Sarah Običan

Teratogen update: Methotrexate

Methotrexate and aminopterin are folic acid antagonists that inhibit dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate has been used for the treatment of malignancy, rheumatic disorders, and psoriasis and termination of intrauterine pregnancy. Recently, methotrexate has become a standard treatment for ectopic pregnancy. The misdiagnosis of an intrauterine pregnancy as an ectopic pregnancy can result in exposure of a continuing pregnancy to dose levels of methotrexate of 50 mg/m(2) (maternal body surface area). Experimental animal studies have associated methotrexate therapy with embryo death in mice, rats, rabbits, and monkeys. Structural malformations have been most consistently produced in rabbits at a maternal dose level of 19.2 mg/kg. Abnormalities in rabbits include hydrocephalus, microphthalmia, cleft lip and palate, micrognathia, dysplastic sacral and caudal vertebrate, phocomelia, hemimelia, syndactyly, and ectrodactyly. Based on human case reports of methotrexate exposure during pregnancy, a methotrexate embryopathy has been described that includes growth deficiency, microcephaly, hypoplasia of skull bones, wide fontanels, coronal or lambdoidal craniosynostosis, upswept frontal scalp hair, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low-set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly. This syndrome may be associated with exposures between 6 and 8 weeks after conception and dose levels of 10 mg/week or greater. More recent case reports of methotrexate exposure for the misdiagnosis of ectopic pregnancy involve treatment before 6 weeks after conception and have raised the suggestion of a distinct syndrome due to such early exposures. Tetralogy of Fallot and perhaps other neural crest cell-related abnormalities may be features of this early syndrome. A disproportionality analysis of methotrexate and aminopterin case reports and series provides support for pulmonary atresia, craniosynostosis, and limb deficiencies as reported more often than expected in methotrexate-exposed children. Denominator-based data will be welcome to better define elements of a methotrexate embryopathy and possibly to distinguish an early exposure syndrome from anomalies traditionally associated with methotrexate exposure.

Folic acid in early pregnancy: a public health success story

Folate is a water‐soluble B vitamin that must be obtained in the diet or through supplementation. For > 50 yr, it has been known that folate plays an integral role in embryonic development. In mice, inactivation of genes in the folate pathway results in malformations of the neural tube, heart, and craniofacial structures. It has been shown that diets and blood levels of women who had a fetus with a neural tube defect are low for several micronutrients, particularly folate. Periconceptional use of folic acid containing supplements decreased recurrent neural tube defects in the offspring of women with a previously affected child and the occurrence of a neural tube defect and possibly other birth defects in the offspring of women with no prior history. Based on these findings, the U.S. Public Health Service recommended that all women at risk take folic acid supplements, but many did not. Mandatory food fortification programs were introduced in numerous countries, including the United States, to improve folate nutritional status and have resulted in a major decrease in neural tube defect prevalence. The success story of folate represents the cooperation of embryologists, experimentalists, epidemiologists, public health scientists, and policymakers.—Običan, S. G., Finnell, R. H., Mills, J. L., Shaw, G. M., Scialli, A. R. Folic acid in early pregnancy: a public health success story. FASEB J. 24, 4167–4174 (2010). www.fasebj.org

Teratology public affairs committee position paper: Iodine deficiency in pregnancy

Iodine deficiency is an important nutritional deficiency, with more than 2 billion people worldwide estimated to be at risk. The developing fetus and young children are particularly at risk. During pregnancy and lactation, iodine requirements increase, whether in iodine-poor or iodine-sufficient countries, making the mother and the developing fetus vulnerable. The American Thyroid Association (ATA) recommends 250 micrograms per day of iodine intake for pregnant and lactating women. The thyroid gland is able to adapt to the changes associated with pregnancy as long as sufficient iodine is present. Dietary intake is the sole source of iodine, which is essential to the synthesis of thyroid hormones. Iodine is found in multiple dietary sources including iodized salt, dairy products, seaweed, and fish. Prenatal vitamins containing iodine are a good source of iodine, but iodine content in multivitamin supplements is highly variable. Congenital hypothyroidism is associated with cretinism. Clinical hypothyroidism has been associated with increased risk of poor perinatal outcome including prematurity, low birth weight, miscarriage, preeclampsia, fetal death, and impaired fetal neurocognitive development. Subclinical hypothyroidism is also associated with poor pregnancy outcomes and potential fetal neurocognitive deficits, but the data are more variable than those for clinical hypothyroidism. We concur with the ATA recommendation that all pregnant and lactating women should ingest (through diet and supplements) 250 micrograms of iodine daily. To achieve this goal, we recommend that all pregnant and lactating women take daily iodine supplementation of 150 micrograms.

