Alexander J.C. Mittnacht, MD

• Director, Pediatric Cardiac Anesthesia
• Associate Professor
• Department of Anesthesiology
• Mount Sinai Medical Center
• New York, New York

The mean renal clearances of the antibiotic during the three administrations were 143 women's health yakima buy discount clomid 100 mg on line, 170 pregnancy hormone levels trusted clomid 100mg, and 103 mL/minute women's health clinic victoria hospital winnipeg order clomid 25 mg, respectively women's health clinic gympie discount clomid 100 mg without a prescription. Plasma and milk samples were collected between 2 and 4 days of therapy (total number of doses received averaged 12 pregnancy labor symptoms discount 50mg clomid free shipping. The mean maternal plasma levels of the antibiotic just prior to a dose and 1 hour after a dose were 7 breast cancer 5k harrisonburg va purchase clomid 25mg with mastercard. The mean concentrations in breast milk before a dose and at 1 and 3 hours after a dose were 3. Three potential problems exist for the nursing infant exposed to ceftazidime in milk: modification of bowel flora, direct effects on the infant, and interference with the interpretation of culture results if a fever workup is required. The American Academy of Pediatrics classifies ceftazidime as compatible with breastfeeding (7). Cho N, Suzuki H, Mitsukawa M, Tamura T, Yamaguchi Y Maruyama M, Aoki K, Fukunaga K, Kuni K. The concentrations of ceftazidime and thiopental in maternal plasma, placental tissue and amniotic fluid in early pregnancy. No teratogenesis or fetal harm was found in studies with rats and rabbits at doses up to approximately 8. Low concentrations of other cephalosporins are excreted into milk, however, and the presence of ceftibuten in milk should be expected. Three potential problems exist for the nursing infant exposed to ceftibuten in milk: modification of bowel flora, direct effects on the infant, and interference with the interpretation of culture results if a fever workup is required. The American Academy of Pediatrics classifies other cephalosporin antibiotics as compatible with breastfeeding (for example, see Cefadroxil and Cefazolin). In addition, no detectable teratogenic risk with cephalosporin antibiotics was found in a large 2001 study (see Cephalexin). The placental transfer of ceftizoxime and cefoperazone were studied in an in vitro perfused human placental system (2). The steady-state fetal concentrations of the two agents were 4­5 and 4 mcg/mL, respectively. Amniotic fluid concentrations were lower with peak levels of 10­20 mcg/mL at 2­3 hours. In a different study, maternal, fetal, and amniotic concentrations were measured in women who had received at least three doses of ceftizoxime 2 g at 8-hour intervals (8). A 1993 report found that protein binding of ceftizoxime was significantly less in fetal blood than in maternal blood (9). Even though these levels are low, three potential problems exist for the nursing infant: modification of bowel flora, direct effects on the infant, and interference with the interpretation of culture results if a fever workup is required. Although not specifically listing ceftizoxime, the American Academy of Pediatrics classifies other cephalosporin antibiotics as compatible with breastfeeding (for example, see Cefadroxil and Cefazolin). Transfer of ceftizoxime surpasses that of cefoperazone by the isolated human placental perfused in vitro. Clinical studies on transplacental diffusion of ceftizoxime into fetal blood and treatment of infections in obstetrics and gynecology. Seiga K, Minagawa M, Egawa J, Yamaji K, Sugiyama Y Clinical and laboratory studies on ceftizoxime. Steady-state cord and amniotic fluid ceftizoxime levels continuously surpass maternal levels. Reproduction studies in rats found no evidence of impaired fertility or reproduction performance at a dose approximately 20 times the recommended human dose or, in mice, rats, and nonhuman primates, of embryotoxicity, fetotoxicity, or teratogenicity at doses approximately 20, 20, and 3 times, respectively, the recommended human dose (1). No accumulation of the antibiotic was noted and the pharmacokinetic profile was similar to healthy, nonpregnant adults. Ceftriaxone concentrations in the first voided newborn urine were highly variable, ranging from 6 to 92 mcg/mL. In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 60 newborns had been exposed to ceftriaxone during the 1st trimester (F. However, other cephalosporin antibiotics from this study have shown possible associations with congenital malformations (see also Cefaclor, Cephalexin, and Cephradine). The treatment was compared with approximately similar numbers of pregnant women treated with spectinomycin or amoxicillin with probenecid. Ceftriaxone and spectinomycin