Symptoms are transient and normally resolve over time (Landing and Kamos.h.i.ta, 1970).

Neonatal hyperparathyroidism secondary to low maternal calcium (Loughhead et al et al., 1990) is a.s.sociated with neonatal skeletal disease and bone demineralization.

Medications for hypoparathyroidism VITAMIN D.

Vitamin D comes in a variety of commercially available forms which incur a similar metabolic fate, thus having a very similar effect on the mother and fetus. Along with calcium, vitamin D is used to treat hypoparathyroidism in both the pregnant and nonpregnant state. Pregnant patients treated for hypoparathyroidism with vitamin D apparently do not have an increased incidence of embryotoxic effects or fetal malformations (Goodenday and Gordon, 1971a,b; Sadeghi-Nejad et al et al., 1980; Wright et al et al., 1969), even high doses of 1,25 dihydroxy vitamin D were used (Marx et al et al., 1980).

PITUITARY GLAND.

Maternal pituitary function Adenohypophysis, or the anterior lobe of the pituitary gland, doubles or triples in size during normal pregnancy due to hypertrophy and hyperplasia of the lactotrophs (Goluboff and Ezrin, 1969). Physiologic changes that occur during pregnancy are outlined in Box 4.2.

Certain abnormalities in pituitary function are a.s.sociated with infertility (e.g., hyperprolactinemia, Cushing's disease), but with proper therapy fertility may be restored.

Pituitary disorders that may complicate pregnancy include: enlargement of a prolactinoma, acromegaly, Cushing's disease, and diabetes insipidus.

Prolactinoma The pituitary gland enlarges during pregnancy and the presence of prolactinoma and its enlargement in pregnant women is a concern. A review of 16 investigations and 246 patients revealed a low incidence of symptomatic microadenoma (less than 10 mm in size) enlargement of 1.6 percent, and an incidence of symptomatic macroadenoma (more than 10 mm in size) enlargement of 15.5 percent during pregnancy (Gemzell and w.a.n.g, 1979).

Pituitary gland 85.Box 4.2 Pituitary gland function changes during pregnancy *

Low basal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, blunted gonadotropin response to gonadotrophin-releasing hormone (GnRH) infusion (Jeppsson et al., 1977; Reyes et al., 1976) secondary to a negative feedback inhibition from elevated levels of estrogen and progesterone.

Low basal growth hormone (GH) levels and blunted response to insulin-induced hypoglycemia and arginine infusion (Spellacy et al., 1970; Tyson et al., 1969).

Normal to low adrenocorticotropic hormone (ACTH) levels, that rise markedly during labor and delivery (Beck et al., 1968; Carr et al., 1981).

Normal levels of thyroid-stimulating hormone (TSH) with a similar response to thyroid-releasing hormone (TRH) stimulation, as in the nonpregnant state (Fisher, 1983a).

Ten- to 20-fold increase in serum prolactin levels (Rigg et al., 1977; Tyson et al., 1972), secondary to marked hypertrophy and hyperplasia of the lactotrophs.

Neurophysins are intraneuronal protein carriers for oxytocin and vasopressin that are present in the neurohypophysis, and their plasma concentrations may be elevated during pregnancy (Robinson et al., 1973). However, maternal plasma oxytocin and vasopressin levels are low and do not vary throughout gestation (Fisher, 1983b).

MEDICATIONS FOR PROLACTINOMAS BROMOCRIPTINE (PARLODEL) Bromocriptine is a dopamine agonist and ergot alkaloid known to have prolactin-lowering activity, and is commonly used to treat hyperprolactinemia a.s.sociated with infertility. Bromocriptine is a dopamine agonist and ergot alkaloid known to have prolactin-lowering activity, and is commonly used to treat hyperprolactinemia a.s.sociated with infertility.

Bromocriptine crosses the placenta and is a.s.sociated with fetal hypoprolactinemia (del Pozo et al et al., 1977, 1980). Effects on fetal neuroendocrine development are unknown.

Outcomes of 1410 pregnancies in 1135 women who received bromocriptine in the early weeks of pregnancy was a.s.sociated with a higher frequency of spontaneous abortion (11.1 percent), but a congenital anomaly rate (3.5 percent) similar to that observed in the general population (Turkalj et al et al., 1982). Children ( n n = 212) from this study who were followed for up to 5 years were normal on mental and physical development a.s.sessments. Similar findings with fewer patients were reported by other investigators (Ca.n.a.les = 212) from this study who were followed for up to 5 years were normal on mental and physical development a.s.sessments. Similar findings with fewer patients were reported by other investigators (Ca.n.a.les et al et al., 1981; Hammond et al et al., 1983; Konopka et al et al., 1983). Evidence indicates that there is no increased risk to the fetuses of women treated with bromocriptine during pregnancy, and if symptomatic tumor enlargement should occur, bromocriptine therapy is preferred to surgical intervention (MacCagnan et al et al., 1995).

