, Timoptic, Timoptic-XE) showing no fetal harm in one newborn and growth restriction in the other.

Among the miotics, there are limited human eye data for pilocarpine (Isopto Carpine) and no fetal harm was observed. For echothiophate iodide (Phospholine Iodide), there is one case report of a normal full-term infant whose mother was treated with the agent up to 32 weeks’ gestation and then with pilocarpine for 8 weeks (Arch Ophthalmol. 1968 Mar;79[3]:283-5).

Fuse/Thinkstock.com

Carbonic anhydrase inhibitors include brinzolamide (Azopt), which has no human eye data, and dorzolamide (Trusopt), which has growth restriction in one case treated with fixed combination of dorzolamide and timolol. There are no human eye data for unoprostone isopropyl (Rescula), a synthetic docosanoid.

Of the four prostaglandin analogs, three have no human eye data, bimatoprost (Lumigan), tafluprost (Zioptan), and travoprost (Travatan Z). There were 11 pregnancies exposed to latanoprost (Xalatan). The outcomes of these cases were one lost to follow-up, one miscarriage, and nine infants without congenital anomalies (Am J Ophthalmol. 2004 Aug;138[2]:305-6).

Mitomycin (Mitosol) is an antimetabolite that is given topically to the surgical site of glaucoma filtration surgery. No reports of its use in pregnant humans have been located. According to the manufacturer, clinically significant systemic concentrations are not expected.

Antiseptics

Povidone-iodine (Betadine) is indicated for prepping of the periocular region. There does not appear to be any risk to the embryo-fetus or nursing infant from this indication.

Antihistamines

The four ophthalmic agents in this class are alcaftadine (Lastacaft), azelastine (Optivar), emedastine (Emadine), and epinastine (Elestat). There are no human eye data for these agents but, like antihistamines given systemically, they are probably compatible in pregnancy and lactation.

Antihistamine-mast cell stabilizers

There are no human eye data for bepotastine (Bepreve), ketotifen (Alaway), and olopatadine (Pataday, Patanol). Peak plasma concentrations of bepotastine were 5.1-7.3 ng/mL for 1-2 hours after instillation and were less than 2 ng/mL at 24 hours. It appears that these drugs can also be classified as compatible in pregnancy and lactation.

Anti-infectives

Ten anti-infectives are available for topical treatment of eye infections (systemic concentrations if known): besifloxacin (Besivance) (0.43 ng/mL), ciprofloxacin (less than 2.5 ng/mL), gentamicin, gatifloxacin (Zymaxid) (less than 5 ng/mL), levofloxacin (Iquix) (10.9 ng/mL), moxifloxacin (Vigamox) (2.7 ng/mL), ofloxacin (1.9 ng/mL), sulfacetamide (Isopto Cetamide), and tobramycin. The tenth agent, natamycin (Natacyn), is an antifungal. According to the manufacturer, systemic absorption is not expected.

None of these agents have human eye data, but they are usually considered compatible in pregnancy and breastfeeding when systemic formulations are used, so they should be compatible when used in the eye.

Antivirals

Ganciclovir (Zirgan) has no human eye data but, according to the manufacturer, the daily ophthalmic dose is about 0.04% and 0.1% of the oral and IV doses, respectively. Thus, minimal systemic exposure is expected. Trifluridine (Viroptic) also has no eye human data. As reported in the product information, detectable blood concentrations of the drug were not found in healthy normal subjects indicating that systemic absorption was negligible.

Corticosteroids

Among the nine corticosteroid products, six are suspensions or ointments, one is an injection, and two are implants. In most nonpregnant patients receiving the dexamethasone (Ozurdex) intravitreal implant, plasma dexamethasone concentrations were undetectable (less than 50 pg/mL) but, in some, ranged from 52 pg/mL to 102 pg/mL. There is only one case report describing the use of topical dexamethasone suspension (Maxidex) in pregnancy. In that case, dexamethasone and clindamycin were given in the first and second trimesters and the woman eventually gave birth to a normal full term infant (Int Ophthalmol. 1998-1999;22[2]:85-8).

For the fluocinolone (Retisert) ocular implant, systemic absorption of detectable amounts of the drug have not been observed. In a second report, a patient who had type 1 diabetes and was 6 months pregnant received a 2-mg intravitreal injection of triamcinolone (Triesence) in both eyes. No adverse effects in the mother or fetus were noted (Clin Ophthalmol. 2011;5:439-41).

There are no human eye data for five topical corticosteroids: difluprednate (Durezol), fluorometholone (Flarex, Fluor-OP, FML), loteprednol (Alrex, Lotemax), prednisolone (Econopred), and rimexolone (Vexol). Only two of the five drugs had information about systemic absorption. For difluprednate, blood levels were below the quantification limit (50 ng/mL). Extremely low levels were detected after the use of rimexolone with a mean serum concentration of 130 pg/mL (range less than 80-470 pg/mL).

Cycloplegics-mydriatics

This class includes four anticholinergic agents: atropine, cyclopentolate (Cyclogyl), homatropine, and tropicamide (Mydriacyl). Systemic absorption has not been studied for these drugs and there are no reports of their use in pregnancy or lactation.

Cystine-depleting agents

There are no reports describing the use of cysteamine (Cystaran) in human pregnancy or lactation. Since the drug is given as one drop in each eye every waking hour, transfer to the systemic circulation should be expected, but the amount, if it occurs, has not been reported.

Immunologics

There are no reports on the use of cyclosporine (Restasis) eye drops in human pregnancy or during breastfeeding. However, data for the systemic use of the drug during these conditions has shown it to be low risk. After long term ophthalmic use, blood concentrations of the drug were below the quantitation limit of 0.1 ng/mL.

Local anesthetics

The three drugs in this class are lidocaine, proparacaine (Alcaine), and tetracaine (Altacaine, Tetravisc). There is no information regarding the use of these agents in pregnancy or lactation. Since they are used for brief periods, the risk to an embryo or nursing infant appears to be nil.

Mast cell stabilizers

There are three drugs in this class that can be used topically in the eye: cromolyn, lodoxamide (Alomide), and nedocromil (Alocril). There are no human eye data for these agents. Systemic concentrations of lodoxamide were below the detection limit of 2.5 ng/mL.

Miotics

The two miotics are acetylcholine (Miochol E) and carbachol (Carbastat, Miostat). Both are used immediately before eye surgery. The amount, if any, in the systemic circulation is unknown. No reports of human eye use in pregnancy or lactation have been found.

NSAIDs

The five drugs in this class are bromfenac (Xibrom), diclofenac (Voltaren), flurbiprofen (Ocufen), ketorolac, and nepafenac (Nevanac). Although it has not been studied, the estimated plasma level for bromfenac is less than 50 ng/mL. For diclofenac, the plasma concentration was below the limit of quantification (10 ng/mL). In a study conducted with ketorolac, only 5 of 26 subjects had detectable plasma concentrations (10.7 to 22.5 ng/mL). These levels were about 2% of the peak plasma levels after oral dosing. For nepafenac, the peak plasma concentrations of the parent drug and active metabolite were 0.3 and 0.4 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant are nil.

Photodynamic therapy

Verteporfin (Visudyne) is given intravenously. Three reports have described its use in three pregnancies. In all cases, the infants were healthy at birth and had normal growth (Acta Ophthalmol Scand. 2004 Oct;82[5]:623-4, Eye [Lond]. 2009 Jun;23[6]:1479, and Aust N Z J Obstet Gynaecol. 2009 Apr;49[2]:236-7).

Proteolytic enzymes

No human eye data were found for ocriplasmin (Jetrea), an agent given as an intravitreal injection. Although it was not studied, detectable levels of the drug in the systemic circulation are not expected, according to the manufacturer.

Selective vascular endothelial growth factor antagonists

There are three agents in this class: aflibercept (Eylea), pegaptanib (Macugen), and ranibizumab (Lucentis). There are no human eye data for these drugs. All are given as intravitreal injection. The systemic concentrations of the three drugs were a mean 0.02 mcg/mL; 80 ng/mL (after a dose of 10 times the recommended dose); and an estimated minimum 0.22 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant is nil.

Sympathomimetics (decongestants)

There are four ophthalmic agents in this class and none have human eye data. Naphazoline (Naphcon, Vasocon) is the only one of the four that requires a prescription. No reports describing the systemic absorption, if any, have been found. The other three agents are available over the counter. They are oxymetazoline (Visine L.R.), phenylephrine, and tetrahydrozoline (Opti-Clear). Although the amount reaching the systemic circulation was not provided by the manufacturers for these three agents, a caution was placed on phenylephrine stating that systemic absorption, although rare, might cause alpha-adrenergic effects, such as a rise in blood pressure and reflex atropine-sensitive bradycardia.

The risk to the embryo-fetus or nursing infant from ophthalmic drugs appears to be low, with the possible exception of phenylephrine. Nevertheless, if any of these agents are used in pregnancy or during breastfeeding, careful assessment of the embryo-fetus and nursing infant should be conducted. Moreover, research on the potential effects of ophthalmic drugs on the embryo-fetus and nursing infant are desperately needed.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

A number of drugs are available for ophthalmic use. This review focuses on single drug products and, although combination drug products are not discussed, these formulations typically include the drugs reviewed here.

Since it appears that ophthalmic medications are commonly used for a wide range of conditions and ages, one would expect to see numerous reports of their use in the eyes of pregnant or breastfeeding patients. Unfortunately, the opposite is true. The majority of the drugs have no human pregnancy or lactation data. When there are human data, it invariably involves the systemic use of the drug for other indications, rather than its ophthalmic use. Moreover, the animal reproduction data are usually not relevant because they involve systemic drugs (e.g., IV or oral). Consequently, determining the level of risk an ophthalmic drug presents to an embryo and/or fetus is primarily based on time and dose, the two cardinal principles of teratology.

Avoiding exposure during organogenesis – the period when a drug can cause developmental toxicity (altered growth, structural anomalies, functional and/or behavioral deficits, or death) – is usually best, but may not be possible in some cases, including glaucoma, eye infections, and eye surgery. Fortunately, the systemic concentrations of drugs applied topically to the eye are typically thought to be low, even though the levels of most drugs have not been studied. Thus, the risk to the embryo and/or fetus in most cases can be considered low and the drug classified as compatible in pregnancy and breastfeeding.

If a topical eye drug must be used during pregnancy or lactation, teach the patient how to decrease the amount of drug reaching the systemic circulation. This involves placing pressure over the tear duct in the corner of the eye for 1 minute or more, then removing any excess solution with absorbent tissue.

In the sections below, drugs are shown by indication or by pharmacologic class. The term “human eye data” refers to the use of the drug in pregnancy and/or lactation.

Glaucoma

If you are caring for a pregnant patient who is being treated for glaucoma, two recent reviews may be helpful: Surv Ophthalmol. 2011 Jul-Aug;56(4):324-35 and Curr Opin Ophthalmol. 2014 Mar;25(2):93-7.

Sympathomimetics (alpha-adrenergic agonists) include apraclonidine (Iopidine), which has no human eye data, and brimonidine (Alphagan P), which has one case report in pregnancy and breastfeeding showing no fetal or nursing infant harm.

Four of the five beta-adrenergic blockers have no human eye data: betaxolol (Betoptic), carteolol (Ocupress), levobunolol (Betagan), and metipranolol, but there are two case reports for timolol (Betimol, Istalol, Timoptic, Timoptic-XE) showing no fetal harm in one newborn and growth restriction in the other.