were similar in efficacy and both were superior to the amoxicillin/probenecid regimen. High protein binding in maternal serum probably limited transfer to the milk (3,4). The American Academy of Pediatrics classifies ceftriaxone as compatible with breastfeeding (11). Ceftriaxone distribution between maternal blood and fetal blood and tissues at parturition and between blood and milk postpartum. Cho N, Kunii K, Fukunago K, Komoriyama Y Antimicrobial activity, pharmacokinetics and clinical. In: Proceedings of the 13th International Congress on Chemotherapy, Vienna, Austria, August 28­September 2, 1983. Pyelonephritis in pregnancy: once-a-day ceftriaxone versus multiple doses of cefazolin. Maternal and fetal and tissue levels of, ceftriaxone following preoperative prophylaxis in emergency cesarean section. Cefuroxime readily crosses the placenta in late pregnancy and labor, achieving therapeutic concentrations in fetal serum and amniotic fluid (2­7). Therapeutic antibiotic levels in infants can be demonstrated up to 6 hours after birth with measurable concentrations persisting for 26 hours. The antibiotic has been used for the treatment of pyelonephritis in pregnancy (9). The mean concentrations of the antibiotic in the mothers (1 hour after a dose), umbilical cord plasma, placenta, and membranes were 35. In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 143 newborns had been exposed to cefuroxime during the 1st trimester (F. These data do not support an association between the drug and congenital defects (see also Cefaclor, Cephalexin, and Cephradine for contrasting results). The pregnancy outcomes of 106 women exposed in the 1st trimester to cefuroxime were described in a 2000 study (12). Compared with 106 matched controls, there was no difference in pregnancy outcomes in terms of live births, spontaneous abortions, gestational age at birth, prematurity, birth weight, fetal distress, method of delivery, and major or minor malformations. Induced abortions, however, occurred in significantly more cefuroxime-exposed women than in controls, possibly due to misinformation and misperception of the risk the antibiotic posed to a pregnancy (12). Even though the levels are low, three potential problems exist for the nursing infant exposed to cefuroxime in milk: modification of bowel flora, direct effects on the infant, and interference with the interpretation of culture results if a fever workup is required. Although not specifically listing cefuroxime, the American Academy of Pediatrics classifies other cephalosporin antibiotics as compatible with breastfeeding (for example, see Cefadroxil and Cefazolin). Transplacental transfer of cefuroxime in uncomplicated pregnancies and those complicated by hydrops or changes in amniotic fluid volume. Achievement of therapeutic concentrations of cefuroxime in early preterm gestations with premature rupture of the membranes. Berkovitch M, Segal-Socher I, Greenberg R, Bulkowshtein M, Arnon J, Perlob P, Or-Noy A. These drugs also have been shown to inhibit labor and prolong pregnancy, both in humans (4) and in animals (5). Similar effects should be expected if celecoxib is used during the 3rd trimester or close to delivery. Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including celecoxib, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (6,7). Celecoxib is indicated for the relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis (8). Celecoxib was not mutagenic or clastogenic in Chinese hamster ovary cells or clastogenic in an in vivo micronucleus test in rat bone marrow. Two studies in pregnant rabbits were designed to test the hypothesis that celecoxib was effective in preventing preterm delivery and did not adversely affect fetal ductus arteriosus patency (9,10). Concentrations of prostanoids, cytokines, and nitric oxide were altered by the treatment, resulting in decrease in the incidence compared with controls of preterm parturition. In the second study, no adverse effect on the fetal ductus arteriosus was observed (10). The molecular weight (about 381) is low enough that passage to the fetus should be expected. Celecoxib metabolism is mediated by the cytochrome P450 2C9 enzyme, resulting in at least three inactive metabolites (8). Women, in whom metabolism by this enzyme is known or suspected to be deficient, may have abnormally high plasma levels of celecoxib and, thus, more of the drug will be available for placental transfer. A population-based pregnancy registry (N = 36,387) was developed by linking three databases in Quebec. There also was a significant association with anomalies of the respiratory system 9. For the cases involving septal closure, 61% were atrial septal defects and 31% were ventricular septal defects. An in vitro study demonstrated that