Acromegaly Acromegaly is caused by the overproduction of growth hormone (GH) resulting in the over-growth and thickening of bones and soft tissues. The most common cause is a pituitary adenoma, and therapy often consists of surgery, radiation, medical therapy, or some combination. Menstrual irregularity (amenorrhea) is frequent and fecundity is low in acromegalic women. Acromegaly during pregnancy is extremely rare (van der Spuy and Jacobs, 1984).

Symptomatic tumor expansion may arise during gestation as a result of increased maternal estrogen levels (Yap et al et al., 1990). Optimal management is conservative and definitive therapy is preferably postponed until after delivery. The human placenta secretes its specific GH 86.Endocrine disorders, contraception, and hormone therapy during pregnancy variant in increasing amounts up to delivery (Frankenne variant in increasing amounts up to delivery (Frankenne et al et al., 1987). A recent study of GH secretory patterns in two pregnant acromegalic women suggests that the increased insulin-like growth factor (IGF-I) level present in late pregnancy is not pituitary-GH-dependent (Beckers et al et al., 1990). In addition, there is no evidence that excessive maternal GH crosses the placenta to any significant degree. Bromocriptine is used to treat acromegaly.

Cushing's syndrome and Cushing's disease Cushing's syndrome is characterized by increased cortisol secretion, whether the etiology is from overproduction of corticotropin-releasing factor (CRF), excessive pituitary adrenocorticotrophic hormone (ACTH) stimulating the adrenals (Cushing's disease), adrenal hyperplasia/adenoma, ectopic sources of ACTH or cortisol, or excessive glucocorticoid therapy. Hence, Cushing's disease refers simply to pituitary-dependent Cushing's syndrome. The etiology of Cushing's syndrome is usually a pituitary adenoma or hyperplasia, and during pregnancy the frequency of primary adrenal lesions is much higher (Gormley et al et al., 1982). Pregnancy is very uncommon among women with Cushing's syndrome because most such patients are amenorrheic (Gormley et al et al., 1982; Grimes et al et al., 1973).

The diagnosis may be difficult because many of the symptoms (hypertension, weight gain, fatigue, striae, and increased pigmentation) are common in normal pregnancies. Thinning of the skin, spontaneous bruising and muscle weakness are symptoms more specific of Cushing's syndrome. Hirsutism and acne are common in pregnant women with Cushing's syndrome because of increased adrenal androgens (Grimes et al et al., 1973). Pregnancy outcome is extremely poor, with approximately 50 percent of gestations ending in spontaneous abortion, premature delivery or stillbirth (Aaron et al et al., 1990; Gormley et al et al., 1982; Grimes et al et al., 1973). Treatment depends on the etiology of the disorder and the stage of pregnancy at diagnosis. Pituitary and adrenal adenomas should be removed surgically (van der Spuy and Jacobs, 1984). In the first trimester, pregnancy termination may be considered, especially if adrenal carcinoma is suspected. In late gestation, medical therapy with metyrapone may be considered until delivery of the infant, after which definitive surgery may be undertaken.

METYRAPONE FOR CUSHING'S DISEASE Metyrapone is a 11-hydroxylase inhibitor that causes a decrease in cortisol production if given to normal subjects. This is followed by a subsequent rise of desoxycortisol, the immediate precursor of cortisol. Animal studies have shown that metyrapone does cross the placenta (Baram and Schultz, 1990). Metyrapone has been used infrequently during late pregnancy as medical therapy for Cushing's disease to delay surgical intervention until after delivery (Connell et al et al., 1985b; Gormley et al et al., 1982). In summary, the ideal therapy for Cushing's disease in pregnancy is surgical intervention. However, surgery should be postponed until fetal maturity.

Diabetes insipidus Diabetes insipidus (DI) in pregnancy occurs in approximately three per 100 000 pregnancies (Hime and Richardson, 1978). Hypothalamic or neurogenic diabetes insipidus is a disorder caused by deficient arginine vasopressin (AVP) release from the posterior Adrenal gland Adrenal gland 87.pituitary in response to normal physiologic stimuli. This results in low blood levels of AVP and impaired renal conservation of water. Clinical characteristics are polyuria, excessive thirst, polydipsia, and low urinary specific gravity. The etiology is idiopathic, inherited as autosomal dominant, or secondary to trauma or tumor. Patients with diabetes insipidus who are successfully treated do not have impaired fertility, and fetal outcome is not adversely affected by the disease (Hime and Richardson, 1978; Jouppila and Vuopala, 1971). Therapy consists of hormonal replacement, and the drug of choice in pregnancy is DDAVP (1-deamino-8-arginine vasopressin) administered as a nasal spray.