Among the miotics, there are limited human eye data for pilocarpine (Isopto Carpine) and no fetal harm was observed. For echothiophate iodide (Phospholine Iodide), there is one case report of a normal full-term infant whose mother was treated with the agent up to 32 weeks’ gestation and then with pilocarpine for 8 weeks (Arch Ophthalmol. 1968 Mar;79[3]:283-5).

Fuse/Thinkstock.com

Carbonic anhydrase inhibitors include brinzolamide (Azopt), which has no human eye data, and dorzolamide (Trusopt), which has growth restriction in one case treated with fixed combination of dorzolamide and timolol. There are no human eye data for unoprostone isopropyl (Rescula), a synthetic docosanoid.

Of the four prostaglandin analogs, three have no human eye data, bimatoprost (Lumigan), tafluprost (Zioptan), and travoprost (Travatan Z). There were 11 pregnancies exposed to latanoprost (Xalatan). The outcomes of these cases were one lost to follow-up, one miscarriage, and nine infants without congenital anomalies (Am J Ophthalmol. 2004 Aug;138[2]:305-6).

Mitomycin (Mitosol) is an antimetabolite that is given topically to the surgical site of glaucoma filtration surgery. No reports of its use in pregnant humans have been located. According to the manufacturer, clinically significant systemic concentrations are not expected.

Antiseptics

Povidone-iodine (Betadine) is indicated for prepping of the periocular region. There does not appear to be any risk to the embryo-fetus or nursing infant from this indication.

Antihistamines

The four ophthalmic agents in this class are alcaftadine (Lastacaft), azelastine (Optivar), emedastine (Emadine), and epinastine (Elestat). There are no human eye data for these agents but, like antihistamines given systemically, they are probably compatible in pregnancy and lactation.

Antihistamine-mast cell stabilizers

There are no human eye data for bepotastine (Bepreve), ketotifen (Alaway), and olopatadine (Pataday, Patanol). Peak plasma concentrations of bepotastine were 5.1-7.3 ng/mL for 1-2 hours after instillation and were less than 2 ng/mL at 24 hours. It appears that these drugs can also be classified as compatible in pregnancy and lactation.

Anti-infectives

Ten anti-infectives are available for topical treatment of eye infections (systemic concentrations if known): besifloxacin (Besivance) (0.43 ng/mL), ciprofloxacin (less than 2.5 ng/mL), gentamicin, gatifloxacin (Zymaxid) (less than 5 ng/mL), levofloxacin (Iquix) (10.9 ng/mL), moxifloxacin (Vigamox) (2.7 ng/mL), ofloxacin (1.9 ng/mL), sulfacetamide (Isopto Cetamide), and tobramycin. The tenth agent, natamycin (Natacyn), is an antifungal. According to the manufacturer, systemic absorption is not expected.

None of these agents have human eye data, but they are usually considered compatible in pregnancy and breastfeeding when systemic formulations are used, so they should be compatible when used in the eye.

Antivirals

Ganciclovir (Zirgan) has no human eye data but, according to the manufacturer, the daily ophthalmic dose is about 0.04% and 0.1% of the oral and IV doses, respectively. Thus, minimal systemic exposure is expected. Trifluridine (Viroptic) also has no eye human data. As reported in the product information, detectable blood concentrations of the drug were not found in healthy normal subjects indicating that systemic absorption was negligible.

Corticosteroids

Among the nine corticosteroid products, six are suspensions or ointments, one is an injection, and two are implants. In most nonpregnant patients receiving the dexamethasone (Ozurdex) intravitreal implant, plasma dexamethasone concentrations were undetectable (less than 50 pg/mL) but, in some, ranged from 52 pg/mL to 102 pg/mL. There is only one case report describing the use of topical dexamethasone suspension (Maxidex) in pregnancy. In that case, dexamethasone and clindamycin were given in the first and second trimesters and the woman eventually gave birth to a normal full term infant (Int Ophthalmol. 1998-1999;22[2]:85-8).

For the fluocinolone (Retisert) ocular implant, systemic absorption of detectable amounts of the drug have not been observed. In a second report, a patient who had type 1 diabetes and was 6 months pregnant received a 2-mg intravitreal injection of triamcinolone (Triesence) in both eyes. No adverse effects in the mother or fetus were noted (Clin Ophthalmol. 2011;5:439-41).

There are no human eye data for five topical corticosteroids: difluprednate (Durezol), fluorometholone (Flarex, Fluor-OP, FML), loteprednol (Alrex, Lotemax), prednisolone (Econopred), and rimexolone (Vexol). Only two of the five drugs had information about systemic absorption. For difluprednate, blood levels were below the quantification limit (50 ng/mL). Extremely low levels were detected after the use of rimexolone with a mean serum concentration of 130 pg/mL (range less than 80-470 pg/mL).

Cycloplegics-mydriatics

This class includes four anticholinergic agents: atropine, cyclopentolate (Cyclogyl), homatropine, and tropicamide (Mydriacyl). Systemic absorption has not been studied for these drugs and there are no reports of their use in pregnancy or lactation.

Cystine-depleting agents

There are no reports describing the use of cysteamine (Cystaran) in human pregnancy or lactation. Since the drug is given as one drop in each eye every waking hour, transfer to the systemic circulation should be expected, but the amount, if it occurs, has not been reported.

Immunologics

There are no reports on the use of cyclosporine (Restasis) eye drops in human pregnancy or during breastfeeding. However, data for the systemic use of the drug during these conditions has shown it to be low risk. After long term ophthalmic use, blood concentrations of the drug were below the quantitation limit of 0.1 ng/mL.

Local anesthetics

The three drugs in this class are lidocaine, proparacaine (Alcaine), and tetracaine (Altacaine, Tetravisc). There is no information regarding the use of these agents in pregnancy or lactation. Since they are used for brief periods, the risk to an embryo or nursing infant appears to be nil.

Mast cell stabilizers

There are three drugs in this class that can be used topically in the eye: cromolyn, lodoxamide (Alomide), and nedocromil (Alocril). There are no human eye data for these agents. Systemic concentrations of lodoxamide were below the detection limit of 2.5 ng/mL.

Miotics

The two miotics are acetylcholine (Miochol E) and carbachol (Carbastat, Miostat). Both are used immediately before eye surgery. The amount, if any, in the systemic circulation is unknown. No reports of human eye use in pregnancy or lactation have been found.

NSAIDs

The five drugs in this class are bromfenac (Xibrom), diclofenac (Voltaren), flurbiprofen (Ocufen), ketorolac, and nepafenac (Nevanac). Although it has not been studied, the estimated plasma level for bromfenac is less than 50 ng/mL. For diclofenac, the plasma concentration was below the limit of quantification (10 ng/mL). In a study conducted with ketorolac, only 5 of 26 subjects had detectable plasma concentrations (10.7 to 22.5 ng/mL). These levels were about 2% of the peak plasma levels after oral dosing. For nepafenac, the peak plasma concentrations of the parent drug and active metabolite were 0.3 and 0.4 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant are nil.

Photodynamic therapy

Verteporfin (Visudyne) is given intravenously. Three reports have described its use in three pregnancies. In all cases, the infants were healthy at birth and had normal growth (Acta Ophthalmol Scand. 2004 Oct;82[5]:623-4, Eye [Lond]. 2009 Jun;23[6]:1479, and Aust N Z J Obstet Gynaecol. 2009 Apr;49[2]:236-7).

Proteolytic enzymes

No human eye data were found for ocriplasmin (Jetrea), an agent given as an intravitreal injection. Although it was not studied, detectable levels of the drug in the systemic circulation are not expected, according to the manufacturer.

Selective vascular endothelial growth factor antagonists

There are three agents in this class: aflibercept (Eylea), pegaptanib (Macugen), and ranibizumab (Lucentis). There are no human eye data for these drugs. All are given as intravitreal injection. The systemic concentrations of the three drugs were a mean 0.02 mcg/mL; 80 ng/mL (after a dose of 10 times the recommended dose); and an estimated minimum 0.22 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant is nil.

Sympathomimetics (decongestants)

There are four ophthalmic agents in this class and none have human eye data. Naphazoline (Naphcon, Vasocon) is the only one of the four that requires a prescription. No reports describing the systemic absorption, if any, have been found. The other three agents are available over the counter. They are oxymetazoline (Visine L.R.), phenylephrine, and tetrahydrozoline (Opti-Clear). Although the amount reaching the systemic circulation was not provided by the manufacturers for these three agents, a caution was placed on phenylephrine stating that systemic absorption, although rare, might cause alpha-adrenergic effects, such as a rise in blood pressure and reflex atropine-sensitive bradycardia.

The risk to the embryo-fetus or nursing infant from ophthalmic drugs appears to be low, with the possible exception of phenylephrine. Nevertheless, if any of these agents are used in pregnancy or during breastfeeding, careful assessment of the embryo-fetus and nursing infant should be conducted. Moreover, research on the potential effects of ophthalmic drugs on the embryo-fetus and nursing infant are desperately needed.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

A number of drugs are available for ophthalmic use. This review focuses on single drug products and, although combination drug products are not discussed, these formulations typically include the drugs reviewed here.

Since it appears that ophthalmic medications are commonly used for a wide range of conditions and ages, one would expect to see numerous reports of their use in the eyes of pregnant or breastfeeding patients. Unfortunately, the opposite is true. The majority of the drugs have no human pregnancy or lactation data. When there are human data, it invariably involves the systemic use of the drug for other indications, rather than its ophthalmic use. Moreover, the animal reproduction data are usually not relevant because they involve systemic drugs (e.g., IV or oral). Consequently, determining the level of risk an ophthalmic drug presents to an embryo and/or fetus is primarily based on time and dose, the two cardinal principles of teratology.

Avoiding exposure during organogenesis – the period when a drug can cause developmental toxicity (altered growth, structural anomalies, functional and/or behavioral deficits, or death) – is usually best, but may not be possible in some cases, including glaucoma, eye infections, and eye surgery. Fortunately, the systemic concentrations of drugs applied topically to the eye are typically thought to be low, even though the levels of most drugs have not been studied. Thus, the risk to the embryo and/or fetus in most cases can be considered low and the drug classified as compatible in pregnancy and breastfeeding.

If a topical eye drug must be used during pregnancy or lactation, teach the patient how to decrease the amount of drug reaching the systemic circulation. This involves placing pressure over the tear duct in the corner of the eye for 1 minute or more, then removing any excess solution with absorbent tissue.

In the sections below, drugs are shown by indication or by pharmacologic class. The term “human eye data” refers to the use of the drug in pregnancy and/or lactation.

Glaucoma

If you are caring for a pregnant patient who is being treated for glaucoma, two recent reviews may be helpful: Surv Ophthalmol. 2011 Jul-Aug;56(4):324-35 and Curr Opin Ophthalmol. 2014 Mar;25(2):93-7.

Sympathomimetics (alpha-adrenergic agonists) include apraclonidine (Iopidine), which has no human eye data, and brimonidine (Alphagan P), which has one case report in pregnancy and breastfeeding showing no fetal or nursing infant harm.

Four of the five beta-adrenergic blockers have no human eye data: betaxolol (Betoptic), carteolol (Ocupress), levobunolol (Betagan), and metipranolol, but there are two case reports for timolol (Betimol, Istalol, Timoptic, Timoptic-XE) showing no fetal harm in one newborn and growth restriction in the other.