celecoxib had significant uterine relaxant effects (15). A 2002 randomized, double-blind, placebo-controlled study compared the tocolytic effects of celecoxib (100 mg orally every 12 hours for 4 doses) and indomethacin (100 mg rectally, then 50 mg orally every 6 hours for 7 doses) (16). Partial premature constriction of the fetal ductus arteriosus occurred in the indomethacin group, but not in the celecoxib group. A transient decrease in amniotic fluid volume was observed in both groups, but more so with indomethacin. Both drugs were equally effective in the maintenance of tocolysis, but the authors concluded that the safety of celecoxib was superior to that of indomethacin (16). A 40-year-old woman who was breastfeeding her 5-month-old daughter was admitted to the hospital for surgery. In the postoperative period, she received four doses of celecoxib (100 mg twice/day) in addition to other medications. Starting about 5 hours after her last dose, four milk samples were obtained by hand expression over a 24-hour interval. These data suggest that celecoxib would be eliminated from breast milk about 24 hours after the last dose. Although maternal plasma was not obtained, the estimated milk:plasma ratios (based on reported adult plasma levels) were 0. If she had nursed, the estimated maximum infant dose would have been about 40 mcg/kg/day (18). A 2004 study of five breastfeeding women taking celecoxib, three at steady state (200 mg once daily) and two after a single 200-mg dose, measured a mean milk concentration of 66 mcg/L and a mean milk:plasma ratio of 0. Plasma concentrations in two infants at 17 and 22 months of age, who were nursing every 3­4 hours during the day and once at night, were below the limit of detection (10 mcg/L) (19). Six lactating women, who stopped nursing after taking celecoxib, were included in a 2005 report (20). After a single 200-mg dose, the median absolute infant dose was 13 mcg/kg/day and the relative infant dose was 0. Although only 3 of the 12 patients studied were breastfeeding when taking celecoxib, the authors of the studies concluded that celecoxib was unlikely to pose a risk to a nursing infant. Effect of the antenatal administration of, celecoxib during the second and third trimesters of pregnancy on prostaglandin, cytokine, and nitric oxide levels in rabbits. Response of fetal prostanoids, nitric oxide, and ductus arteriosus to the short- and long-term antenatal administration of celecoxib, a selective cyclo-oxygenase-2 inhibitor, in the pregnant rabbit. Animal reproduction studies have not been conducted, and the absence of human pregnancy experience prevents any assessment of the embryo­fetal risk. It appears, however, that the maternal benefit outweighs the unknown embryo­fetal risk. Therefore, if indicated, the antivenom should not be withheld because of pregnancy. The antivenom is indicated for the treatment of clinical signs of scorpion envenomation. Moreover, studies for carcinogenic and mutagenic potential have not been conducted, nor have been fertility impairment studies (1). The molecular weight is probably very high, because the product is a polyvalent preparation of equine immune globulin F(ab)2 fragments. Exposure of the fetus, at least in early pregnancy, might be clinically insignificant. However, the long elimination half-life will allow the antivenom to be at the maternal­fetal interface for a several days. The molecular weight probably is very high, because the product is a polyvalent preparation of equine immune globulin F(ab)2 fragments. Moreover, the antivenom has a long elimination half-life (159 ± 57 hours) and, if it was given shortly before birth, this might allow excretion of small amounts during the colostral phase. Reproduction studies found no evidence in rats, at doses up to 500 mg/kg, of impaired fertility or reproductive performance or, in mice and rats, of fetal harm (1). Several published reports have described the administration of cephalexin to pregnant patients in various stages of gestation (2­12). None of these has linked the use of cephalexin with congenital defects or toxicity in the newborn. However, even though cephalosporins are usually considered safe to use during pregnancy, a surveillance study described below found results contrasting to the published data. In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 3613 newborns had been exposed to cephalexin during the 1st trimester (F. Specific data were available for six defect categories, including (observed/expected) 44/36 cardiovascular defects, 11/5 oral clefts, 3/2 spina bifida, 3/10 polydactyly, 1/6 limb reduction defects, and 8/9 hypospadias. However, similar findings were measured for another cephalosporin antibiotic with more than a thousand exposures (see Cefaclor).

