Maternal use of prescribed drugs associated with recognized fetal adverse drug reactions

Joyce M. Piper, DrPH," Carlene Baum, PhD," Dianne L. Kennedy, RPh, MPH," and Phill Price, MD<

Nashville, Tennessee, and Rockville, Maryland

To quantitate the frequency of exposure in pregnancy to selected drugs listed by the American Medical Association's Department of Drugs as having known or suspected association with fetal adverse drug reactions, we examined the prescription records of 18,886 Michigan Medicaid recipients who delivered a liveborn infant between April 1, 1981, and March 31, 1983. Focusing only on specific trimesters considered risk periods for each drug-fetal occurrence of adverse drug reaction, the use of tetracyclines during the first trimester of pregnancy was the most prevalent (21.3 exposed women/ 1000) prescribed drug associated with known or suspected fetal adverse drug reactions. The second most prevalent was phenobarbital in the first trimester, with 10.8 women exposed/1000. Following a close third was the use of the sulfonamides in the second trimester, with 10.0 women exposed/1000. The prescribing of nitrofurantoin and the sulfonamides in the last trimester and tetracyclines throughout pregnancy appears excessive. There are few indications for the outpatient use of the tetracyclines during pregnancy. Practitioners caring for pregnant women need to carefully evaluate the need for these drugs and consider when risks may outweigh benefits. (AM J OssTET GvNECOL 1988;159:1173-7.)

Key words: Drug use, pregnancy, prenatal care

Fetal adverse drug reactions include both teratogenic effects and other adverse physiologic reactions in the fetus resulting from drug exposure. Such reactions may cause temporary or permanent fetal disability, injury, or death. Since a patient may have an indication for treatment unrelated to pregnancy and therefore may be seen by physicians other than obstetricians, the issue of fetal adverse drug reactions concerns all who pre­scribe medication for women in the childbearing age group.

This study quantitates the frequency of exposure in­curred by a large number of relatively healthy pregnant women to medications generally associated with fetal adverse drug reactions. Although we cannot determine why the drugs were prescribed (lack of awareness of the pregnancy, lack of knowledge that the drug might adversely affect the fetus, or a deliberate assessment that benefits outweighed risks), we can identify mater­nal exposures. These data may then be used to iden-

From the Department of Preventive Medicine,' Vanderbilt University School of Medicine, and the Divisions of Epidemiology and Surv­eillance' and Endocrine and Metabolic Drug Products,' Center for Drug Evaluation and Research, Food and Drug Administration.

This article contains the views of the authors and does not necessarily reflect those of the Food and Drug Administration.

Received for publication January 13, 1988; revised April 12, 1988; accepted May 27, 1988 . .

Reprint requests: Joyce M. Piper, DrPH, Department of Preventive Medicine, Vanderbilt University School of Medicine, S-3301 Med­ical Center North, Nashville, TN 37232.

tify prescribing patterns that might benefit from re­evaluation.

Methods

Data were derived from all paid Medicaid claims for Michigan women, ages 15 to 44 years (age in 1982), who delivered a liveborn infant from April 1, 1981, through March 31, 1983. The methodology used in handling these billing data for this population has been previously described. 1

The list of drugs associated with embryonic and fetal adverse drug reactions was adapted from a published list of potential fetal adverse drug reactions prepared by the American Medical Association's Department of Drugs, Division of Drugs and Technology.2 The list is stated as noninclusive, but is illustrative of the scope and type of adverse drug reactions that may occur when certain drugs are used during various stages of preg­nancy. We have further limited the American Medical Association's list to include only known or suspected reactions in the human embryo or fetus when exposure occurs during pregnancy in the outpatient setting. We cannot evaluate some drugs on the American Medical Association list associated with recognized fetal adverse drug reactions, including illicit drugs (e.g., heroin), drugs never approved for use in the United States (e.g., thalidomide), drugs that had not come into common use during the time period we studied (e.g., isotreti­noin), drugs used exclusively to manage preterm labor

1173

1174 Piper et al. November 1988 Am J Obstet Gynecol

Table I. Exposures per 1000 women by 90-day period for drugs associated with known or suspected fetal

adverse drug reactions in 18,886 Michigan Medicaid recipients (Michigan Medicaid livebirth deliveries,