Other modes of therapy in the patient with partial diabetes insipidus are not recommended for use during pregnancy (chlorpropamide, clofibrate, and carbamazepine).

Note that DDAVP is not effective for the treatment of nephrogenic diabetes insipidus.

ADRENAL GLAND.

Maternal adrenal function A number of changes occur in maternal adrenal function during pregnancy. The rise in estrogen during gestation causes an increase in the liver production of cortisol-binding globulin (CBG), and thus a rise in plasma cortisol levels. Plasma ACTH concentrations are low (Carr et al et al., 1981). There is a two- to three-fold increase in plasma-unbound cortisol coupled with a two-fold increase in free cortisol excretion (Clerico et al et al., 1980; Nolten et al et al., 1980). In spite of the elevation of free cortisol in pregnancy, clinical evidence of cortisol hypersecretion is not seen (Gibson and Tulchinsky, 1980). Increased renin activity is a.s.sociated with elevated aldosterone levels, although this does not appear to be clinically significant (Smeaton et al et al., 1977). Certain adrenal disorders that may complicate pregnancy include Addison's disease, Cushing's syndrome, and congenital adrenal hyperplasia. Cushing's syndrome was discussed in the previous section on the pituitary gland.

Maternal adrenal insufficiency (Addison's disease) Adrenal corticosteroid insufficiency may be caused by insufficient ACTH secretion by the pituitary, insufficient adrenal secretion of corticosteroids, or inadequate steroid replacement. Atrophy of the adrenals secondary to autoimmune disease accounts for 75 percent of the cases. The diagnosis of Addison's disease in pregnancy can be difficult because the signs and symptoms (weakness, fatigue, anorexia, nervousness, increased skin pigmentation) are very similar to those occurring in a normal pregnancy. This disorder may take a chronic, indolent course or progress into a true medical emergency characterized by an 'Addisonian crisis' severe nausea and vomiting, diarrhea, abdominal pain, and hypotension. Pregnancy may exacerbate the course of Addison's disease; however, the spontaneous abortion rate, prematurity rate, and neonatal outcome are apparently not affected by the disease (Brent, 1950; Satterfield and Williamson, 1976).

Chronic adrenal insufficiency requires adequate adrenal replacement in the form of cortisone acetate or prednisone and 9-alpha-fluoro-hydrocortisone. During labor, delivery, and the first few days postpartum, the mother should be monitored closely, ensuring a good state of hydration with normal saline and adequate cortisol hemisuccinate 88 88 Endocrine disorders, contraception, and hormone therapy during pregnancy replacement. It is common for women with adrenal insufficiency to be diagnosed for the first time during the puerperium when they develop adrenal crisis (Brent, 1950). replacement. It is common for women with adrenal insufficiency to be diagnosed for the first time during the puerperium when they develop adrenal crisis (Brent, 1950).

Treatment involves replacement steroids during an Addisonian crisis including cortisol hemisuccinate (Solu-Cortef), with fluid replacement as isotonic saline, and glucose administration.

Medications for Addison's disease CORTISONE ACETATE.

Cortisone is a glucocorticoid normally excreted by the adrenal gland. It is used for replacement therapy and to treat allergic and inflammatory diseases. The Collaborative Perinatal Project included 34 pregnancies exposed during the first trimester to cortisone, and the frequency of congenital anomalies among the exposed pregnancies was no greater than expected (Heinonen et al et al., 1977a).

Prednisone and prednisolone Prednisone and prednisolone are synthetic glucocorticoids. Prednisone is biologically inert but is metabolized in the liver to prednisolone, a biologically active compound.

Prednisone and prednisolone are used for replacement therapy and to treat a variety of allergic and inflammatory conditions. Among infants born to 43 and 204 women who had been treated with prednisone/prednisolone during the first trimester of pregnancy, the frequency of malformation was not increased (Heinonen et al et al., 1977b; Kallen, 1998). Perinatal death does not appear to be excessively frequent in most series of infants born to women treated with prednisone or prednisolone, but the incidence of fetal growth r.e.t.a.r.dation may be increased (Reinisch et al et al., 1978). No such effect was apparent in two smaller studies, one of which also involved women treated throughout pregnancy (Lee et al et al., 1982; Walsh and Clark, 1967). Newborn infants of women who take prednisone throughout pregnancy usually have normal adrenocortical reserves and no symptoms of adrenal suppression (Arad and Landau, 1984). Dose-related fetal growth r.e.t.a.r.dation, cleft palate, genital anomalies, and behavioral alterations occur in the offspring of mice treated in pregnancy with prednisone or prednisolone in doses within or above the human therapeutic range (Ballard et al et al., 1977; Gandelman and Rosenthal, 1981; Pinsky and DiGeorge, 1965; Reinisch et al et al., 1978). Increased frequencies of cleft palate are also observed among the offspring of pregnant hamsters treated during pregnancy with prednisolone in doses 80240 times that used in humans (Shah and Kilistoff, 1976).