No signs or symptoms of withdrawal were noted in the newborn or in the infant when breastfeeding was stopped about 1 month after birth (3) women's health center redwood city discount clomid 100mg otc. While unique women's health birth control methods generic 100mg clomid amex, the two cases below confirm that the drug and its metabolite are present in milk and that the concentrations of meprobamate exceed those in the maternal plasma menopause questionnaire buy cheap clomid 25mg online. A 2001 case report described the use of carisoprodol (700 mg) women's health center lynchburg va clomid 50mg mastercard, propoxyphene (70 mg) menstrual 3 days late order 100 mg clomid free shipping, and acetaminophen (900 mg) three times daily throughout gestation and during the first 6 months of breastfeeding (2) menopause rash order clomid visa. Levels of carisoprodol and meprobamate were measured in breast milk on 4 consecutive days. Neither the timing of the samples in relationship to the maternal dose nor the maternal plasma levels were specified. Based on an estimated milk intake of 150 mL/kg/day, the absolute and relative doses of carisoprodol plus meprobamate that would have been ingested by an exclusively breastfed infant were 1. No signs or symptoms of withdrawal were noted in the infant who had normal psychomotor development at 6 months of age. However, the infant was partially fed formula because of insufficient maternal milk production (2). In a similar case, a woman took carisoprodol (700 mg) four times daily before and throughout gestation, and during the first postpartum month for severe back muscle spasm (3). The mother also took an analgesic combination (hydrocodone plus acetaminophen) for a short period after delivery. Peak carisoprodol and meprobamate blood concentrations, obtained 2 hours postdose, were 3 and 9 mcg/mL, respectively, whereas the milk concentrations, obtained at the same time, were 1. Trough blood concentrations, obtained about 4 hours postdose, were <2 and <4 mcg/mL, respectively, whereas the milk values were 0. A blood sample from the infant, obtained 2 hours after breastfeeding that was started 1. No signs or symptoms of withdrawal or other adverse effects were noted in the newborn or when breastfeeding was stopped about 1 month later (3). Although the human data are very limited, both cases involved mothers taking carisoprodol doses that were much higher than the recommended dose of 1050­1400 mg/day. The lack of detectable adverse effects in both infants suggests that the risk of toxicity is low, at least in infants that also were exposed during pregnancy. Starting carisoprodol treatment during breastfeeding may have different results in a nursing infant. The American Academy of Pediatrics classifies another centrally acting skeletal muscle relaxant as compatible with breastfeeding (see Baclofen). However, until additional data are available, women taking this drug and who elect to nurse should closely monitor their infants for sedation and other changes in behavior or functions. However, only two reports have described the use of carmustine in human pregnancy. In one of these, a woman was treated with carmustine before and during the first two trimesters. In the other case, a woman who was not treated until late in the 2nd trimester was electively delivered prematurely because of her disease. Her infant was growth restricted 17 months after birth but had apparently normal mental and motor development. As with other cancer chemotherapeutic agents, treatment after the 1st trimester does not appear to result in newborn toxicity, although bone marrow suppression has been reported when multiple agents were used close to delivery. Until proven otherwise, carmustine should be considered a potential teratogen if used during the period of organogenesis. Therefore, a woman whose condition requires treatment during organogenesis, or who conceives while under treatment, should be informed of the potential risk to her embryo. The antineoplastic and toxic properties of carmustine are thought to be secondary to metabolites. The most severe toxicities are delayed bone marrow suppression and pulmonary toxicity (1,2). The agent was mutagenic in in vitro assays and clastogenic in both in vivo and in vitro tests (2). Reproduction studies have been conducted with carmustine in pregnant rats and rabbits (1,2). In another animal study, pregnant rats were given an intraperitoneal dose of 20 mg/kg on embryonic day 15 (3). Of interest, cortical dysplasia is associated with epilepsy in children and adults (3). The molecular weight (about 214) is low enough that exposure of the embryo or fetus should be expected. Two characteristics of carmustine, its high lipid solubility and its relatively lack of ionization at physiologic pH, will promote transfer of the drug across the placenta. The very short plasma half-life may lessen the transfer of the parent drug, but the pharmacology and pharmacokinetics of the active metabolites have not been fully elucidated. A 1984 report described a 21-year-old woman with diffuse histiocytic lymphoma who received carmustine and procarbazine for 5 months before conception and throughout the first 24 weeks of pregnancy (4). A second nitrosourea agent, streptozocin, replaced carmustine and procarbazine in the 2nd trimester. Before pregnancy, the patient had received multiple courses of chemotherapy, including cyclophosphamide, doxorubicin, vincristine, bleomycin, methotrexate, cytarabine, and etoposide, in addition to radiation therapy to the neck. The initial blood test revealed a normal hemoglobin, white blood cell and platelet counts. All other clinical tests were within normal