April 1, 1981, to March 31, 1983

Exposure rates per 1000 women by days before estimated date of birth

I I I I Known or suspected fetal

Category I agents 450-361 360-271 270-181 180-90 90-0 adverse drug reactioni2t

Adrenergic drugs Propranolol 2.1 2.1 1.6 0.8*t 0.9*t Decreased cardiac out-

putt; hypoglycemia in the neonatet

Terbutaline 1.1 0.7 0.6 0.9*t i.7*t Tachycardiat Antibiotics

Chloramphenicol:j: 0.1 0.1 0.0 O.Ot 0.0* Neonatal gray babyt Nitrofurantoin 3.5 2.6 3.2 5.7*t 8.0*t H yperbilirubinemia t

Hemolytic anemiat Sulfonamides:j: 25.4 24.5 16.7 10.0*t 7.8*t H yperbilirubinemiat Tetracycline:j: 43.1 42.7 21.3*t 6.0*t§ 3.2*t Staining of deciduous

teeth,t inhibition of bone growth,§ enamel hypoplasia,§ microme-lia, syndactyly§

Anticholinergics Atropines 16.3 15.0 11.3 6.7*t 6.3*t Brad ycardia t Scopolamine 10.6 9.7 7.2 3.4*t 2.1 *t Brad ycardia t Methscopolamine 0.6 0.3 0.4 0.2*t 0.3*t Bradycardiat

Anticoagulants Warfarin 0.4 0.2 0.0*t§ O.O*t O.O*t Intrauterine growth re-

tardation,t mental re-tardation, hemor-rhage, t syndrome of stippled cartilage, mid-line facial depression, blindnesst§

Anticonvulsants Phenobarbital 15.8 13.8 10.8*§ 6.0 7.0 General malformations§

Valproate 0.3 0.3 0.2*t 0.2 0.2 Neural tube defectst

Phenytoin 2.6 2.3 2.4*t 2.2*§ 2.2*§ Syndrome of facial char-acteristics, t intrauterine growth retardation,§ mental retardation§

Antithyroid drugs Propylthiouracil 0.0 0.1 O.O*t O.I*t 0.1 *t Goitert Methimazole 0.0 0.1 O.O*t O.l*t 0.1 *t Goitert

Central nervous sys-tern drugs Lithium 0.3 0.3 0.3*§ 0.0 0.1 Cardiac malformations§

Diuretics Thiazides 14.7 13.3 9.4*§ 4.7*§ 9.8*§ Potassium and water im-

balance,§ jaundice,§ thrombocytopenia,§ ion imbalance§

Drugs acting on the reproductive system Androgens 0.2 0.3 O.O*t 0.0 0.0 Masculinization of the fe-

male fetust Diethylstilbesterol 0.2 0.0 O.O*t 0.0 0.0 Vaginal rumors,t uterine

and cervical adenosis, t male genital malfor-mationst

Miscellaneous Ergot alkaloids 3.1 2.6 l.O*t 0.3*t 0.3*t Oxytocic effectst

*Period of risk for fetal adverse drug reaction.

tKnown adverse drug reaction. :j:Does not include topical exposures.

§Suspected adverse drug reaction.

Volume 159 Number 5

(e.g., ritodrine), drugs that are only available as inject­

ables (e.g., streptomycin), drugs not used by our Mich­

igan population (e.g., antimalarials), drugs removed

from the Michigan Medicaid Formulary during the

study period (e.g., diazepam), and drugs used for di­

agnostic procedures (e.g., iodide 125 or 131). We did

not examine topical use of chloramphenicol, genta­

micin, the sulfonamides, and the tetracyclines because

there is some question regarding the extent of fetal

exposure from these medications when used as topical

preparations. In addition, exposures to synthetic pro­

gestins are not reported here. The Drug Product Information File (April 1986 ver­

sion)' was used to assign specific chemical ingredients

(as many as 12) to each drug product. Product ingre­

dients were used to calculate the number of women

exposed to any specific chemical (drug) per 1000

women in each 90-day period. For example, atropine

exposures in a given 90-day time period were based on

the number of women filling at least one Medicaid­

reimbursed prescription for any product containing

atropine in its top 12 ingredients during the 90-day

time window. Thus this rate reflects exposure to pure

atropine sulfate, as well as atropine that is contained in

cough and cold preparations, antispasmodics, seda­

tives, and other combination products.

Results

Table I shows exposure rates by 90-day periods for

the study drugs. Adrenergic drugs. Propranolol, a !)-antagonist,

showed a decline in use as pregnancy was recognized.