Corticosteroids in general In one study of 631 whose mothers used therapeutic corticosteroids during the first trimester, the risk of non-syndromic cleft palate was increased more than sixfold (Rodriguez-Pinilla and Martinez-Frias, 1998). However, given the prevalence of the use of these drugs and of cleft palate, the absolute risk is probably less than 1 percent in pregnancies exposed to corticosteroids in the first trimester (Shepard et al et al., 2002), if the a.s.sociation is causal.

Contraception 89.FLUDROCORTISONE.

No epidemiologic studies have been reported regarding malformations in women treated with this drug during pregnancy.

CORTISOL HEMISUCCINATE.

No epidemiologic studies have been reported regarding malformations in women treated with this drug during pregnancy.

CONGENITAL ADRENAL HYPERPLASIA.

Five princ.i.p.al enzymatic steps are required for the conversion of cholesterol to cortisol in the adrenal gland. An inherited defect in any one of these enzymes may result in congenital adrenal hyperplasia (CAH). In over 90 percent of cases, the deficient enzyme is 21-hydroxylase (New et al et al., 1983). This enzyme is necessary for the conversion of 17-hydroxyprogesterone to 11-desoxycortisol, and a deficiency results in a decrease in cortisol, and a compensatory rise in ACTH, followed by adrenal hyperplasia with elevated cortisol precursors and adrenal androgens. Cla.s.sical CAH is the most severe form; it is characterized by a salt-wasting crisis soon after birth owing to impaired aldosterone production. Genital virilization is common in female infants, and both s.e.xes manifest electrolyte imbalance and hypotension that can be life-threatening if not promptly treated by steroid hormone replacement. Simple virilizing CAH is a less severe form characterized by female virilization, but without the salt-wasting component. Adult-onset CAH may not manifest until adolescence, with (in females) oligomenorrhea, progressive hirsutism, and relatively short stature. Chorionic villus sampling, using DNA probes for HCA genes, when compared to parental chromosomes, will allow an earlier diagnosis. Currently, all known heterozygotes are treated with high-dose glucocorticoids until chorionic villus sampling occurs. If a male fetus is present, treatment stops. If a female fetus is present, treatment is continued because virilization of affected females can be prevented. Once DNA/HLA results are known, medication is discontinued only if the female fetus is unaffected.

Medications used to treat congenital adrenal hyperplasia include prednisone, fludrocortisone (see the section on Medications for Addison's disease), and dexamethasone.

CONTRACEPTION.

Oral contraceptives A wide variety of oral contraceptive formulations are available, including estrogen/progestin combinations and progestational agents that suppress ovulation and implantation.

If exposure to oral contraceptives during embryogenesis increases the risk of birth defects, the increase is small compared to the risk of malformations in the general population (3.55 percent). Congenital anomalies were not increased in frequency among more than 500 infants born to women who took oral contraceptives during the first trimester (Harlap and Eldor, 1980; Heinonen et al et al., 1977b; Nora et al et al., 1978; Vessey et et al al., 1979). A slight increase of congenital anomalies was a.s.sociated with use of oral contraceptives in the first trimester in several studies, but it is generally accepted that the risk is not real, or extremely small.

90.Endocrine disorders, contraception, and hormone therapy during pregnancy Norplant Norplant The Norplant system is a unique subdermal contraceptive system providing 5 years of continuous birth control.

No epidemiologic studies have been published regarding malformations in the offspring of women who became pregnant with a Norplant system in place. Levonorgestrel is the progestin component in many oral contraceptive preparations.

Intrauterine device Pregnancy with an intrauterine device (IUD) in place is a.s.sociated with increased incidence of spontaneous abortion, approximately threefold greater than among women without an IUD (Lewit, 1970; Tatum et al et al., 1976; Vessey et al et al., 1974). When the device is removed or expelled spontaneously, spontaneous abortion is reduced to approximately 2030 percent, which is much closer to the rates of miscarriage in the general population (Alvior, 1973; Tatum et al et al., 1976). Several studies of women who had copper-containing IUDs in place during pregnancy have found no increase in the rate of abnormalities over the expected rate in the general population (Guillebaud, 1981; Poland, 1970; Tatum et et al al., 1976). The frequency of congenital anomalies in the offspring of women who had progesterone-containing IUDs in place during pregnancy has not been published.

