Methyltestosterone is a synthetic derivative of testosterone, the primary endogenous androgen. More than a dozen female infants were born to women treated with methyltestosterone during pregnancy, and they all had varying degrees of virilization of the external genitalia (c.l.i.toral enlargement and labioscrotal fusion) (Grumbach and Ducharme, 1960; Schardein, 1985). Paralleling other androgenic agents, c.l.i.toral enlargement may be induced by exposure to methyltestosterone throughout the postem-bryonic period, but labioscrotal fusion seems restricted to the period between the 8th and 13th weeks of gestation, and the degree of virilization appears dose related.

Successful surgical correction of the defects a.s.sociated with virilization is available.

s.e.xual maturation seems normal, while menarche in virilized girls seems close to the median, following a healthy course.

Female rats, dogs, and rabbits born to mothers treated with methyltestosterone in doses similar to those used medically had a dose-dependent increased frequency of virilization (Jost, 1947; Kawashima et al et al, 1975; Neumann and Junkmann, 1963; Shane et et al al., 1969) similar to humans.

Methyltestosterone and testosterone proprionate were a.s.sociated with c.l.i.toromegaly with or without fusion of the l.a.b.i.a minora. Hoffman and colleagues (1955) reported a masculinized fetus following administration to the mother of testosterone enanthate from the 4th to the 9th months. Grumbach and Ducharme (1960) summarized the human reports and concluded that masculinization of the female fetus was a significant risk with the use of these drugs.

NANDROLONE.

Nandrolone is an androgenic and anabolic steroid administered parenterally to treat metastatic breast cancer. Illicitly, it is used to increase muscle ma.s.s and enhance athletic General hormonal therapy General hormonal therapy 97.Table 4.2 Summary of endocrine drugs: TERIS and FDA risk estimates Drug Summary of endocrine drugs: TERIS and FDA risk estimates Drug Risk Risk rating Acetohexamide Undetermined C.

Bromocriptine Unlikely Cm Carbimazole Unlikely D.

Clorpropamide Undetermined Cm Conjugated estrogens None NA.

Cortisone Unlikely C*

Danazol Undetermined Xm Desmopressin Unlikely Bm Dexamethasone Minimal C*

Diethylstillbestrol Unknown Xm Ethinyl estradiol Unlikely Xm Ethionamide Undetermined Cm Fludrocortisone None NA.

Glyburide Unlikely Cm Hydrocortisone Unlikely C*

Insulin Unlikely B.

Iodine Unlikely D.

Levothyroxine None Am Liothyronine Unlikely Cm Medroxyprogesterone Unlikely Xm Megestrol Undetermined NA.

Methimazole Goiter: minimal to small D.

Cuts aplasia of scalp: minimal to small Embryopathy: minimal to small Methyltestosterone Undetermined NA.

Metyrapone Undetermined NA.

Nandrolone Undetermined NA.

Norethindrone None Xm Norethynodrel None Xm Norgestrel None Xm Oxymethalone Undetermined NA.

Pota.s.sium iodide Undetermined D.

Prednisone Oral clefts: small C*

Other congenital anomalies: unlikely Propranolol Undetermined C *

m Propylthiouracil Malformations: none D.

Goiter: small to moderate Stanozolol Undetermined NA.

Tolazamide Undetermined Cm Tolbutamide Unlikely Cm Vitamin D None A*

NA, not available.

Compiled from: Friedman et al., Obstet Gynecol 1990; 75 75: 594; Briggs et al., 2005; Friedman and Polifka, 2006.

98.Endocrine disorders, contraception, and hormone therapy during pregnancy performance. No studies have been published that have a.n.a.lyzed congenital anomalies among infants born to women treated with nandrolone during pregnancy. However, the strong androgenic action of this agent would be expected to cause virilization of the external genitalia in female fetuses. Intrauterine deaths were increased in frequency among rats born to mothers who were given up to twice the medically administered dose (Naqvi and Warren, 1971). performance. No studies have been published that have a.n.a.lyzed congenital anomalies among infants born to women treated with nandrolone during pregnancy. However, the strong androgenic action of this agent would be expected to cause virilization of the external genitalia in female fetuses. Intrauterine deaths were increased in frequency among rats born to mothers who were given up to twice the medically administered dose (Naqvi and Warren, 1971).

STANOZOLOL.

No animal or human studies of the use of stanozolol, an anabolic steroid, during pregnancy have been published. As with other androgenic steroids, it is reasonable to expect virilization of the external genitalia of a female fetus with maternal use of stanozolol.

OXYMETHALONE.

Another anabolic androgen is oxymethalone, which is used to treat anemia.

Oxymethalone possesses significant androgenic action, and would be expected to cause virilization of the external genitalia of female fetuses.