Among the miotics, there are limited human eye data for pilocarpine (Isopto Carpine) and no fetal harm was observed. For echothiophate iodide (Phospholine Iodide), there is one case report of a normal full-term infant whose mother was treated with the agent up to 32 weeks’ gestation and then with pilocarpine for 8 weeks (Arch Ophthalmol. 1968 Mar;79[3]:283-5).

Fuse/Thinkstock.com

Carbonic anhydrase inhibitors include brinzolamide (Azopt), which has no human eye data, and dorzolamide (Trusopt), which has growth restriction in one case treated with fixed combination of dorzolamide and timolol. There are no human eye data for unoprostone isopropyl (Rescula), a synthetic docosanoid.

Of the four prostaglandin analogs, three have no human eye data, bimatoprost (Lumigan), tafluprost (Zioptan), and travoprost (Travatan Z). There were 11 pregnancies exposed to latanoprost (Xalatan). The outcomes of these cases were one lost to follow-up, one miscarriage, and nine infants without congenital anomalies (Am J Ophthalmol. 2004 Aug;138[2]:305-6).

Mitomycin (Mitosol) is an antimetabolite that is given topically to the surgical site of glaucoma filtration surgery. No reports of its use in pregnant humans have been located. According to the manufacturer, clinically significant systemic concentrations are not expected.

Antiseptics

Povidone-iodine (Betadine) is indicated for prepping of the periocular region. There does not appear to be any risk to the embryo-fetus or nursing infant from this indication.

Antihistamines

The four ophthalmic agents in this class are alcaftadine (Lastacaft), azelastine (Optivar), emedastine (Emadine), and epinastine (Elestat). There are no human eye data for these agents but, like antihistamines given systemically, they are probably compatible in pregnancy and lactation.

Antihistamine-mast cell stabilizers

There are no human eye data for bepotastine (Bepreve), ketotifen (Alaway), and olopatadine (Pataday, Patanol). Peak plasma concentrations of bepotastine were 5.1-7.3 ng/mL for 1-2 hours after instillation and were less than 2 ng/mL at 24 hours. It appears that these drugs can also be classified as compatible in pregnancy and lactation.

Anti-infectives

Ten anti-infectives are available for topical treatment of eye infections (systemic concentrations if known): besifloxacin (Besivance) (0.43 ng/mL), ciprofloxacin (less than 2.5 ng/mL), gentamicin, gatifloxacin (Zymaxid) (less than 5 ng/mL), levofloxacin (Iquix) (10.9 ng/mL), moxifloxacin (Vigamox) (2.7 ng/mL), ofloxacin (1.9 ng/mL), sulfacetamide (Isopto Cetamide), and tobramycin. The tenth agent, natamycin (Natacyn), is an antifungal. According to the manufacturer, systemic absorption is not expected.

None of these agents have human eye data, but they are usually considered compatible in pregnancy and breastfeeding when systemic formulations are used, so they should be compatible when used in the eye.

Antivirals

Ganciclovir (Zirgan) has no human eye data but, according to the manufacturer, the daily ophthalmic dose is about 0.04% and 0.1% of the oral and IV doses, respectively. Thus, minimal systemic exposure is expected. Trifluridine (Viroptic) also has no eye human data. As reported in the product information, detectable blood concentrations of the drug were not found in healthy normal subjects indicating that systemic absorption was negligible.

Corticosteroids

Among the nine corticosteroid products, six are suspensions or ointments, one is an injection, and two are implants. In most nonpregnant patients receiving the dexamethasone (Ozurdex) intravitreal implant, plasma dexamethasone concentrations were undetectable (less than 50 pg/mL) but, in some, ranged from 52 pg/mL to 102 pg/mL. There is only one case report describing the use of topical dexamethasone suspension (Maxidex) in pregnancy. In that case, dexamethasone and clindamycin were given in the first and second trimesters and the woman eventually gave birth to a normal full term infant (Int Ophthalmol. 1998-1999;22[2]:85-8).

For the fluocinolone (Retisert) ocular implant, systemic absorption of detectable amounts of the drug have not been observed. In a second report, a patient who had type 1 diabetes and was 6 months pregnant received a 2-mg intravitreal injection of triamcinolone (Triesence) in both eyes. No adverse effects in the mother or fetus were noted (Clin Ophthalmol. 2011;5:439-41).

There are no human eye data for five topical corticosteroids: difluprednate (Durezol), fluorometholone (Flarex, Fluor-OP, FML), loteprednol (Alrex, Lotemax), prednisolone (Econopred), and rimexolone (Vexol). Only two of the five drugs had information about systemic absorption. For difluprednate, blood levels were below the quantification limit (50 ng/mL). Extremely low levels were detected after the use of rimexolone with a mean serum concentration of 130 pg/mL (range less than 80-470 pg/mL).

Cycloplegics-mydriatics

This class includes four anticholinergic agents: atropine, cyclopentolate (Cyclogyl), homatropine, and tropicamide (Mydriacyl). Systemic absorption has not been studied for these drugs and there are no reports of their use in pregnancy or lactation.

Cystine-depleting agents

There are no reports describing the use of cysteamine (Cystaran) in human pregnancy or lactation. Since the drug is given as one drop in each eye every waking hour, transfer to the systemic circulation should be expected, but the amount, if it occurs, has not been reported.

Immunologics

There are no reports on the use of cyclosporine (Restasis) eye drops in human pregnancy or during breastfeeding. However, data for the systemic use of the drug during these conditions has shown it to be low risk. After long term ophthalmic use, blood concentrations of the drug were below the quantitation limit of 0.1 ng/mL.

Local anesthetics

The three drugs in this class are lidocaine, proparacaine (Alcaine), and tetracaine (Altacaine, Tetravisc). There is no information regarding the use of these agents in pregnancy or lactation. Since they are used for brief periods, the risk to an embryo or nursing infant appears to be nil.

Mast cell stabilizers

There are three drugs in this class that can be used topically in the eye: cromolyn, lodoxamide (Alomide), and nedocromil (Alocril). There are no human eye data for these agents. Systemic concentrations of lodoxamide were below the detection limit of 2.5 ng/mL.

Miotics

The two miotics are acetylcholine (Miochol E) and carbachol (Carbastat, Miostat). Both are used immediately before eye surgery. The amount, if any, in the systemic circulation is unknown. No reports of human eye use in pregnancy or lactation have been found.

NSAIDs

The five drugs in this class are bromfenac (Xibrom), diclofenac (Voltaren), flurbiprofen (Ocufen), ketorolac, and nepafenac (Nevanac). Although it has not been studied, the estimated plasma level for bromfenac is less than 50 ng/mL. For diclofenac, the plasma concentration was below the limit of quantification (10 ng/mL). In a study conducted with ketorolac, only 5 of 26 subjects had detectable plasma concentrations (10.7 to 22.5 ng/mL). These levels were about 2% of the peak plasma levels after oral dosing. For nepafenac, the peak plasma concentrations of the parent drug and active metabolite were 0.3 and 0.4 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant are nil.

Photodynamic therapy

Verteporfin (Visudyne) is given intravenously. Three reports have described its use in three pregnancies. In all cases, the infants were healthy at birth and had normal growth (Acta Ophthalmol Scand. 2004 Oct;82[5]:623-4, Eye [Lond]. 2009 Jun;23[6]:1479, and Aust N Z J Obstet Gynaecol. 2009 Apr;49[2]:236-7).

Proteolytic enzymes

No human eye data were found for ocriplasmin (Jetrea), an agent given as an intravitreal injection. Although it was not studied, detectable levels of the drug in the systemic circulation are not expected, according to the manufacturer.

Selective vascular endothelial growth factor antagonists

There are three agents in this class: aflibercept (Eylea), pegaptanib (Macugen), and ranibizumab (Lucentis). There are no human eye data for these drugs. All are given as intravitreal injection. The systemic concentrations of the three drugs were a mean 0.02 mcg/mL; 80 ng/mL (after a dose of 10 times the recommended dose); and an estimated minimum 0.22 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant is nil.

Sympathomimetics (decongestants)

There are four ophthalmic agents in this class and none have human eye data. Naphazoline (Naphcon, Vasocon) is the only one of the four that requires a prescription. No reports describing the systemic absorption, if any, have been found. The other three agents are available over the counter. They are oxymetazoline (Visine L.R.), phenylephrine, and tetrahydrozoline (Opti-Clear). Although the amount reaching the systemic circulation was not provided by the manufacturers for these three agents, a caution was placed on phenylephrine stating that systemic absorption, although rare, might cause alpha-adrenergic effects, such as a rise in blood pressure and reflex atropine-sensitive bradycardia.

The risk to the embryo-fetus or nursing infant from ophthalmic drugs appears to be low, with the possible exception of phenylephrine. Nevertheless, if any of these agents are used in pregnancy or during breastfeeding, careful assessment of the embryo-fetus and nursing infant should be conducted. Moreover, research on the potential effects of ophthalmic drugs on the embryo-fetus and nursing infant are desperately needed.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

Pregnancy registries are valuable sources of information. For many drugs, they are the primary source of human pregnancy experience. The new Food and Drug Administration prescription drug information format may increase the amount of information available, at least from registries conducted by drug manufacturers, because they will be required to list all substantive changes made within the year. Although most of the registries use the word “pregnancy,” it is important to note that many also enroll women who took the target drug shortly before conception.

©PhotoDisk

The strengths of pregnancy registries are their prospective nature and enrollment across a wide geographical area. Typically, two types of pregnancy outcomes are obtained: those with birth defects and those without known birth defects (classified as live births, fetal deaths, and spontaneous abortions).

Registries can identify early signals of teratogenicity, but they have several limitations, including voluntary reporting that results in selection bias, pregnancies lost to follow-up that may have had different outcomes than those with documented outcomes, and a lack of control groups (with some exceptions).

Other limitations are that registry cases are not representative of target populations, and pregnancies lost to follow-up lack details on elective terminations and fetal deaths without birth defects, as well as all spontaneous abortions. Additionally, publication of results may be delayed and does not appear in a peer-reviewed journal.

Since the total number of exposed pregnancies is unknown, registry data cannot be used to calculate prevalence, but can be used to estimate the proportion of birth defects. Some registries also collect data on retrospective reports, which are less representative of the target population because they can be biased toward the reporting of more unusual and severe outcomes. However, they may be helpful in detecting unusual patterns of birth defects.

MothertoBaby Registry

The large Organization of Teratology Information Specialists (OTIS) MothertoBaby registry (877-311-8972) involves four different categories: autoimmune diseases(rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis, Crohn’s disease, and multiple sclerosis); asthma; antiviral agents; and vaccines.

The drugs for autoimmune diseases are tocilizumab (Actemra), leflunomide (Arava), teriflunomide (Aubagio), certolizumab pegol (Cimzia), etanercept (Enbrel), adalimumab (Humira), abatacept (Orencia), apremilast (Otezla), ustekinumab (Stelara), tofacitinib (Xeljanz), infliximab (Remicade), and methotrexate.

The asthma drugs are formoterol (Foradil, Perforomist, Symbicort, Dulera), albuterol, levalbuterol, metaproterenol, pirbuterol (Maxair), and terbutaline.

The antiviral agents are oseltamivir (Tamiflu) and zanamivir (Relenza).