NEW INTRAUTERINE DEVICES.

New IUD devices available ease insertion and removal, and reduce pain, bleeding, and expulsion rates. They include the intrauterine system (IUS) that gradually releases levono-gestrel (Mirena), or progesterone (Progesterasert). Rather than T-shaped copper IUDs of the 1980s and 1990s, the frameless IUD devices (e.g. GyneFix) are copper cylinders secured together with a string.

Spermicidal agents (nonoxynols) Spermicidal intrav.a.g.i.n.al sponges, foams, creams, and suppositories contain nonoxynols, surfactants that are extremely toxic to sperm. The risk of congenital anomalies was not increased in frequency among more than 1200 infants whose mothers used nonoxynol spermicides during embryogenesis (Heinonen et al et al., 1977a; Mills et al et al., 1982). Similar results were found in large studies of the frequency of congenital anomalies among infants whose mothers used a multiagent spermicide that contained nonoxynol (Huggins et al et al., 1982; Polednak et al et al., 1982; Strobino et al et al., 1988). The frequency of heterogenous anomalies (chromosomal abnormalities, hypospadias, limb reduction defects, neoplasms) was statistically increased in more than 700 infants born to women who had used any v.a.g.i.n.al spermicide within 10 months of conception (Jick et al et al., 1981). However, method-ological flaws in that study (Cordero and Layde, 1983), combined with simple data errors in cla.s.sification of spermicidal exposures in the cases, cast doubt on the meaning of this study. It is now widely accepted that neither nonoxynols nor other spermicides are a.s.sociated with an increased risk for chromosomal abnormalities and congenital anomalies (Bracken, 1985). A casecontrol study of the use of topical contraceptives among mothers of infants with chromosomal abnormalities or limb reduction defects found no General hormonal therapy General hormonal therapy 91.difference in the frequency of spermicide use around the time of conception between the case and the normal control groups (Cordero and Layde, 1983).

However, it was spermicides that sp.a.w.ned the term 'litogen.' Despite overwhelming scientific data that indicate spermicides are harmless, more than $3 million were awarded to parents of an infant born with multiple congenital anomalies whose mother had used nonoxynol during pregnancy.

Depo-Provera This agent is discussed under Progestational agents (p. 93).

INFERTILITY.

Ovulation induction agents CLOMIPHENE CITRATE (CLOMID).

This drug has nonsteroidal estrogenic and antiestrogenic activity, and is given orally to stimulate ovulation. It is sometimes inadvertently given in an unrecognized early pregnancy. Women using clomiphene should be cautioned that pregnancy is to be excluded before each new course of the drug.

Malformations were not increased in frequency among 1500 infants of women who had clomiphene preconceptionally (Barrat and Leger, 1979; Harlap, 1976; Kurachi et et al al., 1983). Multiple casecontrol studies of neural tube defects failed to find a significant a.s.sociation with artificial induction of ovulation and risk of a congenital anomaly (Cornel et al et al., 1989; Cuckle and Wald, 1989; Czeizel, 1989). In a well-designed, casecontrol study, the frequency of clomiphene usage was not increased among more than 500 women who delivered children with a neural tube defect compared with a similar number of normal controls (Mills et al et al., 1990). In summary, clomiphene is not a.s.sociated with an increased risk of congenital anomalies.

HUMAN MENOPAUSAL GONADOTROPINS (PERGONAL, METRODIN).

Pergonal is an extract of urine from postmenopausal women; it contains follicle-stimulating hormone (FSH) and luteinizing hormone (LH). It is administered by intramuscular injection and is used to stimulate multiple ovarian follicular development in ovulation induction cycles. Metrodin is a purified extract of urine from postmenopausal women and primarily contains FSH. It is similar to Pergonal in its administration protocols. No epidemiologic studies have been reported regarding malformations in the offspring of women exposed to Pergonal or Metrodin before or during pregnancy. However, the risk does not appear to be high, although a very small risk cannot be excluded.

GONADOTROPIN-RELEASING HORMONE AGONISTS.