No human studies are published of oxymethalone exposure during pregnancy. Embryonic loss occurred frequently after injection of about four times the usual human dose of oxymethalone in rats in early pregnancy (Naqvi and Warren, 1971). Significant virilization was found in female rats born to mothers given large doses of oxymethalone during pregnancy (Naqvi and Warren, 1971), and embryonic death was increased in frequency in pregnant rats given several times the medically administered dose (Kawashima et al et al., 1977).

TIBOLONE.

Tibolone is an antiandrogenic compound used primarily to treat menopausal symptoms and osteoporosis. It is contraindicated for use during pregnancy. No studies are published of its use during pregnancy.

SPECIAL CONSIDERATIONS.

Morning after pill The morning after pill, formerly RU-486, contains mifepristone. Other formulations may sometimes contain levonorgestrel. These drugs act by preventing implantation, rather than by preventing conception. The effects of either of these drugs on a post-implantation pregnancy are unknown. Friedman and Polifka (2006) state that the risk of congenital anomalies is unknown following a failed attempt at abortion but 'this risk may be substantial because the process of attempted abortion may disrupt normal embryogenesis or fetal development'.

Breast cancer Aromatase inhibitors may be used to replace tamoxifen, because of fewer untoward effects, in the treatment of breast cancer. These agents include anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara). These drugs are contraindicated for use during pregnancy.

Key references 99.Hyperprolactinemia Excess pituitary prolactin secretion can lead to symptoms of galactorrhea, menstrual irregularities, and infertility. Menstrual cycle abnormalities caused by hyperprolactinemia include primary and secondary amenorrhea, oligomenorrhea, and luteal phase defects. Hyperprolactinemia may result from a variety of different causes (pituitary adenoma, hypothyroidism, various pharmacologic agents). Etiology should be established prior to beginning therapy. Primary therapy for idiopathic hyperprolactinemia, or a small pituitary adenoma, is an ergot alkaloid compound, such as bromocriptine. Many physicians prefer to use carbergone (Dostinex) to treat hyperprolactinoma instead of bromocriptine to avoid side effects. Dopamine agonist activity suppresses prolactin release from the pituitary. Surgical therapy is reserved for very large pituitary tumors or those unresponsive to medical treatment (see earlier sections on Prolactinoma and Bromocriptine).

Endometriosis Endometriosis is the presence of endometrial implants (glands and stroma) outside the endometrial cavity. Most frequently implanted sites are the pelvic viscera and peri-toneum. Various therapeutic regimens have been used to treat all stages of disease, including surgical ablation and extirpation, drug therapy, or both. Medical therapy for endometriosis includes hormonal regimens of oral contraceptives, danocrine, or gonadotropin-releasing hormone (GnRH) agonists. Pregnancy usually resolves endometriosis; therefore, treatment during pregnancy is probably not an issue.

SUMMARY.

Hormonal agents should usually not be administered during pregnancy. Inadvertent oral contraceptive use during embryogenesis is not a.s.sociated with an increased risk of congenital anomalies. Diethylstilbestrol, high doses of progestins derived from testosterone, and all androgens are strictly contraindicated during pregnancy A summary of endocrinedrugs and their risk estimates appears in Table 4.2.

Key references Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. A Reference Guide to Fetal and Neonatal Risk, 6th edn. Philadelphia: Lippincott Williams & Wilkins, 2005: 628.

Elliott CL, Read GF, Wallace EM. The pharmac.o.kinetics of oral and intramuscular administration of dexamethasone in late pregnancy. Acta Obstet Gynecol Scand 1996; 75 75: 213.

Kallen B. Drug treatment of rheumatic diseases during pregnancy. The teratogenicity of antirheumatic drugs what is the evidence? Scand J Rheumatol1998; 27 27 (Suppl. 107): 119. (Suppl. 107): 119.

Little BB. Pharmac.o.kinetics during pregnancy. Evidence-based maternal dose formulation.

Obstet Gynecol 1999; 93 93: 858.

100.Endocrine disorders, contraception, and hormone therapy during pregnancy MacCagnan P, Macedo CL, Kayath MJ, Nogueira RG, Abucham J. Conservative management of pituitary apoplexy. A prospective study. J Clin Endocrinol Metab 1995; MacCagnan P, Macedo CL, Kayath MJ, Nogueira RG, Abucham J. Conservative management of pituitary apoplexy. A prospective study. J Clin Endocrinol Metab 1995; 80 80: 2190.

Masiukiewicz US, Burrow GN. Hyperthyroidism in pregnancy. Diagnosis and treatment.

Thyroid 1999; 9 9: 647.

Ramin-Wilms L, Tseng AL, Wighardt S, Einarson TR, Koren G. Fetal genital effects of first trimester s.e.x hormone exposure. A meta-a.n.a.lysis. Obstet Gynecol 1995; 85 85: 141.

Rodriguez-Pinilla E, Martinez-Frias ML. Corticosteroids during pregnancy and oral clefts. A casecontrol study. Teratology 1998; 58 58: 2.

Shepard TH, Brent RL, Friedman JM et al. Update on new developments in the study of human teratogens. Teratology 2002; 65 65: 153.