The vaccines include pertussis (Tdap), seasonal influenza, and meningococcal disease (Menveo). In addition to a control group in each category, a unique aspect of this registry is that many exposed infants will undergo dysmorphology examinations.

Vaccine registries

A second vaccine for meningococcal disease (Menactra) is being studied in the Menactra vaccine Pregnancy Registry (800-822-2463 / www.sanofipasteurpregnancy.com).

Two other registries also include influenza vaccines: Flu vaccine Pregnancy Registry, PPD (Flucelvax) (877-413-4759 / email: NovartisPregnancyregistries@ppdi.com) and the GSK Seasonal Influenza Vaccine Pregnancy Registry, GlaxoSmithKline (888-825-5249 / pregnancyregistry.gsk.com/seasonalinfluenzavaccines.html), which includes the Fluarix and FluLaval vaccines.

Asthma

Women with asthma who are being treated with omalizumab (Xolair) are the target population for the EXPECT Pregnancy Registry (866-496-5247 Option 3 / www.xolairpregnancyregistry.com).

GSK registries

GlaxoSmithKline is also conducting three other registries: the Belimumab (Benlysta) Pregnancy Registry for patients with systemic lupus erythematosus treated with belimumab (877-681-6296 / belimumab.pregnancy@ppdi.com); and the Twinrix Pregnancy Registry for women who have received the Twinrix hepatitis A and B vaccine (888-825-5249).

Atypical antipsychotics

TheNational Pregnancy Registry for Atypical Antipsychotics (866-961-2388 / registry@womens mentalhealth.org) is studying 10 drugs: aripiprazole (Abilify), clozapine (Clozaril), iloperidone (Fanapt), paliperidone (Invega), lurasidone (Latuda), risperidone (Risperdal), asenapine (Saphris), quetiapine (Seroquel), ziprasidone (Geodon), and olanzapine (Zyprexa).

TAPP registry

Acitretin is under study by the Take Action to Prevent Pregnancy (T.A.P.P.) registry (855-850-2138 / www.tevagenerics.com/acitretin).

MPS I registry

The MPS I (Mucopolysaccharidosis I) Registry, Genzyme Corp (617-591-5500 / help@mpsiregistry.com), is studying the use of laronidase (Aldurazyme) for Hurler syndrome, Scheie syndrome, and Hurler-Scheie syndrome.

MPS VI registry

The use of galsulfase (Naglazyme) for Maroteaux-Lamy syndrome during pregnancy is under study by the Mucopolysaccharidosis VI (MPS VI) Clinical Surveillance Program(415-506-6849 or 415-506-6703)

Epilepsy drugs

The Antiepileptic Drug Pregnancy Registry (888-233-2334 / www.aedpregnancyregistry.org) is studying antiepileptic drugs.

Type 2 diabetes

The Exenatide Pregnancy Registry, conducted by INC Research for AstraZeneca (800-633-9081 / www.exenatidepregnancyregistry.com), examines the use of exenatide (Byetta, Bydureon) for the treatment of type 2 diabetes.

Renal transplant

Renal transplant patients exposed to mycophenolate (Cellcept) can be enrolled in the Mycophenolate Pregnancy Registry (800-617-8191) or the National Transplantation Pregnancy Registry (877-955-6877). The NTPR is enrolling renal transplant patients exposed to belatacept (Nulojix).

Cymbalta

The antidepressant duloxetine (Cymbalta), when used for major depressive or generalized anxiety disorders, diabetic peripheral neuropathic pain, or fibromyalgia is being studied by the Cymbalta Pregnancy Registry, INC Research (pregnancyregistries@incresearch.com / www.cymbaltapregancyregistry.com).

Fabry disease

The Fabry Registry, Genzyme Corp (617-581-5500 / help@FabryRegistry.com) is studying the use in pregnancy of agalsidase beta (Fabrazyme) for Fabry disease.

MS registry

Novartis Pharmaceuticals is conducting the Gilenya (fingolimod) Pregnancy Registry (877-598-7237 / gpr@outcome.com) for patients with multiple sclerosis who are taking fingolimod (Gilenya).

Cancer

The MotHER Pregnancy Registry, INC Research (800-690-6720 / pregnancyregistries@incresearch.com / themotherpregnancyregistry.com) is enrolling breast cancer patients who have been treated during pregnancy with ado-trastuzumab (Kadcyla), trastuzumab (Herceptin), or pertuzumab (Perjeta).

Merck registries

Merck Pregnancy Registries (800-986-8999) include a registry for type 2 diabetes – sitagliptin/metformin (Janumet) or sitagliptin (Januvia) (www.merckpregancyregistries.com/januvia.html); a registry for rizatriptan (Maxalt) (www.merckpregancyregistries.com/maxalt.html), for migraine headaches; and a registry for the 9-valent human papillomavirus (HPV) (Gardasil 9) vaccine (www.merckpregnancyregistries.com/gardasil9.html).

The registry for the asthma drug montelukast (Singulair) and the registry for Gardasil, the quadrivalent HPV vaccine, are now closed to new enrollment, but new cases of pregnancy exposures can be reported to the company at: 877-888-4231.

Osteoporosis

Amgen’s Pregnancy Surveillance Program (800-772-6436) is enrolling pregnant subjects with osteoporosis who are being treated with denosumab (Prolia).

Hepatitis C

The Ribavirin Pregnancy Registry, INC Research (800-593-2214/ pregnancyregisteries@incresearch.com / ribavirinpregnancyregistry.com) is looking for subjects with hepatitis C who have been treated with ribavirin (Copegus).

Fibromyalgia

The Savella Pregnancy Registry (877-643-3010/ pregnancyresgistries@incresearch.com / savellapregnancyregistry.com) is looking for patients with fibromyalgia who are being treated with milnacipran (Savella).

Skin infections

An antibacterial, telavancin (Vibativ), indicated for skin infections is being studied by the Vibativ Pregnancy Registry (888-658-4228 / www.clinicaltrial.gov).

Pompe disease

Pregnant women treated with alglucosidase alfa (Myozyme) for Pompe disease can enroll in the Pompe Registry (800-745-4447 x 15500 / www.pompe.com/en/healthcare-professionals/pompe-registry.aspx).

Sleep disorders

Armodafinil (Nuvigil) used to treat excessive sleepiness associated with narcolepsy and other sleep disorders is being studied in the Nuvigil Pregnancy Registry (866-404-4106 / www.nuvigilpregnancyregistry.com). A second drug with the same indication and telephone number, modafinil (Provigil), is in the Provigil Pregnancy Registry (provigilpregnancyregistry.com).

Additional details, including fax numbers and addresses of the registries reviewed above, can be obtained from the FDA website, List of Pregnancy Exposure Registries. Since the strength of a registry is based on numbers, health care professionals are encouraged to enroll potential subjects or have their patients call to enroll themselves.

Before retirement, Mr. Briggs was a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; he remains a clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He had no relevant financial disclosures. Contact him at obnews@frontlinemedcom.com.

Pregnancy registries are valuable sources of information. For many drugs, they are the primary source of human pregnancy experience. The new Food and Drug Administration prescription drug information format may increase the amount of information available, at least from registries conducted by drug manufacturers, because they will be required to list all substantive changes made within the year. Although most of the registries use the word “pregnancy,” it is important to note that many also enroll women who took the target drug shortly before conception.

©PhotoDisk

The strengths of pregnancy registries are their prospective nature and enrollment across a wide geographical area. Typically, two types of pregnancy outcomes are obtained: those with birth defects and those without known birth defects (classified as live births, fetal deaths, and spontaneous abortions).

Registries can identify early signals of teratogenicity, but they have several limitations, including voluntary reporting that results in selection bias, pregnancies lost to follow-up that may have had different outcomes than those with documented outcomes, and a lack of control groups (with some exceptions).

Other limitations are that registry cases are not representative of target populations, and pregnancies lost to follow-up lack details on elective terminations and fetal deaths without birth defects, as well as all spontaneous abortions. Additionally, publication of results may be delayed and does not appear in a peer-reviewed journal.

Since the total number of exposed pregnancies is unknown, registry data cannot be used to calculate prevalence, but can be used to estimate the proportion of birth defects. Some registries also collect data on retrospective reports, which are less representative of the target population because they can be biased toward the reporting of more unusual and severe outcomes. However, they may be helpful in detecting unusual patterns of birth defects.

MothertoBaby Registry

The large Organization of Teratology Information Specialists (OTIS) MothertoBaby registry (877-311-8972) involves four different categories: autoimmune diseases(rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis, Crohn’s disease, and multiple sclerosis); asthma; antiviral agents; and vaccines.

The drugs for autoimmune diseases are tocilizumab (Actemra), leflunomide (Arava), teriflunomide (Aubagio), certolizumab pegol (Cimzia), etanercept (Enbrel), adalimumab (Humira), abatacept (Orencia), apremilast (Otezla), ustekinumab (Stelara), tofacitinib (Xeljanz), infliximab (Remicade), and methotrexate.

The asthma drugs are formoterol (Foradil, Perforomist, Symbicort, Dulera), albuterol, levalbuterol, metaproterenol, pirbuterol (Maxair), and terbutaline.

The antiviral agents are oseltamivir (Tamiflu) and zanamivir (Relenza).

The vaccines include pertussis (Tdap), seasonal influenza, and meningococcal disease (Menveo). In addition to a control group in each category, a unique aspect of this registry is that many exposed infants will undergo dysmorphology examinations.

Vaccine registries

A second vaccine for meningococcal disease (Menactra) is being studied in the Menactra vaccine Pregnancy Registry (800-822-2463 / www.sanofipasteurpregnancy.com).

Two other registries also include influenza vaccines: Flu vaccine Pregnancy Registry, PPD (Flucelvax) (877-413-4759 / email: NovartisPregnancyregistries@ppdi.com) and the GSK Seasonal Influenza Vaccine Pregnancy Registry, GlaxoSmithKline (888-825-5249 / pregnancyregistry.gsk.com/seasonalinfluenzavaccines.html), which includes the Fluarix and FluLaval vaccines.

Asthma

Women with asthma who are being treated with omalizumab (Xolair) are the target population for the EXPECT Pregnancy Registry (866-496-5247 Option 3 / www.xolairpregnancyregistry.com).

GSK registries

GlaxoSmithKline is also conducting three other registries: the Belimumab (Benlysta) Pregnancy Registry for patients with systemic lupus erythematosus treated with belimumab (877-681-6296 / belimumab.pregnancy@ppdi.com); and the Twinrix Pregnancy Registry for women who have received the Twinrix hepatitis A and B vaccine (888-825-5249).

Atypical antipsychotics

TheNational Pregnancy Registry for Atypical Antipsychotics (866-961-2388 / registry@womens mentalhealth.org) is studying 10 drugs: aripiprazole (Abilify), clozapine (Clozaril), iloperidone (Fanapt), paliperidone (Invega), lurasidone (Latuda), risperidone (Risperdal), asenapine (Saphris), quetiapine (Seroquel), ziprasidone (Geodon), and olanzapine (Zyprexa).

TAPP registry

Acitretin is under study by the Take Action to Prevent Pregnancy (T.A.P.P.) registry (855-850-2138 / www.tevagenerics.com/acitretin).

MPS I registry

The MPS I (Mucopolysaccharidosis I) Registry, Genzyme Corp (617-591-5500 / help@mpsiregistry.com), is studying the use of laronidase (Aldurazyme) for Hurler syndrome, Scheie syndrome, and Hurler-Scheie syndrome.