limits, including electrolytes, multiple chemistry, urinalysis, renal ultrasound, and chromosome studies (4). Approximately 9 months earlier an enlarged nevus had been removed from her left shoulder and the pathology had revealed the melanoma. Two months later, the woman was readmitted for severe back pain, which was attributed to diffuse metastatic disease of the spine. Corticosteroids were administered for fetal lung maturity and as an antiemetic for chemotherapy. The 325-g placenta had malignant melanoma in the intervillous space and melanin pigment granules in villous Hofbauer cells and syncytial trophoblasts. Examination revealed age-appropriate evaluations for mental age, motor age, and language scores (5). A number of reports have described pregnancy outcomes after the use of carmustine before conception (6­11). In four studies, the outcomes of 16 pregnancies (12 women) were 14 normal newborns, one stillbirth (twins), and one elective abortion (6­9). A 2000 study analyzed the pregnancy outcomes of 340 cancer survivors who had one or more pregnancies after treatment with carmustine and 11 other alkylating agents (10). The cases were divided into five mutually exclusive treatment groups: nonsterilizing surgery, chemotherapy with alkylating agents, abdominal­pelvic radiation, alkylating agents plus abdominal­pelvic radiation, and all other treatments. The study found no evidence of an increased risk of birth defects or spontaneous abortions (10). In a 2002 study, 1915 women had 4029 pregnancies after chemotherapy with or without radiation (11). No statistical differences in pregnancy outcomes (live births and spontaneous abortions) by treatment group were found, including the 126 pregnancies in women treated with carmustine. The low molecular weight (about 214), high lipid solubility, and relative lack of ionization at physiologic pH suggest that carmustine will be excreted into breast milk. The short elimination half-life in the plasma may limit the amount of parent drug in milk, but the pharmacology and pharmacokinetics of the active metabolites have not been adequately characterized. Because there is substantial risk of harm for a nursing infant, women who are being treated with carmustine should not nurse. Congenital anomalies in children of patients who received chemotherapy for cancer in childhood and adolescence. If used near delivery, the newborn infant should be closely observed for 24­48 hours for signs and symptoms of -blockade. Longterm effects of in utero exposure to -blockers have not been studied but warrant evaluation. No teratogenic effects were observed in pregnant mice and rabbits treated with doses much higher than the maximum recommended human dose (1­3). If carteolol is used during nursing, the infant should be closely observed for hypotension, bradycardia, and other signs or symptoms of blockade. The animal data and the experience with other, similar agents, suggest that the risk of teratogenicity is low. Although growth restriction is a serious concern, the benefits of maternal therapy with carvedilol (or other /-blockers), in some cases, might outweigh the risks to the fetus and must be judged on a case-by-case basis. The 1adrenoreceptor blocking activity has been associated with vasodilation and a reduction in peripheral vascular resistance. Carvedilol is extensively metabolized and some of the metabolites are weakly active. Plasma protein binding, primarily to albumin, is >98% and the mean terminal elimination half-life of the parent compound is 7­10 hours (1). The dose in rats, which was maternal toxic, was also associated with a decrease in fetal weight and an increase in frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). The molecular weight (about 407) and long terminal elimination half-life suggest that exposure of the embryo­fetus probably occurs. However, the high plasma protein binding should limit the amount crossing the placenta. An examination 18 days later revealed normal amniotic fluid volume and normal cranial anatomy. The molecular weight (about 407) and long terminal elimination half-life (7­10 hours) suggest that the drug will be excreted into breast milk, but the high plasma protein binding (>98%) should limit the amount. The potential effects of this exposure on a nursing infant include bradycardia, hypotension, and other symptoms of /-blockade. However, a similar agent is classified by the American Academy of Pediatrics as compatible with breastfeeding (see Labetalol). Although the data are limited, there is no evidence that drugs in this class pose a risk to the embryo­ fetus. No evidence of an increased risk for malformations was found (see also Cascara Sagrada). In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 96 newborns had been exposed to casanthranol during the 1st trimester (F. Specific data were available for six defect categories, including (observed/expected) 2/1 cardiovascular defects, 1/0 spina bifida, and 1/0. No anomalies were observed in the other three categories (oral clefts, limb-reduction defects, and hypospadias. Although diarrhea in a nursing infant is a potential effect, the drug is probably compatible with breastfeeding. Although the data are limited, there is no evidence that drugs in this class pose a risk to the embryo­fetus. Although the numbers are small, no evidence for an increased risk of malformations was found. The relative risk for benign tumors was higher than expected, but independent confirmation is required (1, pp. A 1977 study found that more than 50% of the women taking laxatives during pregnancy had taken a laxative of the anthraquinone type (2). Danthron (1:8 dihydroxyanthraquinone) was administered