Towner D, Kjos SL, Leung B et al. Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care 1995; 18 18: 1446.

Further references are available on the book's website at http://www.drugsandpregnancy.com 5.Antiasthma agents during pregnancy Treatment regimens 102.

Miscellaneous agents 110.

Beta-adrenergic agents 105.

Risk summary 111.

Antiinflammatory agents 107.

Special considerations 112.

Chromones 110.

Key references 113.

Asthma is an obstructive pulmonary disease characterized by reversible airway hyperre-activity to a variety of stimuli (Box 5.1). During an acute asthmatic attack, resistance of the airways is increased while forced expiratory flow and volume rates are decreased.

Asthma complicates approximately 1 percent of pregnancies (0.44 percent) pregnancy (deSwiet, 1977; Hernandez et al et al., 1980; National Asthma Education Program, 1993; Weinstein et al et al., 1979), and is increasing (ACOG, 1996). It is unclear whether or not pregnancy affects the severity of asthma. Among more than 1000 patients reported in nine investigations, 48 percent of gravid asthmatics experienced no change in clinical severity of their symptoms, 29 percent improved, and in 23 percent the disease worsened in severity (Gluck and Gluck, 1976). Other data indicate that approximately one-third of women with asthma experienced worsened disease severity during pregnancy (Cunningham, 1994; Schatz et al et al., 1988; Stenius-Aarniala et al et al., 1988). Most severe Box 5.1 Stimuli that exacerbate asthma Box 5.1 Stimuli that exacerbate asthma Allergies Poison ivy, pollen Household pets, odors Cold weather Drugs Acetyl salicylic acid Indomethacin Beta-blockers (Inderal) Emotional stress Environmental pollutants (dust, smog, air pollution) Exercise Occupational factors (asbestos, plaster) Respiratory tract infections (viral, bacterial) 102.

Antiasthma agents during pregnancy asthma occurred among 0.10.2 percent of pregnancies (Hernandez et al et al., 1980; Mabie et al et al., 1992), implying that 1020 percent of asthmatics have severe pregnancy-a.s.sociated sequelae. Adverse effects of asthma on pregnancy include a doubling in the rate of preterm labor, low birth weight, and preeclampsia (ACOG, 1996; Clark, 1993; Gordon et al et al., 1970; Kallen et al et al., 2000; Lehrer et al et al., 1993; Wendel et al et al., 1996). In contrast, no differences in the frequency of prematurity, low birth weight, and perinatal mortality were found among 182 pregnancies complicated by asthma compared to 364 nonasthmatic controls. Importantly, complications were increased among gravidas with severe uncontrolled asthma (Jana et al et al., 1995).

TREATMENT REGIMENS.

Most medications to treat asthma can be used safely during pregnancy. The objectives of asthma treatment are: (1) to decrease the frequency and number of asthmatic exacerbations; (2) to prevent status asthmaticus severe obstruction persisting for days or weeks; (3) to avoid respiratory failure; and (4) to prevent death (Greenberger and Patterson, 1983). Additional treatment objectives during pregnancy include: (1) maintenance of sufficient oxygenation to the fetus and (2) minimize fetal effects of the phar-macotherapy (ACOG, 1996).

These goals can be accomplished with available antiasthma agents at no added risk to either mother or fetus (Greenberger and Patterson, 1978; Turner et al et al., 1980). There are several categories of treatment modalities for asthma (Box 5.2): methylxanthines, beta-adrenergic agonists, antiinflammatory agents and antihistamines, decongestants and antibiotics, glucocorticoids, chromones, anticholinergics, immunotherapy, and miscellaneous others. One medical authority has indicated that inhaled corticosteroids are the most efficacious of antiasthma agents (Dombrowski, 1997).

Box 5.2 Medications utilized for the treatment of asthma during pregnancy pregnancy Antiinflammatory agents Antihistamines Beclomethasone Chlorpheniramine Cromolyn sodium Tripelennamine Prednisone Decongestants Beta-adrenergic agonists Oxymetazoline Albuterol Pseudoephedrine Epinephrine Cough medications Isoetharine Dextramethorphan Isoproterenol Guaifenesin Metaproterenol Terbutaline Other Antibiotics Methylxanthines Anticholinergics Aminophylline Theophylline Adapted in part from the National Asthma Education Program, 1993; ACOG, 1996.

Table 5.1 Pharmac.o.kinetics of xanthines and beta-agonists during pregnancy Agent Pharmac.o.kinetics of xanthines and beta-agonists during pregnancy Agent n EGA.

Route AUC.

V.

C.

C.

t Cl PPB.

Control groupa Authors d max SS.

1/2.

(weeks) Theophylline 10.1339 PO.

Yes (2) Gardner et al. (1987) Theophylline 5.2438 PO.

Yes (2) Frederiksen et al. (1986) Theophylline 8.1539 PO.

Yes (2) Carter et al. (1986) Caffeine 34.1138 PO.