Age-Stratified Risk of Unexpected Uterine Sarcoma Following Surgery for Presumed Benign Leiomyoma

BACKGROUND Estimates of unexpected uterine sarcoma following surgery for presumed benign leiomyoma that use age-stratification are lacking. PATIENTS AND METHODS A retrospective cohort of 2,075 patients that had undergone myomectomy was evaluated to determine the case incidence of unexpected uterine sarcoma. An aggregate risk estimate was generated using a meta-analysis of similar studies plus our data. Database-derived age distributions of the incidence rates of uterine sarcoma and uterine leiomyoma surgery were used to stratify risk by age. RESULTS Of 2,075 patients in our retrospective cohort, 6 were diagnosed with uterine sarcoma. Our meta-analysis revealed 8 studies from 1980 to 2014. Combined with our study, 18 cases of leiomyosarcoma are reported in 10,120 patients, for an aggregate risk of 1.78 per 1,000 (95% confidence interval [CI]: 1.1-2.8) or 1 in 562. Eight cases of other uterine sarcomas were reported in 6,889 patients, for an aggregate risk of 1.16 per 1,000 (95% CI: 0.5-4.9) or 1 in 861. The summation of these risks gives an overall risk of uterine sarcoma of 2.94 per 1,000 (95% CI: 1.8-4.1) or 1 in 340. After stratification by age, we predict the risk of uterine sarcoma to range from a peak of 10.1 cases per 1,000, or 1 in 98, for patients aged 75-79 years to <1 case per 500 for patients aged <30 years. CONCLUSION The risk of unexpected uterine sarcoma varies significantly across age groups. Our age-stratified predictive model should be incorporated to more accurately counsel patients and to assist in providing guidelines for the surgical technique for leiomyoma.

Vitamin D and maternal and child health: Overview and implications for dietary requirements

The essentiality of vitamin D for normal growth and development has been recognized for over 80 years, and vitamin D fortification programs have been in place in the United States for more than 70 years. Despite the above, vitamin D deficiency continues to be a common finding in certain population groups. Vitamin D deficiency has been suggested as a potential risk factor for the development of preeclampsia, and vitamin D deficiency during infancy and early childhood is associated with an increased risk for numerous skeletal disorders, as well as immunological and vascular abnormalities. Vitamin D deficiency can occur through multiple mechanisms including the consumption of diets low in this vitamin and inadequate exposure to environmental ultraviolet B rays. The potential value of vitamin D supplementation in high-risk pregnancies and during infancy and early childhood is discussed. Currently, there is vigorous debate concerning what constitutes appropriate vitamin D intakes during early development as exemplified by differing recommendations from the Institute of Medicine Dietary Reference Intake report and recent recommendations by the Endocrine Society. As is discussed, a major issue that needs to be resolved is what key biological endpoint should be used when making vitamin D recommendations for the pregnant woman and her offspring.

Pulmonary arterial hypertension in pregnancy

Pulmonary hypertension is a medical condition characterized by elevated pulmonary arterial pressure and secondary right heart failure. Pulmonary arterial hypertension is a subset of pulmonary hypertension, which is characterized by an underlying disorder of the pulmonary arterial vasculature. Pulmonary hypertension can also occur secondarily to structural cardiac disease, autoimmune disorders, and toxic exposures. Although pregnancies affected by pulmonary hypertension and pulmonary arterial hypertension are rare, the pathophysiology exacerbated by pregnancy confers both high maternal and fetal mortality and morbidity. In light of new treatment modalities and the use of a multidisciplinary approach to care, maternal outcomes may be improving.