MPS VI registry

The use of galsulfase (Naglazyme) for Maroteaux-Lamy syndrome during pregnancy is under study by the Mucopolysaccharidosis VI (MPS VI) Clinical Surveillance Program(415-506-6849 or 415-506-6703)

Epilepsy drugs

The Antiepileptic Drug Pregnancy Registry (888-233-2334 / www.aedpregnancyregistry.org) is studying antiepileptic drugs.

Type 2 diabetes

The Exenatide Pregnancy Registry, conducted by INC Research for AstraZeneca (800-633-9081 / www.exenatidepregnancyregistry.com), examines the use of exenatide (Byetta, Bydureon) for the treatment of type 2 diabetes.

Renal transplant

Renal transplant patients exposed to mycophenolate (Cellcept) can be enrolled in the Mycophenolate Pregnancy Registry (800-617-8191) or the National Transplantation Pregnancy Registry (877-955-6877). The NTPR is enrolling renal transplant patients exposed to belatacept (Nulojix).

Cymbalta

The antidepressant duloxetine (Cymbalta), when used for major depressive or generalized anxiety disorders, diabetic peripheral neuropathic pain, or fibromyalgia is being studied by the Cymbalta Pregnancy Registry, INC Research (pregnancyregistries@incresearch.com / www.cymbaltapregancyregistry.com).

Fabry disease

The Fabry Registry, Genzyme Corp (617-581-5500 / help@FabryRegistry.com) is studying the use in pregnancy of agalsidase beta (Fabrazyme) for Fabry disease.

MS registry

Novartis Pharmaceuticals is conducting the Gilenya (fingolimod) Pregnancy Registry (877-598-7237 / gpr@outcome.com) for patients with multiple sclerosis who are taking fingolimod (Gilenya).

Cancer

The MotHER Pregnancy Registry, INC Research (800-690-6720 / pregnancyregistries@incresearch.com / themotherpregnancyregistry.com) is enrolling breast cancer patients who have been treated during pregnancy with ado-trastuzumab (Kadcyla), trastuzumab (Herceptin), or pertuzumab (Perjeta).

Merck registries

Merck Pregnancy Registries (800-986-8999) include a registry for type 2 diabetes – sitagliptin/metformin (Janumet) or sitagliptin (Januvia) (www.merckpregancyregistries.com/januvia.html); a registry for rizatriptan (Maxalt) (www.merckpregancyregistries.com/maxalt.html), for migraine headaches; and a registry for the 9-valent human papillomavirus (HPV) (Gardasil 9) vaccine (www.merckpregnancyregistries.com/gardasil9.html).

The registry for the asthma drug montelukast (Singulair) and the registry for Gardasil, the quadrivalent HPV vaccine, are now closed to new enrollment, but new cases of pregnancy exposures can be reported to the company at: 877-888-4231.

Osteoporosis

Amgen’s Pregnancy Surveillance Program (800-772-6436) is enrolling pregnant subjects with osteoporosis who are being treated with denosumab (Prolia).

Hepatitis C

The Ribavirin Pregnancy Registry, INC Research (800-593-2214/ pregnancyregisteries@incresearch.com / ribavirinpregnancyregistry.com) is looking for subjects with hepatitis C who have been treated with ribavirin (Copegus).

Fibromyalgia

The Savella Pregnancy Registry (877-643-3010/ pregnancyresgistries@incresearch.com / savellapregnancyregistry.com) is looking for patients with fibromyalgia who are being treated with milnacipran (Savella).

Skin infections

An antibacterial, telavancin (Vibativ), indicated for skin infections is being studied by the Vibativ Pregnancy Registry (888-658-4228 / www.clinicaltrial.gov).

Pompe disease

Pregnant women treated with alglucosidase alfa (Myozyme) for Pompe disease can enroll in the Pompe Registry (800-745-4447 x 15500 / www.pompe.com/en/healthcare-professionals/pompe-registry.aspx).

Sleep disorders

Armodafinil (Nuvigil) used to treat excessive sleepiness associated with narcolepsy and other sleep disorders is being studied in the Nuvigil Pregnancy Registry (866-404-4106 / www.nuvigilpregnancyregistry.com). A second drug with the same indication and telephone number, modafinil (Provigil), is in the Provigil Pregnancy Registry (provigilpregnancyregistry.com).

Additional details, including fax numbers and addresses of the registries reviewed above, can be obtained from the FDA website, List of Pregnancy Exposure Registries. Since the strength of a registry is based on numbers, health care professionals are encouraged to enroll potential subjects or have their patients call to enroll themselves.

Before retirement, Mr. Briggs was a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; he remains a clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He had no relevant financial disclosures. Contact him at obnews@frontlinemedcom.com.

Pregnancy registries are valuable sources of information. For many drugs, they are the primary source of human pregnancy experience. The new Food and Drug Administration prescription drug information format may increase the amount of information available, at least from registries conducted by drug manufacturers, because they will be required to list all substantive changes made within the year. Although most of the registries use the word “pregnancy,” it is important to note that many also enroll women who took the target drug shortly before conception.

©PhotoDisk

The strengths of pregnancy registries are their prospective nature and enrollment across a wide geographical area. Typically, two types of pregnancy outcomes are obtained: those with birth defects and those without known birth defects (classified as live births, fetal deaths, and spontaneous abortions).

Registries can identify early signals of teratogenicity, but they have several limitations, including voluntary reporting that results in selection bias, pregnancies lost to follow-up that may have had different outcomes than those with documented outcomes, and a lack of control groups (with some exceptions).

Other limitations are that registry cases are not representative of target populations, and pregnancies lost to follow-up lack details on elective terminations and fetal deaths without birth defects, as well as all spontaneous abortions. Additionally, publication of results may be delayed and does not appear in a peer-reviewed journal.

Since the total number of exposed pregnancies is unknown, registry data cannot be used to calculate prevalence, but can be used to estimate the proportion of birth defects. Some registries also collect data on retrospective reports, which are less representative of the target population because they can be biased toward the reporting of more unusual and severe outcomes. However, they may be helpful in detecting unusual patterns of birth defects.

MothertoBaby Registry

The large Organization of Teratology Information Specialists (OTIS) MothertoBaby registry (877-311-8972) involves four different categories: autoimmune diseases(rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis, Crohn’s disease, and multiple sclerosis); asthma; antiviral agents; and vaccines.

The drugs for autoimmune diseases are tocilizumab (Actemra), leflunomide (Arava), teriflunomide (Aubagio), certolizumab pegol (Cimzia), etanercept (Enbrel), adalimumab (Humira), abatacept (Orencia), apremilast (Otezla), ustekinumab (Stelara), tofacitinib (Xeljanz), infliximab (Remicade), and methotrexate.

The asthma drugs are formoterol (Foradil, Perforomist, Symbicort, Dulera), albuterol, levalbuterol, metaproterenol, pirbuterol (Maxair), and terbutaline.

The antiviral agents are oseltamivir (Tamiflu) and zanamivir (Relenza).

The vaccines include pertussis (Tdap), seasonal influenza, and meningococcal disease (Menveo). In addition to a control group in each category, a unique aspect of this registry is that many exposed infants will undergo dysmorphology examinations.

Vaccine registries

A second vaccine for meningococcal disease (Menactra) is being studied in the Menactra vaccine Pregnancy Registry (800-822-2463 / www.sanofipasteurpregnancy.com).

Two other registries also include influenza vaccines: Flu vaccine Pregnancy Registry, PPD (Flucelvax) (877-413-4759 / email: NovartisPregnancyregistries@ppdi.com) and the GSK Seasonal Influenza Vaccine Pregnancy Registry, GlaxoSmithKline (888-825-5249 / pregnancyregistry.gsk.com/seasonalinfluenzavaccines.html), which includes the Fluarix and FluLaval vaccines.

Asthma

Women with asthma who are being treated with omalizumab (Xolair) are the target population for the EXPECT Pregnancy Registry (866-496-5247 Option 3 / www.xolairpregnancyregistry.com).

GSK registries

GlaxoSmithKline is also conducting three other registries: the Belimumab (Benlysta) Pregnancy Registry for patients with systemic lupus erythematosus treated with belimumab (877-681-6296 / belimumab.pregnancy@ppdi.com); and the Twinrix Pregnancy Registry for women who have received the Twinrix hepatitis A and B vaccine (888-825-5249).

Atypical antipsychotics

TheNational Pregnancy Registry for Atypical Antipsychotics (866-961-2388 / registry@womens mentalhealth.org) is studying 10 drugs: aripiprazole (Abilify), clozapine (Clozaril), iloperidone (Fanapt), paliperidone (Invega), lurasidone (Latuda), risperidone (Risperdal), asenapine (Saphris), quetiapine (Seroquel), ziprasidone (Geodon), and olanzapine (Zyprexa).

TAPP registry

Acitretin is under study by the Take Action to Prevent Pregnancy (T.A.P.P.) registry (855-850-2138 / www.tevagenerics.com/acitretin).

MPS I registry

The MPS I (Mucopolysaccharidosis I) Registry, Genzyme Corp (617-591-5500 / help@mpsiregistry.com), is studying the use of laronidase (Aldurazyme) for Hurler syndrome, Scheie syndrome, and Hurler-Scheie syndrome.

MPS VI registry

The use of galsulfase (Naglazyme) for Maroteaux-Lamy syndrome during pregnancy is under study by the Mucopolysaccharidosis VI (MPS VI) Clinical Surveillance Program(415-506-6849 or 415-506-6703)

Epilepsy drugs

The Antiepileptic Drug Pregnancy Registry (888-233-2334 / www.aedpregnancyregistry.org) is studying antiepileptic drugs.

Type 2 diabetes

The Exenatide Pregnancy Registry, conducted by INC Research for AstraZeneca (800-633-9081 / www.exenatidepregnancyregistry.com), examines the use of exenatide (Byetta, Bydureon) for the treatment of type 2 diabetes.

Renal transplant

Renal transplant patients exposed to mycophenolate (Cellcept) can be enrolled in the Mycophenolate Pregnancy Registry (800-617-8191) or the National Transplantation Pregnancy Registry (877-955-6877). The NTPR is enrolling renal transplant patients exposed to belatacept (Nulojix).

Cymbalta

The antidepressant duloxetine (Cymbalta), when used for major depressive or generalized anxiety disorders, diabetic peripheral neuropathic pain, or fibromyalgia is being studied by the Cymbalta Pregnancy Registry, INC Research (pregnancyregistries@incresearch.com / www.cymbaltapregancyregistry.com).

Fabry disease

The Fabry Registry, Genzyme Corp (617-581-5500 / help@FabryRegistry.com) is studying the use in pregnancy of agalsidase beta (Fabrazyme) for Fabry disease.

MS registry

Novartis Pharmaceuticals is conducting the Gilenya (fingolimod) Pregnancy Registry (877-598-7237 / gpr@outcome.com) for patients with multiple sclerosis who are taking fingolimod (Gilenya).

Cancer

The MotHER Pregnancy Registry, INC Research (800-690-6720 / pregnancyregistries@incresearch.com / themotherpregnancyregistry.com) is enrolling breast cancer patients who have been treated during pregnancy with ado-trastuzumab (Kadcyla), trastuzumab (Herceptin), or pertuzumab (Perjeta).