Gonadotropin-releasing hormone (GnRH) agonists are widely used in clinical gynecologic practice for the treatment of endometriosis and uterine leiomyomas. Leuprolide acetate (Lup.r.o.n) is an agent that is frequently used for these conditions. Although no epidemiological studies are published of infants born following Lupon therapy, it is 92 92 Endocrine disorders, contraception, and hormone therapy during pregnancy unlikely that the risk of congenital anomalies is high following exposure to this drug during pregnancy (Friedman and Polifka, 2006). Chronic administration of the agonists downregulates the pituitary gonadotropin receptors, thereby suppressing release of LH unlikely that the risk of congenital anomalies is high following exposure to this drug during pregnancy (Friedman and Polifka, 2006). Chronic administration of the agonists downregulates the pituitary gonadotropin receptors, thereby suppressing release of LH and FSH and leading to a hypoestrogenic state. The likelihood of pregnancy occurring while a woman is given GnRH agonists is extremely low. However, GnRH agonists may also be used prior to HMG therapy in infertile women undergoing in vitro in vitro fertilization cycles. Typically, administration is begun in the luteal phase of the cycle, when a patient may be in the early stage of a pregnancy. No epidemiologic studies are published on the risk malformations in the offspring of women treated with this drug during pregnancy. fertilization cycles. Typically, administration is begun in the luteal phase of the cycle, when a patient may be in the early stage of a pregnancy. No epidemiologic studies are published on the risk malformations in the offspring of women treated with this drug during pregnancy.

GENERAL HORMONAL THERAPY.

Estrogens ETHINYL ESTRADIOL.

Ethinyl estradiol is a synthetic estrogen used to treat menopausal symptoms and menstrual disorders. This drug and progestin are common combinations in oral contraception. Congenital anomalies were not increased in frequency among infants born to women given ethinyl estradiol during embryogenesis or at any time during pregnancy (Heinonen et al et al., 1977a). Results from two other studies of ethinyl estradiol use during pregnancy showed that it was not a.s.sociated with an increased risk of congenital anomalies (Kullander and Kallen, 1976; Spira et al et al., 1972). Congenital anomalies were not increased in frequency in teratology studies of three species of nonhuman primates given large doses of ethinyl estradiol during pregnancy (Hendrickx et al et al., 1987). An increased frequency of intrauterine deaths was observed at doses that were also maternally lethal in one monkey species studied. Miscarriages occurred more frequently among monkeys given approximately 100 times the amount of ethinyl estradiol included in oral contraceptive dose regimens (Prahalada and Hendrickx, 1983). In rodent teratology studies, no increase in the frequency of congenital anomalies after embryonic treatment was found, but early intrauterine deaths were increased in frequency at the highest doses (Chemnitius et al et al., 1979; Yasuda et al et al., 1981).

CONJUGATED ESTROGENS.

Conjugated estrogens are a mixture of estrogens obtained from natural sources, and are used to treat menopausal symptoms, osteoporosis, and hypothalamic amenorrhea. They are not indicated for use during pregnancy. Among 614 infants born to women who used estrogenic compounds during gestation, an increase in certain congenital anomalies was found cardiovascular, eye and ear defects, and Down's syndrome (Heinonen et al et al., 1977b). However, this a.s.sociation was reevaluated in another report, and the link between estrogens and cardiac malformations was not borne out (Wiseman and Dodds-Smith, 1984).

DIETHYLSTILBESTROL.

This nonsteroidal synthetic estrogen, approved by the Food and Drug Administration in 1942 for use in pregnancy to prevent miscarriages, is strongly a.s.sociated with an General hormonal therapy General hormonal therapy 93.increased frequency of clear-cell adenocarcinoma of the v.a.g.i.n.a and cervix among daughters of women treated with diethylstilbestrol (DES) early in pregnancy. Between 500 000 and two million pregnant women took this drug. In a registry including more than 400 cases of clear-cell adenocarcinoma of the v.a.g.i.n.a and cervix diagnosed in the USA since 1971, no less than 65 percent of patients' mothers took DES in early pregnancy (Herbst, 1981). Of the women who took DES early in pregnancy, 80 percent had taken it during the 12 weeks prior to conception. The malignancy was diagnosed among females 730 years old, with a median age of 19 years. Estimates suggest that 0.141.4 per 1000 daughters of women treated with diethylstilbestrol during pregnancy will develop clear-cell adenocarcinoma of the v.a.g.i.n.a or cervix by the age of 24.

Nonmalignant abnormalities, especially adenosis, are common among the daughters of pregnant women who were treated with diethylstilbestrol. Gross structural abnormalities of the cervix or v.a.g.i.n.a are identified in about one quarter and abnormalities of the v.a.g.i.n.al epithelium in one-third to one-half of women whose mothers took diethylstilbestrol during gestation (Bibbo, 1979; Herbst et al et al., 1978; Robboy et al et al., 1984; Stillman, 1982). T-shaped uterus, constricting bands of the uterine cavity, uterine hypoplasia or paraovarian cysts also occur with increased frequency among females exposed in utero in utero (Kaufman (Kaufman et al et al., 1984). Among males exposed to DES in utero in utero, epididymal cysts, hypoplastic testes, and cryptorchidism are reported with increased frequency (Stillman, 1982). Preterm delivery, spontaneous abortions, and ectopic pregnancy occurred with increased frequency in females whose mothers took diethylstilbestrol during gestation (Barnes et al et al., 1980; Herbst, 1981).

