Bracha Stahl

Tetrada of the possible mycophenolate mofetil embryopathy: A review

Mycophenolate mofetil (MFM) is an immunosuppressant agent used in organ transplantation, rheumatoid arthritis and lupus nephritis. Experimental data show that doses roughly equivalent to those used clinically in transplant patients may cause fetal resorption and malformations in pregnant rats and rabbits. There are limited data regarding the use of MFM in pregnant women. The human experience is based on 9 case reports, 1 case series, and 2 registry data. The most frequent structural anomalies described in 12 newborns exposed to MFM were as follows: microtia (11); auditory canal atresia (8); cleft lip and palate (6); micrognathia (4); hypertelorism (4); ocular coloboma (3); short fingers (2) and hypoplasic nails (2). The distinctive and unique phenotype associated with MFM exposure during pregnancy (EMFO tetrada: Ear, Mouth, Fingers, Ocular/Organ malformation) raised the hypothesis that MFM may be a real teratogenic drug. Appropriate recommendations to prevent this possible new embryopathy are given.

Is immunosuppression therapy in renal allograft recipients teratogenic? A single‐center experience

The aim of the study was to determine whether immunosuppressive agents used in renal allograft recipients are teratogenic or otherwise associated with pregnancy outcome. The study population consisted of 38 renal allograft recipients treated with combinations of prednisone, azathioprine, cyclosporin A, and tacrolimus attending our Hypertension in Pregnancy Clinic. The 48 live offspring of 73 pregnancies in this group were evaluated for major congenital malformations and mild errors of morphogenesis. Findings were compared with those in 48 offspring of 41 women with primary renal disease not treated with immunosuppressive drugs. Pregnancy outcome parameters were also compared between the study and control groups in the perinatal period and on a long‐term basis (2–7 years after birth). Two major anomalies (4.2%), subcoronal hypospadias and rudimentary thumb, and 10 mild errors of morphogenesis (20.8%) were detected in the study group. These rates did not differ significantly from those in the control group (4.2% and 16.6%, respectively). Pregnancy outcome was worse in the renal transplant patients than in the women with primary renal disease in terms of prematurity (60% vs. 21%, P = 0.001), growth restriction (52% vs. 17%, P = 0.001), and hospitalization in a neonatal intensive care unit (35% vs. 6%, P = 0.01). In conclusion, the similar prevalence of major anomalies and mild errors of morphogenesis in offspring of the renal transplant patients and the women with primary renal disease suggests that immunosuppressive therapy is not a teratogenic factor. It may, however, be associated with worse pregnancy outcome.

Outcome of Infants Exposed to Olanzapine During Breastfeeding

OBJECTIVE This study evaluated the outcome of infants exposed to olanzapine during lactation. METHODS A prospective, controlled observational study design was used. Mothers who contacted Beilinson Teratology Information Service regarding use of olanzapine while breastfeeding were followed by phone interview. Data on lactation, neonatal symptoms, and outcome at the age of 1-2 years were obtained. Mother-infant groups were compared. Mothers breastfeeding while taking olanzapine (n = 22) were compared to two control groups of mothers who continued to take olanzapine but did not breastfeed (n = 15) and to breastfeeding mothers using a drug known to be safe during lactation (n = 51). RESULTS Follow-up was obtained for 37 of 70 women. Comparison of olanzapine-exposed breastfed versus control breastfed infants showed a similar duration of breastfeeding; however, early discontinuation of breastfeeding was more common in the olanzapine-exposed breastfed group (five of 22 vs. none of 51, p = 0.02). The rate of adverse outcomes in olanzapine-exposed breastfed infants did not differ from those of the control groups. Among the 30 newborns exposed in utero to olanzapine, no congenital birth defects were found. Neonatal symptoms were seen in six of 30 of olanzapine-exposed infants versus two of 51 of nonexposed infants (p < 0.05). A withdrawal syndrome was seen in three of 30 (10%) infants. CONCLUSIONS No increase in adverse long-term outcomes in olanzapine-exposed breastfed infants were found. Our data in conjunction with previous estimates of very low drug exposure support continuation of breastfeeding in women treated with olanzapine. However, until additional long-term studies are available, infants exposed to olanzapine through breastmilk should be followed up.