to nine women shortly before induction of labor. Presence of the laxative and/or its metabolite was documented in the amniotic fluid and in the urine of the newborns. A comprehensive review described the excretion of laxatives into human milk, but little is known about the presence of these agents in breast milk (6). Two reports suggest an increased incidence of diarrhea in infants when nursing mothers are given cascara sagrada or senna for postpartum constipation (7,8). However, the American Academy of Pediatrics classifies cascara and danthron as compatible with breastfeeding (9). The animal data are suggestive of human risk, especially if exposure occurs in the 1st trimester. However, the absence of human pregnancy experience prevents an assessment of the embryo­fetal risk. If indicated, maternal treatment should be avoided in the 1st trimester, if possible. It is a semisynthetic lipopeptide (echinocandin) compound that is synthesized from a fermentation product of the fungus Glarea lozoyenis. Caspofungin is approved for the treatment of Candida infections and for invasive aspergillosis in patients who cannot be treated with other antifungals. Plasma clearance of caspofungin is primarily from distribution, rather than by excretion or by metabolism. Other effects included incomplete ossification of the skull and torso and an increased incidence of cervical ribs. In addition, incomplete ossifications of the talus/calcaneus were observed in rabbits (2). Caspofungin crosses the placenta in rats and rabbits (gestational age not specified) and the drug could be detected in fetal plasma (2). The molecular weight (about 1213 for the acetate salt) and extensive plasma protein binding should limit the amount crossing the placenta, but the long -phase half-life should provide substantial amounts of the drug available for transfer. The high molecular weight (about 1213 for the acetate salt) and extensive plasma protein binding (about 97%) should limit the amount of drug excreted in breast milk, but the long -phase half-life may allow for some drug in the milk. However, other drugs from different classes of antifungal agents, such as fluconazole and ketoconazole, are classified as compatible with breastfeeding by the American Academy of Pediatrics (see Fluconazole and Ketoconazole). The risk of harm from exposure to caspofungin also appears to be low, and women being treated with caspofungin should be allowed to breastfeed. Nevertheless, neither the efficacy for this indication nor the fetal/newborn safety has been documented. Castor oil can cause severe maternal morbidity and possibly mortality, but this toxicity appears to be rare.

The chemotherapy consisted of etoposide (100 mg/m2 Ч 3 days/course) women's health clinic uga order cheap clomid on line, bleomycin pregnancy lingerie order generic clomid on line, cisplatin menstruation color purchase clomid 50 mg online, cyclophosphamide menstrual cramps 8 months pregnant order clomid 100 mg fast delivery, dactinomycin women's health center kearny nj cheapest clomid, methotrexate womens health center shelton ct order clomid 50 mg with mastercard, vincristine, and folinic acid. A 1993 report described return of ovulation in 25 women under 40 years of age from a group of 34 patients treated with etoposide for gestational trophoblastic disease (13). In another study, 12 women with methotrexate-resistant gestational trophoblastic disease were treated with etoposide (100 mg/m2/day Ч 5 days every 10 days) (14). Two of the women had successful pregnancies, 3 and 4 years, respectively, after treatment. Etoposide (200 mg/m2/day Ч 5 days) was successfully used to treat a cervical pregnancy in one woman (15). Her baseline menstrual function returned 60 days after completion of therapy, but it was not stated if she attempted to conceive. A man, who had received etoposide for acute nonlymphoblastic leukemia in a cumulative dose of 3193 mg/m2, fathered two children, one of whom had a unspecified birthmark (16). There is no evidence that the treatment, that also included irradiation to the brain and lumbar spine, vincristine, thioguanine, doxorubicin, cyclophosphamide, and cytarabine, resulted in the birth defect. She maintained milk secretion by pumping her breasts during the chemotherapy courses. The peak milk concentrations of etoposide measured on days 3, 4, and 5 of therapy were approximately (exact concentrations or times of sample collections were not specified) 0. Milk concentrations of etoposide were undetectable within 24 hours of drug administration on each day. The rapid disappearance of etoposide from the milk is compatible with the lack of plasma accumulation and an elimination half-life of 4­11 hours in adults (1). Against medical advice, the mother began breastfeeding 21 days after drug administration (see Mitoxantrone). Because of the potential for severe toxicity in a nursing infant, such as bone marrow depression, alopecia, and carcinogenicity, breastfeeding should be stopped for at least 55 hours after the last dose of etoposide to account for the elimination half-life range noted above. Normal pregnancy after curative multiagent chemotherapy for choriocarcinoma with brain metastases. The effect of etoposide on ovarian function in patients with gestational trophoblastic disease. The drug is metabolized by the liver to metabolites that are at least 90% less active than etravirine. In pregnant rats and rabbits, no evidence of fetal harm was observed at exposures equivalent to the exposure from the recommended human dose of 400 mg/day (1). The etravirine umbilical cord blood concentrations in twins from a mother taking 200 mg twice daily were 577 and 1020 ng/mL. The