Progestational agents PROGESTINS: a.n.a.lOGS OF PROGESTERONE.

Progestins are a group of chemically related hormones with similar actions.

Progesterone is the only natural progestin and is not well absorbed by the oral route unless given in micronized form. Synthetic progestins structurally related to progesterone are more commonly used. Low-dose progestins are used for contraception with an estrogen, and are used in the therapy of menstrual disorders at higher doses. In the 1960s and 1970s much higher doses of progesterones were used for oral contraception (Schardein, 1985), and are currently used to treat threatened abortion. In a review, female pseudohermaphroditism, including various degrees of c.l.i.toral hypertrophy with or without labioscrotal fusion, was reported in several-hundred children born to women treated with progesterone a.n.a.logs in high doses during early pregnancy (Schardein, 1980, 1985). The frequency of occurrence of this anomaly varies with different progestins. Fewer than 100 cases of male pseudohermaphroditism have been reported, and the anomaly is usually isolated hypospadias (Aarskog, 1979; Mau, 1981; Schardein, 1985). Exposure to progestational agents during embryogenesis, therefore, seems not to increase substantially the risk for nongenital congenital anomalies in infants born to treated women.

NORETHINDRONE.

Norethindrone is a synthetic progestational agent derived from 19-nortesterone, which is used as an oral contraceptive and to treat menstrual disorders. Among more than 100 94.Endocrine disorders, contraception, and hormone therapy during pregnancy infants born to women who took norethindrone during the first trimester, congenital anomalies were not increased in frequency, or in more than 100 infants whose mothers took this drug after the first trimester (Heinonen infants born to women who took norethindrone during the first trimester, congenital anomalies were not increased in frequency, or in more than 100 infants whose mothers took this drug after the first trimester (Heinonen et al et al., 1977a). Two casecontrol studies of 365 infants with congenital anomalies yielded similar results (Kullander and Kallen, 1976; Spira et al et al., 1972). Several cases were reported in which use of norethindrone during pregnancy, at doses that were much greater than those used in contemporary practice, was a.s.sociated with masculinization of the external female genitalia (c.l.i.toral hypertrophy with or without labioscrotal fusion), but internal genitalia and subsequent p.u.b.ertal development were normal (Schardein, 1980, 1985). The genital anomalies observed include various degrees of masculinization (Wilkins et al et al., 1958). c.l.i.toral hypertrophy may occur in exposures any time after the 8th embryonic week, but labioscrotal fusion is limited to exposure during the 8th to 13th embryonic weeks. The risk for pseudohermaphroditism among female infants born to women who took norethindrone during pregnancy is probably less than 1 percent (Bongiovanni and McPadden, 1960; Ishizuka et al et al., 1962). No increased risk of fetal s.e.xual malformation was reported in a meta-a.n.a.lysis of published reports of women exposed to s.e.x hormones after conception (Ramin-Wilms et al et al., 1995). Masculinized external female genitalia were observed in several species of experimental animals, including nonhuman primates, following maternal treatment with high doses of norethindrone during pregnancy (Hendrickx et al et al., 1983; Schardein, 1985). Nongenital malformations were not increased in frequency among three species of nonhuman primates given up to 100 times the oral contraceptive dose of norethindrone during pregnancy in combination with ethinyl estradiol (Hendrickx et al et al., 1987; Prahalada and Hendrickx, 1983).

Contemporary low-dose therapy with norethindrone is not a risk factor for genital malformations, and probably poses no increased risk for congenital anomalies in general.

NORETHYNODREL.

Norethynodrel is a synthetic progestational agent that is a component of oral contraceptive preparations and is used to treat menstrual disorders. Congenital anomalies were not increased in frequency among more than 150 infants born to women who took norethynodrel during the first trimester, or among more than 150 women who took the drug after the first trimester (Heinonen et al et al., 1977a). Virilization of female fetuses has not been reported in the human; however, female rat fetuses born to mothers that received several-hundred times the human contraceptive dose had masculinized external genitalia (Kawashima et al et al., 1977). Treatment of human pregnancy within the low-dose range presently employed for contraception and for menstrual irregularity will not cause female virilization.

NORGESTREL.