Pregnancy Outcome Following Exposure to Topical Retinoids: A Multicenter Prospective Study

Concerns have been raised about the use of topical retinoids since the publication of isolated cases of characteristic retinoid embryopathy, originally described after oral use. A collaborative study of the European Network of Teratology Information Services was carried out to evaluate the rate of congenital malformations following first‐trimester topical retinoid exposure. A population of 235 exposed pregnant women was compared with 444 controls. No significant differences were observed between groups with regard to the rates of spontaneous abortion (odds ratio [95% confidence interval], 1.5 [0.8–2.7]), minor birth defects (1.3 [0.4–3.7]), and major birth defects (1.8 [0.6–5.4]). No child showed features of retinoid embryopathy. The rate of elective termination in the exposed group was increased 3‐fold (3.4 [1.5–7.8]). In conclusion, these results do not suggest an increased risk of retinoid embryopathy. However, according to current knowledge, topical retinoids cannot be advised for use during pregnancy because their risk/benefit ratio remains questionable.

Oral antihyperglycemic agents during pregnancy and lactation: a review.

The treatment approach of diabetes mellitus during pregnancy requires a combination of diet, exercise, multiple home glucose determinations and intensive insulin regimens. During the last decade there was an increased interest in the use of oral antihyperglycemic agents (OAHAs) as an alternative to insulin in achieving good glycemic control. OAHAs are divided into four groups: derivatives of sulfonylurea, biguanides, glucosidase inhibitors and thiazolidinediones. This review describes the possible teratogenic effects of the use of OAHAs during pregnancy and the effects of these drugs during lactation. Animal and human studies assessing the teratogenic effects of OAHAs have yielded conflicting data because the risk of major malformations in infants of mothers with diabetes appears to be related to maternal glycemic control rather than the antidiabetic therapy.A major concern with the use of OAHAs during pregnancy is neonatal hypoglycemia, which may be severe and persist for days. Therefore, insulin is still the drug of choice because it has not been implicated as a teratogen in human pregnancies. In addition, because of the lack of data regarding the use of OAHAs in pregnancy, we cannot draw firm conclusions about all of the available drugs. However, OAHAs, especially glibenclamide (glyburide), may be beneficial in a situation where the proper use of insulin is problematic. Because there are very limited clinical data on the exposure of OAHAs to the infant via breast milk, and the potentially serious effect of neonatal hypoglycemia, the safest recommendation is not to breast feed while taking OAHAs. Well-conducted, prospective, controlled studies regarding the feasibility of OAHAs in pregnant women with diabetes and during lactation are needed.

The outcomes of pregnancy in women exposed to the new macrolides in the first trimester: a prospective, multicentre, observational study.

AbstractBackground: Macrolides are a group of commonly prescribed antibiotics. There is some doubt surrounding the use of the newer macrolides in pregnancy. Objective: The present study aimed to compare outcomes of pregnancies exposed to the new macrolides clarithromycin, azithromycin and roxithromycin with non-teratogenic preparations. Methods; In this prospective, multinational, multicentre, controlled, observational study, information was obtained either from pregnant women or their healthcare professionals who contacted their local teratogen information services in Italy, Israel, the Czech Republic, the Netherlands and Germany seeking information after exposure to macrolides. The comparison group included women or their healthcare professional who contacted these centreswithquestionsregardingknownnon-teratogenicpreparations. Information on obstetric and other background parameters was collected at enrollment; after delivery, subjects or their healthcare professionals were contacted to ascertain pregnancy outcome parameters and other exposures through the remainder of the pregnancy. Results: A total of 608 women exposed to macrolides during pregnancy were enrolled; 511 of the exposures occurred during the first trimester. The comparison group comprised 773 women exposed to non-teratogenic preparations during the first trimester of pregnancy. No significant difference in the rate of major congenital malformations was found between the study group and the comparison group (3.4% vs 2.4%; p = 0.36; odds ratio (OR) 1.42; 95% CI 0.70, 2.88) or in the rate of cardiovascular malformations (1.6% vs 0.9%; p = 0.265; OR 1.91; 95% CI 0.63, 5.62).No significant differences were found between subgroups of macrolides in the rates of major congenital malformations or cardiac malformations, although for azithromycin this was of borderline significance. Conclusions: This study, in agreement with earlier smaller studies, suggests that the new macrolides do not pose a significantly increased risk of major congenital malformations or cardiac malformations.