Merck registries

Merck Pregnancy Registries (800-986-8999) include a registry for type 2 diabetes – sitagliptin/metformin (Janumet) or sitagliptin (Januvia) (www.merckpregancyregistries.com/januvia.html); a registry for rizatriptan (Maxalt) (www.merckpregancyregistries.com/maxalt.html), for migraine headaches; and a registry for the 9-valent human papillomavirus (HPV) (Gardasil 9) vaccine (www.merckpregnancyregistries.com/gardasil9.html).

The registry for the asthma drug montelukast (Singulair) and the registry for Gardasil, the quadrivalent HPV vaccine, are now closed to new enrollment, but new cases of pregnancy exposures can be reported to the company at: 877-888-4231.

Osteoporosis

Amgen’s Pregnancy Surveillance Program (800-772-6436) is enrolling pregnant subjects with osteoporosis who are being treated with denosumab (Prolia).

Hepatitis C

The Ribavirin Pregnancy Registry, INC Research (800-593-2214/ pregnancyregisteries@incresearch.com / ribavirinpregnancyregistry.com) is looking for subjects with hepatitis C who have been treated with ribavirin (Copegus).

Fibromyalgia

The Savella Pregnancy Registry (877-643-3010/ pregnancyresgistries@incresearch.com / savellapregnancyregistry.com) is looking for patients with fibromyalgia who are being treated with milnacipran (Savella).

Skin infections

An antibacterial, telavancin (Vibativ), indicated for skin infections is being studied by the Vibativ Pregnancy Registry (888-658-4228 / www.clinicaltrial.gov).

Pompe disease

Pregnant women treated with alglucosidase alfa (Myozyme) for Pompe disease can enroll in the Pompe Registry (800-745-4447 x 15500 / www.pompe.com/en/healthcare-professionals/pompe-registry.aspx).

Sleep disorders

Armodafinil (Nuvigil) used to treat excessive sleepiness associated with narcolepsy and other sleep disorders is being studied in the Nuvigil Pregnancy Registry (866-404-4106 / www.nuvigilpregnancyregistry.com). A second drug with the same indication and telephone number, modafinil (Provigil), is in the Provigil Pregnancy Registry (provigilpregnancyregistry.com).

Additional details, including fax numbers and addresses of the registries reviewed above, can be obtained from the FDA website, List of Pregnancy Exposure Registries. Since the strength of a registry is based on numbers, health care professionals are encouraged to enroll potential subjects or have their patients call to enroll themselves.

Before retirement, Mr. Briggs was a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; he remains a clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He had no relevant financial disclosures. Contact him at obnews@frontlinemedcom.com.

Herbs are commonly consumed by pregnant and breast-feeding women, possibly because they believe that “natural products” are safer than drugs. However, even though some have been available for hundreds or thousands of years, little is known about their effects on the embryo, fetus, newborn, or nursing infant. Moreover, as unregulated products, the concentration, contents, and presence of contaminants cannot be easily determined. Detailed reviews of the 22 most commonly used herbs discussed here can be found in “Drugs in Pregnancy and Lactation,” Briggs GG, Freeman RK, 10th ed., Philadelphia: Wolters Kluwer Health, 2014).

In the following discussions, dose, one of the two key factors that determine the risk of developmental toxicity (abnormal growth, structural anomalies, functional and/or neurobehavioral deficits, or death), is rarely reported. In addition, all herbs contain multiple chemical compounds, few of which have been studied during pregnancy or lactation. Thus, with few exceptions, a woman who takes an herb in pregnancy should be informed that the risk to her developing baby is unknown.

Six herbs are considered contraindicated in pregnancy: arnica, black seed /kalanji, blue cohosh, feverfew, salvia divinorum, and valerian.

• Arnica. The dried flowers, and sometimes the roots and rhizomes, are the parts of this perennial plant that are used topically for their anti-inflammatory and analgesic effects. There is no clinical evidence to support this use. Occasional topical use probably represents a low risk, but absorption may occur when it is applied to broken skin. The Food and Drug Administration has classified arnica as an unsafe herb and, when used orally, it is considered a poison. It is a uterine stimulant and an abortifacient. Nevertheless, in homeopathic formulations, it has been promoted for use before and during labor for internal and external bruising of the mother and newborn. In Italy, it is one of the top 10 herbs taken by women (Pharmacoepidemiol. Drug Saf. 2006;15:354-9).

• Black seed/kalanji. This herb has been used for thousands of year as a medicine, food, or spice. Because of this, it is unlikely that it causes teratogenesis. Nevertheless, its use to stimulate menstruation and its potential contraceptive properties suggest that it is contraindicated in pregnancy.

• Blue cohosh. Some of the components of this herb have been shown to be teratogenic and toxic in various animal species, so it should be avoided in the first trimester. The herb has uterine stimulant properties that are used by nurse-midwives to stimulate labor. Blue cohosh was the most frequently used herbal preparation for this purpose. However, some sources believe that the potential fetal and newborn toxicity may outweigh any medical benefit (“PDR for Herbal Medicine,” 2nd ed., Montvale, N.J.: Medical Economics, 2000:109-10; “The Review of Natural Products,” St. Louis, MO: Facts and Comparisons, 2000).

• Feverfew. This herb has been used for labor, menstrual disorders, potential miscarriage, and morning sickness; as an abortifacient; and for several other indications. Because of its antipyretic properties, it has been known as “medieval aspirin.” The doses used for these indications have not been quantified. Because of its emmenagogic (capable of provoking menstruation) activity, the herb should not be used in pregnancy.

• Salvia divinorum. This herb has hallucinogenic effects and is used in certain regions of Mexico for healing and divinatory rituals. It is also thought to have antidiarrheal properties. The herb is either smoked or chewed, or its juices are ingested. When taken orally, systemic effects are dependent upon absorption across the oral mucosa as the active ingredient is destroyed in the GI tract. Persistent psychosis has been observed in people who smoked the herb, so it is contraindicated in pregnancy.

• Valerian. A large number of preparations containing valerian are available. It has been used as a sedative and hypnotic for anxiety, restlessness, and sleep disturbances, as well as several other pharmacologic claims. Because of the risk of cytotoxicity in the fetus and hepatotoxicity in the mother, the herb should be avoided during gestation.

For the remaining 16 herbs, small, infrequent doses probably cause no harm to the mother, embryo, fetus, or newborn. Nevertheless, as noted below, some of these herbs are best avoided during pregnancy.

• Chamomile. Excessive use of this herb should be avoided because it is thought to have uterine stimulant, emmenagogic, and abortifacient properties. Although controversial, some nurse-midwives prescribe chamomile teas for the treatment of morning sickness. Because the plant sources of the herb contain coumarin compounds, ingesting chamomile by pregnant women with coagulation disorders is a concern. However, the herb has been used for thousands of years, so the risk of harm, at least from occasional use, must be very rare.

• Echinacea. This herb is used topically to enhance wound healing and systemically as an immunostimulant. An IV formulation is used in Germany but is not available in the United States. It also has been recommended to assist in the prevention or treatment of viral upper respiratory tract infections. Its use in pregnancy is limited to one small study.

• Evening primrose oil. The oil contains two essential fatty acids: cis-linoleic and gamma-linolenic acid. In a national survey of nurse-midwives, it was the most frequently used herbal preparation for the induction of labor. No adverse effects have been reported in the fetus or newborn from this use. The doses used varied widely and included both oral and vaginal routes of administration. In addition, the oil has been used for rheumatoid arthritis and diabetic neuropathy, but there are no reports of these uses in pregnancy.

• Garlic. Garlic has been used for food flavoring since ancient times and appears to be safe during pregnancy. Some components cross the placenta, as shown by garlic odor in the amniotic fluid and on the newborn’s breath. Very high doses have the potential to induce menstruation or uterine contractions, but apparently these effects have not been reported.

• Ginger. No reports of ginger-induced developmental toxicity have been located. Ginger has been used as antiemetic for nausea and vomiting of pregnancy.

• Ginseng. The root is the most important part of this plant that is found throughout the world and has been used in medicine for more than 2,000 years. The herb has been promoted for multiple pharmacologic effects, including adaptogenic, CNS, cardiovascular, endocrine, ergogenic, antineoplastic, and immunomodulatory effects.

Hypertension and hypoglycemia have been reported in nonpregnant patients, but not in the limited human pregnancy data. A brief 1991 study compared 88 women who took the herb during pregnancy with 88 controls. No differences between the groups were found with regard to the mode of delivery, birth weight, low birth weight (< 2,500 ), preterm delivery (< 37 weeks), low Apgar score (< 7), stillbirths, neonatal deaths, or maternal complications (Asia Oceania J. Obstet. Gynaecol. 1991;17:379-80).

• Ginkgo biloba. The limited animal reproduction data suggest low risk, but there is no reported human pregnancy experience. Nevertheless, it is an ancient herbal preparation that is commonly used for organic brain syndrome, circulatory disorders, asthma, vertigo, and tinnitus. Because of its widespread use, it is doubtful that a major teratogenic effect would have escaped notice, but more subtle or low-incidence toxic effects may not have been detected.

• Kudzu. No human or animal data regarding pregnancy have been located. The herb has been used for more than 2,500 years for the treatment of alcohol hangover, drunkenness, alcoholism, muscle pain, and measles. Many of its chemical constituents can be found in foods. Nevertheless, high, frequent doses should be avoided.

• Nutmeg. This is a commonly used spice but, as with any herb, high doses can produce toxicity. The toxicity is caused by a chemical in the seeds, myristicin, which has anticholinergic properties. A woman at 30 weeks’ gestation misread a recipe and used a whole grated nutmeg rather than 1/8 teaspoon when making cookies. When she ate a cookie, she experienced sinus tachycardia, hypertension, and a sensation of impending doom. The fetus had tachycardia, and atropine-like poisoning was diagnosed. After about 12 hours, both mother and fetus made an uneventful recovery and a healthy infant was born at term.

• Passion flower. The name of this herb may refer to about 400 species of the genus Passiflora. It is available in both oral and topical forms and is used for nervousness, neuralgia, insomnia, pain, asthma, seizures, burns, hemorrhoids, and menopausal complaints. As with many herbs, it contains a large number of chemicals, none of which have undergone reproductive testing. No reports describing the use of this herb in human pregnancy have been located. However, because it has uterine stimulant properties, the oral formulation is best avoided in pregnancy.

• Peppermint. This popular flavoring appears to be harmless for the mother and developing baby when low, recommended doses are ingested. Peppermint oil is available in numerous topical and oral formulations. High oral doses, however, can cause significant toxicity, including death. During pregnancy, ingestion of more than the recommended doses is unsafe because of possible emmenagogic and abortifacient properties.

• Pumpkin seed. This herb, when used as a food, appears to be harmless for the mother and embryo-fetus, but no reports describing its use in pregnancy have been located. High doses, such as those used in traditional medicine or in eating disorders, should be avoided because of the potential for toxic effects from the many chemicals these seeds contain.

• Raspberry leaf. Raspberry leaf tea is commonly used by pregnant women. Nurse-midwives often prescribe the tea to treat nausea and vomiting and as a uterine tonic to shorten labor. A double-blind, randomized, placebo-controlled study evaluated the effect of raspberry leaf tablets (2 tablets/day) on pregnancy outcomes. Compared with controls, no differences were found for length of labor or stages of labor, mode of delivery, admission to the neonatal intensive care unit, Apgar score, and birth weight (J. Midwifery Womens Health 2001;46:51-9).