This synthetic progestational agent is used with estrogen compounds in oral contraceptives and for menstrual disorders. There are no controlled studies of congenital anomalies among infants born to women who used norgestrel during pregnancy. Although no human reports have a.s.sociated the use of norgestrel during pregnancy with masculinization of external female genitalia, large doses administered in the latter two-thirds of pregnancy would be expected to produce virilization based upon clinical experience with other closely related compounds. The frequency of congenital anomalies was not General hormonal therapy General hormonal therapy 95.increased among mouse and rabbit litters born to females treated with very large doses of norgestrel during pregnancy (Heinecke and Kohler, 1983; Klaus, 1983).

MEDROXYPROGESTERONE ACETATE.

Medroxyprogesterone is the most widely used oral and parenteral progestational agent.

It is used to treat menstrual disorders and as an injectable contraceptive. Major congenital anomalies were not increased in frequency among almost 500 infants born to women treated with medroxyprogesterone during the first trimester, or among 217 infants whose mothers took the drug after the first trimester of pregnancy (Heinonen et et al al., 1977a; Yovich et al et al., 1988).

Claimed a.s.sociations between maternal use of high-dose progestins early in pregnancy and masculinization of the genitalia in female children, feminization of the genitalia in male children, a variety of malformations of other organ systems and certain behavioral alterations (Hines, 1982; Schardein, 1980, 1985; Wilson and Brent, 1981) are apparently not true. A large study that included 1274 cases where medroxyprogesterone was taken for first-trimester bleeding failed to reveal an increased rate of malformations when compared to 1146 control infants (Katz et al et al., 1985).

Although ambiguous external genitalia occurred among both sons and daughters of women who were treated with high doses of medroxyprogesterone to prevent miscarriage during pregnancy, these abnormalities were isolated and very rare (Schardein, 1985; Yovich et al et al., 1988). Growth, s.e.xual maturation, and s.e.xually dimorphic behavior were unaltered among 74 teenage boys and 98 teenage girls whose mothers had taken medroxyprogesterone during pregnancy (Jaffe et al et al., 1989, 1990). Animal teratology studies in rats, rabbits, and monkeys demonstrated that nongenital anomalies were not increased in frequency, and genital ambiguity occurred only at very high doses of medroxyprogesterone during pregnancy (Andrew and Staples, 1977; Eibs et al et al., 1982; Foote et al et al., 1968; Kawashima et al et al., 1977; Lerner et al et al., 1962; Prahalada et al et al., 1985a,b; Tarara, 1984).

MEGESTROL ACETATE.

Megestrol is a synthetic oral progestational agent. The risk for virilization of female fetuses appears minimal with maternal use of large doses of this agent during pregnancy.

No studies of congenital anomalies among infants whose mothers were treated with megestrol during pregnancy have been published. External genitalia of female rats born to mothers treated with very large doses of megestrol during pregnancy were virilized (Kawashima et al et al., 1977).

Androgens Androgen use during pregnancy is strictly contraindicated, primarily due to the risk of masculinization of a female fetus.

DANAZOL.

Danazol is a synthetic steroid absorbed by the gastrointestinal tract, metabolized by the liver, and has a half-life of 4.5 h. The drug has moderate androgenic activity, and is used to treat endometriosis. Inadvertent use during early pregnancy results in virilization of 96 96 Endocrine disorders, contraception, and hormone therapy during pregnancy female infants (Duck and Katayama, 1981; Kingsbury, 1985; Peress female infants (Duck and Katayama, 1981; Kingsbury, 1985; Peress et al et al., 1982; Quagliarello and Greco, 1985; Rosa, 1984; Shaw and Farquhar, 1984). A review of fetal exposure to danazol in 129 cases compiled from case reports revealed miscarriages in 12 cases and 23 elective abortions. There were 57 female fetuses whose mothers took danazol during the period of sensitivity to androgenic substances (8th week of embryogenesis and thereafter), and 23 (40 percent) presented with virilization (c.l.i.toromegaly, partial fusion of l.a.b.i.a majora) (Brunskill, 1992). The lowest daily dose that resulted in virilization was 200 mg (Brunskill, 1992). Androgen influences on development of internal genitalia were present in only two cases (Quagliarello and Greco, 1985; Rosa, 1984).

Therefore, the available data strongly indicate that virilization of the female fetus is a risk when there is exposure to danazol during the period of androgen receptor sensitivity (beginning at the 8th week of embryogenesis and continuing through the fetal period). Virilization was not found among any infants exposed before the 8th week of embryogenesis (Rosa, 1984).

Danazol is usually prescribed for only a 36-month course. A patient who becomes pregnant while taking the medication may not be diagnosed until a considerable fetal exposure has occurred because the drug is expected to cause amenorrhea. Therefore, physicians should be aware of the risk of female genital ambiguity occurring in the offspring of women who are prescribed this drug.

METHYLTESTOSTERONE.