presence of the drug in fetal blood is consistent with the molecular weight (about 435), prolonged elimination half-life, and lipid solubility. There were 18 outcomes exposed to etravirine (9 in the 1st trimester and 9 in the 2nd/3rd trimesters) in combination with other antiretroviral agents. In reviewing the birth defects of prospective and retrospective (pregnancies reported after the outcomes were known) registered cases, the Registry concluded that, except for isolated cases of neural tube defects with efavirenz exposure, there was no other pattern of anomalies (isolated or syndromic). Health care professionals are encouraged to register patients exposed to etravirine during pregnancy in the Antiviral Pregnancy Registry by calling 1-800-258-4263. The molecular weight (about 435), long elimination half-life (41 ± 20 hours), and lipid solubility suggest that the drug will be excreted into breast milk. In developing countries, breastfeeding is undertaken, despite the risk because no affordable milk substitutes are available. Following oral administration, etretinate is stored in subcutaneous fat and is slowly released over a prolonged interval (1,2). In some patients after chronic therapy, detectable serum drug levels may occur up to 2. Due to this variable excretion pattern, the exact length of time to avoid pregnancy after discontinuing treatment is unknown (2,3). Data accumulated since release of this drug now indicate that it must be considered a human teratogen as well (1­3,5,6). As of June 1986, a total of 51 pregnancies had occurred during treatment with etretinate (1,7,8). Of these pregnancies, 23 were still ongoing at the time of the reports and were unable to be evaluated (1). In the remaining 28 cases, 17 resulted in normal infants and 3 were normal fetuses after induced abortion. Skeletal anomalies were evident in eight cases: three liveborns, one stillbirth at 5 months, and four induced abortions. In addition, marked cerebral abnormalities, including meningomyeloceles, were observed in the stillborn and in three of the aborted fetuses. A 1988 correspondence listed 22 documented etretinate exposures during pregnancy in West Germany as of September 1988 (9). The outcomes of these pregnancies were six induced abortions (no anomalies observed), four spontaneous abortions (no anomalies observed), six normal infants, and six infants with malformations (9). Fifty-three pregnancies are known to have occurred following discontinuance of etretinate therapy (1,10). Malformations were observed in a fetus and an infant among the 38 pregnancies with known outcomes. In one case, a 22year-old woman, treated intermittently over 5 years, became pregnant 4 months after etretinate therapy had been stopped (1,11,12). Serum concentrations of etretinate and the metabolite, etretin, were 7 and 8 ng/mL, respectively, during the 8th week of gestation (6 months after the last dose). The second case also involved a 22-year-old woman who conceived 51 weeks after her last dose of etretinate (10). Multiple congenital anomalies were noted involving the central nervous system, head, face, and heart, which included tetralogy of Fallot, microcephaly, hair whorls, small mandible, asymmetrical nares, protruding ears with malformed antihelices, absent lobules, and enlarged, keyhole-shaped entrances to the external ear canals, strabismus, left peripheral facial nerve paresis, and poor head control. The author also concluded that women treated with etretinate should avoid conception indefinitely (10). Others have questioned whether an indefinite recommendation to avoid pregnancy is practical or necessary (15,16). In West Germany, 2 years of conception avoidance are recommended followed by determination of serum levels of etretinate and its metabolites (16). In six women treated with etretinate from 4 to 78 months, plasma concentrations of the drug were detected after 12 months in three patients (4, 8, and 8 ng/mL) and after 18 months in one patient (10 ng/mL) (16). The metabolites, acitretin and cis-acitretin, were detectable in two women (at 8 and 18 months) and five women (at 8­18 months). The range of malformations, as listed by the manufacturer, includes meningomyelocele, meningoencephalocele, multiple synostoses, facial dysmorphia, syndactylies, absence of terminal phalanges, malformations of hip, ankle and forearm, low-set ears, high palate, decreased cranial volume, and alterations of the skull and cervical vertebrae (2). Pronounced jaundice with elevations of the transaminase enzymes, glutamicoxaloacetic transaminase and glutamic-pyruvic transaminase, was observed in an otherwise normal male newborn following in utero exposure to etretinate (17). No other abnormalities were observed, and the infant was normal at 5 months of age. One source has suggested that male patients treated with etretinate should avoid fathering children during treatment; if this does occur, ultrasound of the fetus is indicated (18). Although there is no evidence that etretinate adversely affects sperm, and even if it did, that this could result in birth defects, the authors defended their comment as practicing "defensive" medicine (19, 20). The closely related retinoid, vitamin A, is excreted (see Vitamin A) and the presence of etretinate in breast milk should be expected. The manufacturer considers use of the drug during lactation to be contraindicated due to the potential for adverse effects (2). Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. Embryopathy in infant conceived one year after termination of maternal etretinate. Malformation of fetus conceived 4 months after termination of maternal etretinate treatment. Embryopathy in infant conceived one year after termination of maternal etretinate: a reappraisal. Congenital ichthyosiforme erythroderma, pregnancy under aromatic retinoid treatment. The dye has been injected intra-amniotically for diagnosis of ruptured membranes without apparent effect on the fetus except for temporary staining of the skin (2,3). The use of Evans blue during pregnancy for plasma volume determinations has been routine (4­8). Premature rupture of the fetal membranes confirmed by intraamniotic injection of dye (Evans blue T-1824). Correlation of changes in blood volume measured by I131-albumin and Evans blue dye, with measured blood loss. Plasma volume findings in pregnant women with mild hypertension: therapeutic considerations. The embryo­ fetal risk for other purposes or during other portions of pregnancy is unknown. The oil from the commercial variety of evening primrose contains the fatty acids cis-linoleic acid and gamma-linolenic acid in concentrations of 72% and 9%, respectively. Essential fatty acids are involved in cellular structural elements and as precursors of prostaglandins. The typical dose used in clinical trials with nonpregnant patients is 6­8 g/day in adults and 2­4 g/day in children (2). A 2003 review examined the pregnancy outcomes when herbal therapies were used (5). In a placebo-controlled trial, 18 subjects were given a total daily dose of 2800-mg linoleic acid and 320 mg of gamma-linoleic acid, whereas 18 controls received placebos (7). The study was conducted for 8 months starting between the 2nd and 6th month of lactation. Not surprisingly, subjects had significantly higher milk concentrations of the fatty acids at the end of the study, whereas controls had decreased levels. Oral primrose oil: its effect on length of pregnancy and selected intrapartum outcomes in low-risk nulliparous women. The effect of oral evening primrose oil on Bishop score and cervical length among term gravidas (abstract). The effect of maternal supplementation with linoleic and -linolenic acids on the fat composition and content of human milk: a placebo-controlled study. Severe embryo toxicities, in the absence of maternal toxicity, were observed in one animal species at exposures much lower than those occurring in humans taking the recommended dose. The limited human pregnancy experience prevents a full assessment of the embryo­fetal risk. The manufacturer advices women of childbearing potential to use an effective method of contraception during treatment and for up 8 weeks after ending treatment (1). If a woman becomes pregnant while receiving everolimus, she should be advised of the potential for embryo­fetal harm. It is indicated for the treatment of various cancers and for prophylaxis of organ rejection in kidney and liver transplantation. After oral absorption, everolimus is metabolized to relatively inactive metabolites. Plasma protein binding is about 74% and the mean elimination half-life is about 30 hours (1, 2). Oral doses given to rats before mating and through organogenesis resulted in increased resorptions, preimplantation and postimplantation loss decreased number of live fetuses, malformation. However, this dose was associated with a slight reduction in pup body weight and survival, but no drug-related effects on offspring development were observed. In rabbits, embryotoxicity as evident as an increase in resorptions occurred at a dose that was about 1. Two-year studies for carcinogenicity in mice and rats were negative, as were multiple assays for genotoxic and mutagenic effects. Everolimus caused infertility in male rats that was partially reversible when the drug exposure was stopped. In female rats, the increases in preimplantation loss suggested that the drug may reduce female fertility (1). The molecular weight (about 958), moderate plasma protein binding, and long elimination halflife suggest that the drug will cross to the embryo­fetus. In a 2011 case report, a woman with a kidney transplant conceived while receiving everolimus (4). Because of worsening renal function, proteinuria, and severe hypertension during week 30, a cesarean section was performed to deliver a 1. The infant had normal growth without detectable disorders at 12 months of age (4). A 2012 case report described the pregnancy outcome of a woman who had received a kidney transplant 4 years before conceiving (5). The woman received everolimus, cyclosporine, and corticosteroids throughout pregnancy. The molecular weight (about 958), moderate (about 74%) plasma protein binding, and long (about 30 hours) elimination half-life suggest that the drug will be excreted into breast milk. Based on animal data, the concentration in milk may exceed the maternal plasma concentration. However, marked toxicity has been observed in adults, such as gastrointestinal disorders (stomatitis, diarrhea, nausea, vomiting), infections, anorexia, respiratory (cough, dyspnea, epistaxis, pneumonitis), skin and subcutaneous disorders, headache, and other toxicities. The antineoplastic is indicated for postmenopausal women with breast cancer who have been treated with tamoxifen for 2­3 years. Because estrogen is required to maintain pregnancy, exemestane is contraindicated in pregnancy. It is indicated for adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received 2­3 years of tamoxifen and are changed to exemestane for completion of a total of 5 consecutive years of adjuvant hormonal therapy. A 2-year carcinogenicity study in mice resulted in an increased incidence of hepatocellular adenomas and/or carcinomas in both males and females, and an increased incidence of renal tubular adenomas in males.

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