The safety of amoxicillin /clavulanic acid and cefuroxime during lactation

Breast-feeding is considered the gold standard for infant nutrition. In spite of statements about the safe use of drugs in lactation by the American Academy of Pediatrics, medical professionals remain confused regarding the management of drug therapy in nursing mothers, and this can lead to suboptimal prescribing and poor compliance. The aim of our study was to evaluate the safety of 2 of the newer antibiotics, amoxicillin/clavulanic acid and cefuroxime, during lactation. Breast-feeding women who called a drug consultation center to obtain information about the potential risks of amoxicillin/clavulanic acid (67 women) and cefuroxime (38 women) were prospectively recruited. As a control group, women who were treated with antibiotics known to be safe during lactation were recruited: amoxicillin (n = 40) for the amoxicillin/clavulanic acid group and cephalexin (n = 11) for the cefuroxime group. Women in the control group were matched for indication for antibiotic therapy, duration of treatment, and maternal age. Participants were interviewed after treatment termination regarding adverse reactions during therapy. In the amoxicillin/clavulanic acid group, 15 infants (22.3%) had adverse effects, and the rate increased with dosage (P = 0.0139). This was significantly higher than the amoxicillin group, where 3 infants (7.5%) had adverse effects (P = 0.046, relative risk (RR) = 2.99, 95% confidence interval (CI) 0.92-9.68). However, there were no significant differences between rates of specific events. The rate of adverse effects in the cefuroxime group (2.6%) was not significantly different from that in controls (9%) (P = 0.58, OR = 0.92, 95% CI 0.94-1.06). All adverse effects were minor, self-limiting, and did not necessitate interruption of breast-feeding. Our data suggest that amoxicillin/clavulanic acid and cefuroxime may be safe during lactation. Larger studies are needed to confirm these findings.

Cardiac Arrhythmia in a Newborn Infant Associated with Fluoxetine Use during Pregnancy