In contrast to propranolol, terbutaline, a 1)-agonist, in­

creased in use during the last trimester.

Antibiotics. Study mothers had no exposures to ka­

namycin. Our data show extremely low rates of use for

systemic chloramphenicol before pregnancy and no ex­

posures during pregnancy. Nitrofurantoin, a urinary

germicide, was frequently used by our study popula­

tion, and its use actually increased as pregnancy pro­

gressed. Exposure to the oral sulfonamides declined

with each trimester of pregnancy. Exposure ranged

from 16.7 women/ 1000 in the first trimester to 7.8

women/ 1000 in the third trimester. The tetracyclines

(demeclocycline, doxycycline, oxytetracycline, and tet­

racycline) also showed a decline in use as pregnancy

was recognized (Table I). The decline was comparable

for all members of the tetracycline family. Nevertheless,

3.2women/1000 received at least one prescription for

tetracycline during the third trimester of pregnancy.

Anticholinergics. Atropine and scopolamine showed

a decline in use as pregnancy progressed. These drugs

are found in a variet}'. of antispasmodics and gastro­

intestinal products, as well as "hidden" in cough and

Drugs and fetal adverse drug reactions 1175

cold preparations. Their use appeared to decrease in

the second and third trimesters of pregnancy. Meth­

scopolamine, also an anticholinergic, was infrequently used in this population.

Anticoagulants. There were very few exposures to

the anticoagulant, warfarin, and none to dicumarol in

these data. In the few participants who used the drug,

use stopped with the onset of pregnancy.

Anticonvulsants. These drugs accounted for a num­

ber of exposures to fetal adverse drug reaction­

associated drugs. The rate of exposure to phenobar­

bital diminished slightly during the second and third

trimesters of pregnancy. Valproate (valproic acid) was

rarely prescribed for this population. The rate of ex­

posure to phenytoin remained stable across the six

90-day time windows. We had no exposures to tri­

methadione and paramethadione in the 15 months pre­

ceding delivery in our study group. Antithyroids. In our data there are too few expo­

sures to propylthiouracil and methimazole to discern

any trend in use over the 15-month period. Central nervous system drugs. Lithium is the only

drug in this therapeutic category that we could evalu­

ate. Although we have only a small number of expo­

sures in our study group, use decreased in the second

and third trimesters of pregnancy. Cytotoxic drugs. There were no exposures to the

cytotoxic drugs in the 15 months preceding delivery in

our study group. The absence of exposures to these

drugs reflects the exclusion of women hospitalized in

the 15-month time window. Diuretics. Thiazide diuretics represent a large group

of adverse drug reaction-related drug exposures in

this population. Their use decreased with the onset of

pregnancy and diminished further still in the second

trimester (exposure ranged from 9.4 women/ 1000 in

the first trimester to 4.7 women/1000 in the second

trimester) but increased in the last trimester of preg­

nancy (9.8 women/ 1000). Drugs acting on the reproductive system. There

were no exposures to androgens in the 270 preceding

delivery in our study group, and there were no expo­

sures to diethylstilbesterol during pregnancy.

Miscellaneous drugs. Exposure to ergot-containing

products decreased after the onset of pregnancy

(range, 2.6 women/ 1000 before pregnancy to 1.0

women in the first trimester) and remained low during

the second and third trimesters.

Comment

Physicians who prescribe drugs for pregnant Mich­

igan Medicaid recipients appear to limit or reduce pre­

natal exposure to drugs known or suspected of being

associated with fetal adverse drug reactions. Our data

1176 Piper et al.

show that prescribers successfully avoided many of these drugs, and rates of exposure to most of the drugs decreased as pregnancy progressed. However, these data also provide evidence that a few medications were prescribed at a time during pregnancy when the risks could outweigh the benefits.