• Safflower. Safflower oil is commonly used in cooking and has been given for its laxative action. There are no reports describing the use of the herb in pregnancy. It is doubtful if such use would have any adverse effect on a pregnancy. Although abortifacient and emmenagogic effects have been suggested, there is no evidence supporting these effects when used as a food.

• St. John’s wort. No toxicity in pregnant humans has been reported. The use of the herb is widespread and dates back thousands of years. Thus, it is doubtful that the herb is a major teratogen or causes other elements of developmental toxicity. The herb has been used for the management of anxiety, depression, insomnia, inflammation, and gastritis. It is also used as a diuretic and, topically, for the treatment of hemorrhoids and enhanced wound healing.

• Yohimbine. The use of this herb in human pregnancies has not been reported. It has been used as an aphrodisiac and for weight loss, sexual dysfunction, and the treatment of orthostatic hypotension. Although it has no Food and Drug Administration–sanctioned indications, it is also available by prescription for male erectile dysfunction. Due to the lack of data regarding pregnancy, the herb is best avoided during pregnancy.

There are few data regarding the effects of the above herbs on a breast-feeding infant. Depending upon the herb, nursing infants will be exposed to many chemical compounds. For those herbs used as food, nursing is probably safe. The safety of the other herbs during lactation is unknown. However, toxicity has been reported in a 9-day-old term infant whose mother was taking arnica (Clin. Toxicol. 2009;47:726, abstract 120). The infant presented with lethargy, decreased milk intake, anemia, and jaundice but recovered with treatment. After the mother stopped the herb and resumed nursing, no further problems were noted in the infant.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He had no relevant financial disclosures. Contact him at obnews@frontlinemedcom.com.

Herbs are commonly consumed by pregnant and breast-feeding women, possibly because they believe that “natural products” are safer than drugs. However, even though some have been available for hundreds or thousands of years, little is known about their effects on the embryo, fetus, newborn, or nursing infant. Moreover, as unregulated products, the concentration, contents, and presence of contaminants cannot be easily determined. Detailed reviews of the 22 most commonly used herbs discussed here can be found in “Drugs in Pregnancy and Lactation,” Briggs GG, Freeman RK, 10th ed., Philadelphia: Wolters Kluwer Health, 2014).

In the following discussions, dose, one of the two key factors that determine the risk of developmental toxicity (abnormal growth, structural anomalies, functional and/or neurobehavioral deficits, or death), is rarely reported. In addition, all herbs contain multiple chemical compounds, few of which have been studied during pregnancy or lactation. Thus, with few exceptions, a woman who takes an herb in pregnancy should be informed that the risk to her developing baby is unknown.

Six herbs are considered contraindicated in pregnancy: arnica, black seed /kalanji, blue cohosh, feverfew, salvia divinorum, and valerian.

• Arnica. The dried flowers, and sometimes the roots and rhizomes, are the parts of this perennial plant that are used topically for their anti-inflammatory and analgesic effects. There is no clinical evidence to support this use. Occasional topical use probably represents a low risk, but absorption may occur when it is applied to broken skin. The Food and Drug Administration has classified arnica as an unsafe herb and, when used orally, it is considered a poison. It is a uterine stimulant and an abortifacient. Nevertheless, in homeopathic formulations, it has been promoted for use before and during labor for internal and external bruising of the mother and newborn. In Italy, it is one of the top 10 herbs taken by women (Pharmacoepidemiol. Drug Saf. 2006;15:354-9).

• Black seed/kalanji. This herb has been used for thousands of year as a medicine, food, or spice. Because of this, it is unlikely that it causes teratogenesis. Nevertheless, its use to stimulate menstruation and its potential contraceptive properties suggest that it is contraindicated in pregnancy.

• Blue cohosh. Some of the components of this herb have been shown to be teratogenic and toxic in various animal species, so it should be avoided in the first trimester. The herb has uterine stimulant properties that are used by nurse-midwives to stimulate labor. Blue cohosh was the most frequently used herbal preparation for this purpose. However, some sources believe that the potential fetal and newborn toxicity may outweigh any medical benefit (“PDR for Herbal Medicine,” 2nd ed., Montvale, N.J.: Medical Economics, 2000:109-10; “The Review of Natural Products,” St. Louis, MO: Facts and Comparisons, 2000).

• Feverfew. This herb has been used for labor, menstrual disorders, potential miscarriage, and morning sickness; as an abortifacient; and for several other indications. Because of its antipyretic properties, it has been known as “medieval aspirin.” The doses used for these indications have not been quantified. Because of its emmenagogic (capable of provoking menstruation) activity, the herb should not be used in pregnancy.

• Salvia divinorum. This herb has hallucinogenic effects and is used in certain regions of Mexico for healing and divinatory rituals. It is also thought to have antidiarrheal properties. The herb is either smoked or chewed, or its juices are ingested. When taken orally, systemic effects are dependent upon absorption across the oral mucosa as the active ingredient is destroyed in the GI tract. Persistent psychosis has been observed in people who smoked the herb, so it is contraindicated in pregnancy.

• Valerian. A large number of preparations containing valerian are available. It has been used as a sedative and hypnotic for anxiety, restlessness, and sleep disturbances, as well as several other pharmacologic claims. Because of the risk of cytotoxicity in the fetus and hepatotoxicity in the mother, the herb should be avoided during gestation.

For the remaining 16 herbs, small, infrequent doses probably cause no harm to the mother, embryo, fetus, or newborn. Nevertheless, as noted below, some of these herbs are best avoided during pregnancy.

• Chamomile. Excessive use of this herb should be avoided because it is thought to have uterine stimulant, emmenagogic, and abortifacient properties. Although controversial, some nurse-midwives prescribe chamomile teas for the treatment of morning sickness. Because the plant sources of the herb contain coumarin compounds, ingesting chamomile by pregnant women with coagulation disorders is a concern. However, the herb has been used for thousands of years, so the risk of harm, at least from occasional use, must be very rare.

• Echinacea. This herb is used topically to enhance wound healing and systemically as an immunostimulant. An IV formulation is used in Germany but is not available in the United States. It also has been recommended to assist in the prevention or treatment of viral upper respiratory tract infections. Its use in pregnancy is limited to one small study.

• Evening primrose oil. The oil contains two essential fatty acids: cis-linoleic and gamma-linolenic acid. In a national survey of nurse-midwives, it was the most frequently used herbal preparation for the induction of labor. No adverse effects have been reported in the fetus or newborn from this use. The doses used varied widely and included both oral and vaginal routes of administration. In addition, the oil has been used for rheumatoid arthritis and diabetic neuropathy, but there are no reports of these uses in pregnancy.

• Garlic. Garlic has been used for food flavoring since ancient times and appears to be safe during pregnancy. Some components cross the placenta, as shown by garlic odor in the amniotic fluid and on the newborn’s breath. Very high doses have the potential to induce menstruation or uterine contractions, but apparently these effects have not been reported.

• Ginger. No reports of ginger-induced developmental toxicity have been located. Ginger has been used as antiemetic for nausea and vomiting of pregnancy.

• Ginseng. The root is the most important part of this plant that is found throughout the world and has been used in medicine for more than 2,000 years. The herb has been promoted for multiple pharmacologic effects, including adaptogenic, CNS, cardiovascular, endocrine, ergogenic, antineoplastic, and immunomodulatory effects.

Hypertension and hypoglycemia have been reported in nonpregnant patients, but not in the limited human pregnancy data. A brief 1991 study compared 88 women who took the herb during pregnancy with 88 controls. No differences between the groups were found with regard to the mode of delivery, birth weight, low birth weight (< 2,500 ), preterm delivery (< 37 weeks), low Apgar score (< 7), stillbirths, neonatal deaths, or maternal complications (Asia Oceania J. Obstet. Gynaecol. 1991;17:379-80).

• Ginkgo biloba. The limited animal reproduction data suggest low risk, but there is no reported human pregnancy experience. Nevertheless, it is an ancient herbal preparation that is commonly used for organic brain syndrome, circulatory disorders, asthma, vertigo, and tinnitus. Because of its widespread use, it is doubtful that a major teratogenic effect would have escaped notice, but more subtle or low-incidence toxic effects may not have been detected.

• Kudzu. No human or animal data regarding pregnancy have been located. The herb has been used for more than 2,500 years for the treatment of alcohol hangover, drunkenness, alcoholism, muscle pain, and measles. Many of its chemical constituents can be found in foods. Nevertheless, high, frequent doses should be avoided.

• Nutmeg. This is a commonly used spice but, as with any herb, high doses can produce toxicity. The toxicity is caused by a chemical in the seeds, myristicin, which has anticholinergic properties. A woman at 30 weeks’ gestation misread a recipe and used a whole grated nutmeg rather than 1/8 teaspoon when making cookies. When she ate a cookie, she experienced sinus tachycardia, hypertension, and a sensation of impending doom. The fetus had tachycardia, and atropine-like poisoning was diagnosed. After about 12 hours, both mother and fetus made an uneventful recovery and a healthy infant was born at term.

• Passion flower. The name of this herb may refer to about 400 species of the genus Passiflora. It is available in both oral and topical forms and is used for nervousness, neuralgia, insomnia, pain, asthma, seizures, burns, hemorrhoids, and menopausal complaints. As with many herbs, it contains a large number of chemicals, none of which have undergone reproductive testing. No reports describing the use of this herb in human pregnancy have been located. However, because it has uterine stimulant properties, the oral formulation is best avoided in pregnancy.

• Peppermint. This popular flavoring appears to be harmless for the mother and developing baby when low, recommended doses are ingested. Peppermint oil is available in numerous topical and oral formulations. High oral doses, however, can cause significant toxicity, including death. During pregnancy, ingestion of more than the recommended doses is unsafe because of possible emmenagogic and abortifacient properties.

• Pumpkin seed. This herb, when used as a food, appears to be harmless for the mother and embryo-fetus, but no reports describing its use in pregnancy have been located. High doses, such as those used in traditional medicine or in eating disorders, should be avoided because of the potential for toxic effects from the many chemicals these seeds contain.

• Raspberry leaf. Raspberry leaf tea is commonly used by pregnant women. Nurse-midwives often prescribe the tea to treat nausea and vomiting and as a uterine tonic to shorten labor. A double-blind, randomized, placebo-controlled study evaluated the effect of raspberry leaf tablets (2 tablets/day) on pregnancy outcomes. Compared with controls, no differences were found for length of labor or stages of labor, mode of delivery, admission to the neonatal intensive care unit, Apgar score, and birth weight (J. Midwifery Womens Health 2001;46:51-9).

• Safflower. Safflower oil is commonly used in cooking and has been given for its laxative action. There are no reports describing the use of the herb in pregnancy. It is doubtful if such use would have any adverse effect on a pregnancy. Although abortifacient and emmenagogic effects have been suggested, there is no evidence supporting these effects when used as a food.

• St. John’s wort. No toxicity in pregnant humans has been reported. The use of the herb is widespread and dates back thousands of years. Thus, it is doubtful that the herb is a major teratogen or causes other elements of developmental toxicity. The herb has been used for the management of anxiety, depression, insomnia, inflammation, and gastritis. It is also used as a diuretic and, topically, for the treatment of hemorrhoids and enhanced wound healing.