TO THE EDITOR: Fluoxetine is a selective serotonin-reuptake inhibitor widely used for the treatment of depression as well as for obsessive–compulsive disorders and eating disorders.1 The few existing studies2,3 of maternal fluoxetine treatment in the second half of pregnancy reported some toxic effects (neurologic, hematologic) and a withdrawal syndrome in a small number of the infants. We report a cardiac arrhythmia detected preand postnatally in an infant of a mother treated with fluoxetine during the third trimester of pregnancy. Case Report. A 38-week-gestational-age male infant was born by spontaneous vaginal delivery to healthy nonconsanguineous parents. There was no family history of cardiac disturbances. The mother was treated for depression with fluoxetine ≤30 mg/d from week 28 of pregnancy. The drug was tapered and discontinued 5 days prior to delivery. The mother denied taking any other drugs, and there was no history of smoking, alcohol or caffeine intake, or infections during pregnancy. Alpha fetoprotein concentration and targeted fetal ultrasound study (at 22-wk gestation) were normal. On admission for labor, a fetal cardiac arrhythmia with irregular heart sounds was heard on auscultation. Fetal heart monitoring revealed irregular baseline rhythm. The infant was born spontaneously in the vertex position; Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. Birth weight was 2700 g. Physical examination of the newborn, including tonus and reflexes, was normal except for irregular pulse with premature beats and wandering movements with sucking motions. The infant was placed in an incubator with cardiomonitoring. Blood cell count, blood gases, urea, creatinine, electrolytes, calcium, and glucose concentrations were normal. Electrocardiography showed sinus rhythm with multiple atrial and ventricular premature contractions (Figure 1). Echocardiography revealed a normal heart. The mother did not restart fluoxetine after delivery and did not breast-feed the infant. On the infant’s discharge at age 5 days, the arrhythmia persisted, but the premature contractions were much rarer than during the previous days. At follow-up at age 1 month, an electrocardiogram showed normal rhythm without any premature contractions. Discussion. Fluoxetine is thought to have minimal cardiovascular effects. However, several case reports4 in previously healthy adults describe cardiac disturbances such as atrial fibrillation, supraventricular tachycardia, and bradycardia with syncope after fluoxetine use. These arrhythmias appeared with minimal doses of fluoxetine (20 mg/d) and after, in general, 3–6 weeks of use (in 1 patient, after only 24 h). This is the first report describing a newborn infant with atrial and ventricular premature contractions possibly secondary to maternal fluoxetine treatment during the last trimester of pregnancy. The discontinuation of treatment 5 days before delivery does not rule out the possibility that fluoxetine induced the arrhythmia, because of the long half-life of the drug and its metabolite (norfluoxetine), and because of its well-known associated withdrawal syndrome, which typically appears after drug discontinuation. The use of the Naranjo probability scale5 indicated a possible relationship between the atrial and ventricular premature contractions and maternal fluoxetine therapy in our patient. Review of the literature6 indicates up to 1–2% baseline incidence of atrial premature contractions in utero. Therefore, another possible explanation is that the maternal fluoxetine use in this case was just coincidental. The significance of irregular fetal heart rhythm in atrial premature contractions is usually hemodynamically benign. However, fetal and neonatal echocardiography is mandated to exclude structural heart disease. Although fluoxetine-mediated arrhythmias in newborn infants seem to be very rare and not absolutely proven, we report the present case to increase the awareness of clinicians to this potentially important adverse effect.

Levonorgestrel used for emergency contraception during lactation-A prospective observational cohort study on maternal and infant safety.

Objective: To identify possible effects of levonorgestrel used as an emergency contraceptive during breastfeeding on mothers and their infants. Study design: A prospective observational cohort study of all women who contacted the Teratology Information Service between January, 2005 and January, 2010. Breastfeeding women who used levonorgestrel as an emergency contraceptive (study group) were compared to breastfeeding women who used either ethynodiol diacetate or desogestrel (control group). Women were followed for 6–24 months. Main outcome measures were adverse maternal and infant effects and continuation of breastfeeding. Results: We followed 71 of 128 study group women and 72 of 100 control group women. Maternal adverse effects were mainly vaginal bleeding, which was less frequent in the study vs. control group (16 of 71 vs. 27 of 72, p = 0.068). Decreased lactation was uncommon and similar in both groups. Breastfeeding was reinitiated within less than 8 h in 75% of the levonorgestrel group women. Adverse infant effects were rare (0 of 72 infants vs. 2 of 72 infants, p = 0.5 in the study vs. control group). Conclusions: Our findings support the safety of using levonorgestrel as an emergency contraceptive during lactation without the need for withholding breastfeeding.

Spontaneous hemarthrosis following thrombolytic therapy for acute myocardial infarction

We describe a 45-year-old man who developed a spontaneous hemarthrosis of his right knee following thrombolytic therapy with streptokinase and rtPA for acute myocardial infarction. Surprisingly, despite the wide use of thrombolytic therapy, only four cases of spontaneous hemarthrosis following thrombolysis have been previously reported. Prompt aspiration of the joint, after stopping anticoagulant therapy, and splinting will provide early diagnosis and may prevent further damage to the joint.