Antibiotics were a therapeutic category of particular concern. Use of nitrofurantoin increased with the du­ration of pregnancy, which reflects the increased fre­quency of urinary tract infections. More appropriate therapy for urinary tract infections exists in the form of selectively active antibiotics.4 Nitrofurantoin is ca­pable of inducing hemolytic anemia in patients defi­cient in glucose-6-phosphate dehydrogenase and in pa­tients whose red blood cells are deficient in glutathi­one.5 Since the red blood cells of newborns are normally deficient in glutathione, the use of nitrofurantoin could become hazardous to the fetus after the thirty-seventh week of gestation, and care should be exercised in prescribing it late in pregnancy. Use of oral sulfon­amides late in pregnancy should be avoided on similar grounds. Sulfonamides compete with bilirubin for binding to plasma albumin. Risk to the fetus occurs on delivery when free bilirubin can no longer be cleared by the placenta.6 Like nitrofurantoin, the sulfonamides should be used carefully late in pregnancy. Use of any of the tetracyclines in pregnancy is contraindicated be­cause of the well-established association with staining of deciduous teeth and other suspected risks.7 There are few indications for the outpatient use of tetracy­clines that would merit prescription during pregnancy.

The benefits of drug therapy clearly outweigh the risks in the medical management of some obstetric pa­tients. Both hypertension and epilepsy are examples of serious maternal conditions that if left untreated pose real hazards for the well-being of the mother and fetus. The best drug therapy for the management of hyper­tension in pregnancy has been and continues to be debated.8 Both propranolol and thiazide diuretics probably have roles in the judicious management of pregnant, long-term hypertensive patients.9 Similarly, pregnant epileptic patients need careful medical man­agement. For the epileptic woman who needs anticon­vulsant drugs, the dose should be as low as possible. w

The decision regarding how best to treat a pregnant patient should favor drug avoidance when the drug in question carries a risk and the benefit is slight or may be obtained from another drug. From this perspective, the use of thiazide diuretics for the treatment of phys­iologic edema of pregnancy or the use of phenobarbital as a hypnotic sedative is difficult to justify.

Important limitations of these data to be considered when interpreting this study include the limited de­mographic composition of the population, the possible nonrepresentativeness of medical care afforded them,

November 1988 Am J Obstet Gynecol

and our lack of basic information found in medical records. These and additional caveats have been dis­cussed elsewhere. 1

Drugs cited in this article as known or suspected of being associated with fetal adverse drug reactions are on the American Medical Association list either because they have been linked to an adverse fetal physiologic response or to a fetal malformation. The list was not intended to be comprehensive. However, it represents a current attempt to catalog the scope and type of fetal adverse drug reactions that may occur when drugs are used at various stages of pregnancy. Few of the asso­ciations have been demonstrated in controlled epide­miologic studies. Knowledge about risk factors for birth defects in particular has lagged behind other diseases. Because of the low incidence of each specific birth de­fect and the low prevalence of exposure to particular medications, it is difficult to detect risks associated with a given drug exposure in either case-control or cohort studies. For similar reasons, studies of secular trends in birth defects are of limited value. 11 As a result, most teratologic associations are based on case reports or anecdotal data.

Given the limited extent of information concerning the effects of drugs on the fetus, the data from our study are reassuring in that they suggest that medica­tions considered hazardous to the fetus are successfully avoided during the critical periods of pregnancy. How­ever, prescription of nitrofurantoin and the sulfon­amides in the last trimester and the tetracyclines throughout pregnancy appears excessive. Practitioners caring for pregnant women need to evaluate carefully the need for these drugs and consider when the risks may outweigh the benefits.

We thank Dr. Michelle Shaw and the staff of Health Information Design, Inc., for their help in data pro­cessing. We also acknowledge the constructive com­ments of Drs. Franz Rosa, Wayne Ray, and William Schaffner.

REFERENCES

1. Piper JM, Baum C, Kennedy DL. Prescription drug use prior to and during pregnancy in a Medicaid population. AMJ 0BSTET GYNECOL 1987;157:148-56.

2. American Medical Association, Department of Drugs, Di­vision of Drugs and Technology. Drug interactions and adverse drug reactions. In: Drug evaluations. 6th ed. Chi­cago: American Medical Association, 1986:29-52.

3. American Hospital Formulary Service. Drug Information 86. Bethesda: American Society of Hospital Pharmacists, 1986.

4. Sande MA, Mandell GL. Antimicrobial agents: general considerations. In: Gilman AG, Goodman LS, Rall TN, Murad F, eds. The pharmacological bases of therapeutics. 7th ed. New York: MacMillan Publishing Co, 1985:1066-94.

5. Powell RD, DeGowin RL, Alving AS. Nitrofurantoin­induced hemolysis. J Lab Clin Med 1963;62:1002-3.

6. Briggs GG, Bodendorfer TW, Freeman RK, Yaffe SJ.

Volume 159 Number 5

Drugs in pregnancy and lactation: A reference guide to fetal and neonatal risk. Baltimore: Williams & Wilkins, 1983:339-44.