• Yohimbine. The use of this herb in human pregnancies has not been reported. It has been used as an aphrodisiac and for weight loss, sexual dysfunction, and the treatment of orthostatic hypotension. Although it has no Food and Drug Administration–sanctioned indications, it is also available by prescription for male erectile dysfunction. Due to the lack of data regarding pregnancy, the herb is best avoided during pregnancy.

There are few data regarding the effects of the above herbs on a breast-feeding infant. Depending upon the herb, nursing infants will be exposed to many chemical compounds. For those herbs used as food, nursing is probably safe. The safety of the other herbs during lactation is unknown. However, toxicity has been reported in a 9-day-old term infant whose mother was taking arnica (Clin. Toxicol. 2009;47:726, abstract 120). The infant presented with lethargy, decreased milk intake, anemia, and jaundice but recovered with treatment. After the mother stopped the herb and resumed nursing, no further problems were noted in the infant.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He had no relevant financial disclosures. Contact him at obnews@frontlinemedcom.com.

Herbs are commonly consumed by pregnant and breast-feeding women, possibly because they believe that “natural products” are safer than drugs. However, even though some have been available for hundreds or thousands of years, little is known about their effects on the embryo, fetus, newborn, or nursing infant. Moreover, as unregulated products, the concentration, contents, and presence of contaminants cannot be easily determined. Detailed reviews of the 22 most commonly used herbs discussed here can be found in “Drugs in Pregnancy and Lactation,” Briggs GG, Freeman RK, 10th ed., Philadelphia: Wolters Kluwer Health, 2014).

In the following discussions, dose, one of the two key factors that determine the risk of developmental toxicity (abnormal growth, structural anomalies, functional and/or neurobehavioral deficits, or death), is rarely reported. In addition, all herbs contain multiple chemical compounds, few of which have been studied during pregnancy or lactation. Thus, with few exceptions, a woman who takes an herb in pregnancy should be informed that the risk to her developing baby is unknown.

Six herbs are considered contraindicated in pregnancy: arnica, black seed /kalanji, blue cohosh, feverfew, salvia divinorum, and valerian.

• Arnica. The dried flowers, and sometimes the roots and rhizomes, are the parts of this perennial plant that are used topically for their anti-inflammatory and analgesic effects. There is no clinical evidence to support this use. Occasional topical use probably represents a low risk, but absorption may occur when it is applied to broken skin. The Food and Drug Administration has classified arnica as an unsafe herb and, when used orally, it is considered a poison. It is a uterine stimulant and an abortifacient. Nevertheless, in homeopathic formulations, it has been promoted for use before and during labor for internal and external bruising of the mother and newborn. In Italy, it is one of the top 10 herbs taken by women (Pharmacoepidemiol. Drug Saf. 2006;15:354-9).

• Black seed/kalanji. This herb has been used for thousands of year as a medicine, food, or spice. Because of this, it is unlikely that it causes teratogenesis. Nevertheless, its use to stimulate menstruation and its potential contraceptive properties suggest that it is contraindicated in pregnancy.

• Blue cohosh. Some of the components of this herb have been shown to be teratogenic and toxic in various animal species, so it should be avoided in the first trimester. The herb has uterine stimulant properties that are used by nurse-midwives to stimulate labor. Blue cohosh was the most frequently used herbal preparation for this purpose. However, some sources believe that the potential fetal and newborn toxicity may outweigh any medical benefit (“PDR for Herbal Medicine,” 2nd ed., Montvale, N.J.: Medical Economics, 2000:109-10; “The Review of Natural Products,” St. Louis, MO: Facts and Comparisons, 2000).

• Feverfew. This herb has been used for labor, menstrual disorders, potential miscarriage, and morning sickness; as an abortifacient; and for several other indications. Because of its antipyretic properties, it has been known as “medieval aspirin.” The doses used for these indications have not been quantified. Because of its emmenagogic (capable of provoking menstruation) activity, the herb should not be used in pregnancy.

• Salvia divinorum. This herb has hallucinogenic effects and is used in certain regions of Mexico for healing and divinatory rituals. It is also thought to have antidiarrheal properties. The herb is either smoked or chewed, or its juices are ingested. When taken orally, systemic effects are dependent upon absorption across the oral mucosa as the active ingredient is destroyed in the GI tract. Persistent psychosis has been observed in people who smoked the herb, so it is contraindicated in pregnancy.

• Valerian. A large number of preparations containing valerian are available. It has been used as a sedative and hypnotic for anxiety, restlessness, and sleep disturbances, as well as several other pharmacologic claims. Because of the risk of cytotoxicity in the fetus and hepatotoxicity in the mother, the herb should be avoided during gestation.

For the remaining 16 herbs, small, infrequent doses probably cause no harm to the mother, embryo, fetus, or newborn. Nevertheless, as noted below, some of these herbs are best avoided during pregnancy.

• Chamomile. Excessive use of this herb should be avoided because it is thought to have uterine stimulant, emmenagogic, and abortifacient properties. Although controversial, some nurse-midwives prescribe chamomile teas for the treatment of morning sickness. Because the plant sources of the herb contain coumarin compounds, ingesting chamomile by pregnant women with coagulation disorders is a concern. However, the herb has been used for thousands of years, so the risk of harm, at least from occasional use, must be very rare.

• Echinacea. This herb is used topically to enhance wound healing and systemically as an immunostimulant. An IV formulation is used in Germany but is not available in the United States. It also has been recommended to assist in the prevention or treatment of viral upper respiratory tract infections. Its use in pregnancy is limited to one small study.

• Evening primrose oil. The oil contains two essential fatty acids: cis-linoleic and gamma-linolenic acid. In a national survey of nurse-midwives, it was the most frequently used herbal preparation for the induction of labor. No adverse effects have been reported in the fetus or newborn from this use. The doses used varied widely and included both oral and vaginal routes of administration. In addition, the oil has been used for rheumatoid arthritis and diabetic neuropathy, but there are no reports of these uses in pregnancy.

• Garlic. Garlic has been used for food flavoring since ancient times and appears to be safe during pregnancy. Some components cross the placenta, as shown by garlic odor in the amniotic fluid and on the newborn’s breath. Very high doses have the potential to induce menstruation or uterine contractions, but apparently these effects have not been reported.

• Ginger. No reports of ginger-induced developmental toxicity have been located. Ginger has been used as antiemetic for nausea and vomiting of pregnancy.

• Ginseng. The root is the most important part of this plant that is found throughout the world and has been used in medicine for more than 2,000 years. The herb has been promoted for multiple pharmacologic effects, including adaptogenic, CNS, cardiovascular, endocrine, ergogenic, antineoplastic, and immunomodulatory effects.

Hypertension and hypoglycemia have been reported in nonpregnant patients, but not in the limited human pregnancy data. A brief 1991 study compared 88 women who took the herb during pregnancy with 88 controls. No differences between the groups were found with regard to the mode of delivery, birth weight, low birth weight (< 2,500 ), preterm delivery (< 37 weeks), low Apgar score (< 7), stillbirths, neonatal deaths, or maternal complications (Asia Oceania J. Obstet. Gynaecol. 1991;17:379-80).

• Ginkgo biloba. The limited animal reproduction data suggest low risk, but there is no reported human pregnancy experience. Nevertheless, it is an ancient herbal preparation that is commonly used for organic brain syndrome, circulatory disorders, asthma, vertigo, and tinnitus. Because of its widespread use, it is doubtful that a major teratogenic effect would have escaped notice, but more subtle or low-incidence toxic effects may not have been detected.

• Kudzu. No human or animal data regarding pregnancy have been located. The herb has been used for more than 2,500 years for the treatment of alcohol hangover, drunkenness, alcoholism, muscle pain, and measles. Many of its chemical constituents can be found in foods. Nevertheless, high, frequent doses should be avoided.

• Nutmeg. This is a commonly used spice but, as with any herb, high doses can produce toxicity. The toxicity is caused by a chemical in the seeds, myristicin, which has anticholinergic properties. A woman at 30 weeks’ gestation misread a recipe and used a whole grated nutmeg rather than 1/8 teaspoon when making cookies. When she ate a cookie, she experienced sinus tachycardia, hypertension, and a sensation of impending doom. The fetus had tachycardia, and atropine-like poisoning was diagnosed. After about 12 hours, both mother and fetus made an uneventful recovery and a healthy infant was born at term.

• Passion flower. The name of this herb may refer to about 400 species of the genus Passiflora. It is available in both oral and topical forms and is used for nervousness, neuralgia, insomnia, pain, asthma, seizures, burns, hemorrhoids, and menopausal complaints. As with many herbs, it contains a large number of chemicals, none of which have undergone reproductive testing. No reports describing the use of this herb in human pregnancy have been located. However, because it has uterine stimulant properties, the oral formulation is best avoided in pregnancy.

• Peppermint. This popular flavoring appears to be harmless for the mother and developing baby when low, recommended doses are ingested. Peppermint oil is available in numerous topical and oral formulations. High oral doses, however, can cause significant toxicity, including death. During pregnancy, ingestion of more than the recommended doses is unsafe because of possible emmenagogic and abortifacient properties.

• Pumpkin seed. This herb, when used as a food, appears to be harmless for the mother and embryo-fetus, but no reports describing its use in pregnancy have been located. High doses, such as those used in traditional medicine or in eating disorders, should be avoided because of the potential for toxic effects from the many chemicals these seeds contain.

• Raspberry leaf. Raspberry leaf tea is commonly used by pregnant women. Nurse-midwives often prescribe the tea to treat nausea and vomiting and as a uterine tonic to shorten labor. A double-blind, randomized, placebo-controlled study evaluated the effect of raspberry leaf tablets (2 tablets/day) on pregnancy outcomes. Compared with controls, no differences were found for length of labor or stages of labor, mode of delivery, admission to the neonatal intensive care unit, Apgar score, and birth weight (J. Midwifery Womens Health 2001;46:51-9).

• Safflower. Safflower oil is commonly used in cooking and has been given for its laxative action. There are no reports describing the use of the herb in pregnancy. It is doubtful if such use would have any adverse effect on a pregnancy. Although abortifacient and emmenagogic effects have been suggested, there is no evidence supporting these effects when used as a food.

• St. John’s wort. No toxicity in pregnant humans has been reported. The use of the herb is widespread and dates back thousands of years. Thus, it is doubtful that the herb is a major teratogen or causes other elements of developmental toxicity. The herb has been used for the management of anxiety, depression, insomnia, inflammation, and gastritis. It is also used as a diuretic and, topically, for the treatment of hemorrhoids and enhanced wound healing.

• Yohimbine. The use of this herb in human pregnancies has not been reported. It has been used as an aphrodisiac and for weight loss, sexual dysfunction, and the treatment of orthostatic hypotension. Although it has no Food and Drug Administration–sanctioned indications, it is also available by prescription for male erectile dysfunction. Due to the lack of data regarding pregnancy, the herb is best avoided during pregnancy.

There are few data regarding the effects of the above herbs on a breast-feeding infant. Depending upon the herb, nursing infants will be exposed to many chemical compounds. For those herbs used as food, nursing is probably safe. The safety of the other herbs during lactation is unknown. However, toxicity has been reported in a 9-day-old term infant whose mother was taking arnica (Clin. Toxicol. 2009;47:726, abstract 120). The infant presented with lethargy, decreased milk intake, anemia, and jaundice but recovered with treatment. After the mother stopped the herb and resumed nursing, no further problems were noted in the infant.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He had no relevant financial disclosures. Contact him at obnews@frontlinemedcom.com.