7. Briggs GG, Bodendorfer TW, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: A reference guide to fetal and neonatal risk. Baltimore: Williams & Wilkins, 1983:344-8.

8. Collins R, Yusuf S, Peto R. Overview of randomized trials of diuretics in pregnancy. Br Med J l 985;294:358-60.

Drugs and fetal adverse drug reactions

9. Lees KR, Rubin PC. Prescribing in pregnancy: treatment of cardiovascular diseases. Br Med J l 987;294:358-60.

10. Hopkins A. Prescribing in pregnancy: epilepsy. Br Med J 1987;294:497-501.

11. Khoury MJ, Holtzman NA. On the ability of birth defects monitoring to detect new teratogens. Am J Epidemiol 1987; 126: 136-43.

Utilization of red blood cell transfusion in an obstetric setting

Allaudin A. Kamani, MD,' Graham H. McMorland, MB,' and Louis D. Wadsworth, MB• Vancouver, British Columbia, Canada

The transfusion experience for a 1-year period (September 1985 to August 1986) at a tertiary referral obstetric hospital was reviewed retrospectively. During the review period 7731 mothers were delivered and 6003 patients (83%) underwent type-and-screen procedures. A total of 1057 units of red blood cells were crossmatched, and 362 of these 1057 units were transfused to 100 parturient women so that the overall crossmatch /transfusion ratio was 2.9: 1. Five percent of transfused patients received 1 unit; 52% of patients received 2 units, 19% received 3 units and 24% received :;;.4 units of packed red blood cells. Major indications for transfusion were uterine atony, 27%; retained placenta, 17%; trauma, 17%, placenta previa, 7%; and abruptio placentae, 5%. In 12% of patients transfusions were done because of anemia. This study shows the value of audit and confirms that the type-and-screen procedure is an effective way of reducing the crossmatch/transfusion ratio without compromising patient care, even in high-risk patients. (AM J 0BSTET GYNECOL 1988;159:1177-81.)

Key words: Blood typing, blood transfusion, pregnancy

Historically, the ready availability of blood and blood components has resulted in the liberal use of blood transfusion. However, recently increased fear of transfusion-induced infection has led to a reconsider­ation of the indications for blood transfusion. The growing fear of transfusion-transmitted hepatitis, par­ticularly non-A, non-B hepatitis, and acquired immu­nodeficiency syndrome (AIDS) has resulted in a reluc­tance on the part of both patients to undergo and phy­sicians to order transfusion.

Recipients of blood and blood products account for 3% to 15% of all hepatitis cases' and 2% of all AIDS cases.2 There is a linear rise in the incidence of post­transfusion hepatitis with increasing volumes of trans­fusion up to 5 or 6 units. The incidence of hepatitis

From the Division of Obstetric Anaesthesia, Grace Hospital and Uni­versity of British Columbia,' and the Division of Hematopathol­ogyl lmmunohematology, Department of Pathology, British Colum­bia Children's Hospital.•

Received for publication January 29, 1988; revised May 25, 1988; accepted June 17, 1988.

Reprint requests: Allaudin A. Kamani, Department of Anaesthesia, Grace Hospital, 4490 Oak St., Vancouver, British Columbia, Can­ada V6H 2V5.

continues to increase with further transfusion volumes but at a less rapid rate. 1

Crossmatch of donor units for patients who are un­likely to require a transfusion has been shown to be an inefficient manner of utilization of blood and contrib­utes to blood shortage.3 Donor units, reserved for pa­tients who will never require them, are unavailable to

other patients and become outdated and are frequently wasted.

Unnecessary crossmatching procedures also contrib­ute to needless operating expenses for pathology lab­oratories. Ness et al.4 have reported an annual savings of $60,000 by using a type-and-screen procedure for obstetric patients who are unlikely to require transfu­sion. Many institutions have adopted a type-and-screen policy for their obstetric units.4.5

Few reports of blood transfusion practice in an ob­stetric setting are available. This study analyzes blood transfusion practice in a tertiary care maternity hospital performing 7500 to 8000 deliveries per year.

Material and methods

After approval was obtained from the University of British Columbia Clinical Screening Committee for Re-

1177