Prolonged latency of preterm prelabour rupture of membranes and neurodevelopmental outcomes: a secondary analysis

To determine whether prolonged latency after preterm prelabour rupture of membranes (PPROM) is associated with an increased risk for adverse neurodevelopmental outcomes.

Detection of alcohol use in the second trimester among low-income pregnant women in the prenatal care settings in Jefferson County, Alabama

BACKGROUND Prenatal alcohol use, a leading preventable cause of birth defects and developmental disabilities, remains a prevalent public health concern in the United States. This study aims to detect the proportion and correlates of prenatal alcohol use in the prenatal care settings in Alabama. Prenatal care settings were chosen because of their potential as stable locations to screen for and to reduce prenatal alcohol use within a community. METHODS We conducted a cross-sectional study of 3,046 women in the 22 and 23 weeks of gestation who sought prenatal care in 8 community-based public clinics and participated in the Perinatal Emphasis Research Center project in Jefferson County, Alabama, from 1997 to 2001. Frequency and quantity of alcohol use in the past 3 months were assessed by research nurses during face-to-face interviews. We conducted logistic regression analyses to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of correlates of prenatal alcohol use. RESULTS Participants were predominantly young, African American, and unmarried, 86.5% on Medicaid. The proportion of alcohol use in the second trimester of pregnancy was 5.1%; 0.3% of women reported 4 or more drinks on a drinking day to research nurses. Older maternal age (OR = 1.11; 95% CI = 1.08 to 1.15), use of welfare (OR = 1.43; 95% CI = 1.02 to 2.02), and male partner-perpetrated violence (OR = 2.96; 95% CI = 1.92 to 4.56) were positively associated with elevated risk of prenatal alcohol use. Protective factors included higher levels of self-esteem (OR = 0.94; 95% CI = 0.89 to 0.98) and more years of education (OR = 0.88; 95% CI = 0.78 to 0.98). CONCLUSIONS Prenatal alcohol use remains a public health issue among low-income pregnant women in Jefferson County, Alabama. Research nurses detected it in the second trimester. Future studies need to encourage screening for prenatal alcohol use in the prenatal care settings by obstetrician-gynecologists, family physicians, nurses, and midwives. Combined interventions to educate and empower women and strengthen families are needed.

Incidence, pathophysiology, and clinical manifestations of antiphospholipid syndrome

Antiphospholipid syndrome (APLS) is a complex systemic disease with a wide variety of clinical manifestations. In the obstetric population, recurrent early pregnancy loss, fetal loss, and thrombosis are hallmarks of the disease. Patients with APLS have developed one or more pathogenic auto-antibodies directed against plasma and cell surface proteins. These antibodies are characterized by their affinity for anionic phospholipids. Interactions between APLS antibodies and their protein targets influence a wide variety of biological systems and signaling pathways, including monocytes, platelets, the complement system, and endothelial cells. While much research is currently directed at understanding the mechanisms involved in this autoimmune disease, the key clinical presentation is the hypercoagulable state resulting in thrombosis occurring in essentially any arterial or venous location, as well as numerous obstetrical complications. Treatment of APLS is generally directed at preventing thrombosis and poor pregnancy outcomes by ameliorating the hypercoagulable state.

Prolonged latency of preterm premature rupture of membranes and risk of cerebral palsy

Abstract Objective: To determine whether prolonged latency after preterm premature rupture of membranes (PPROM) is associated with an increased risk of death or moderate-to-severe cerebral palsy (CP). Study design: This secondary analysis of the randomized controlled trial of magnesium sulfate for the prevention of CP evaluated whether the time interval between diagnosis of PPROM and delivery was associated with increased risk for CP. Prolonged latency was defined as an interval of ≥4 weeks, latency time was also categorized by week of latency for further analysis. The primary outcome was death or moderate-to-severe CP at 2 years of age. Logistic regression was used to control for confounders. Results: In all, 1522 patients with PPROM were analyzed; of whom, 1328 had a <4-week interval and 194 had an interval of ≥4 weeks. In the unadjusted analysis, the primary outcome was less likely in the PPROM ≥4 weeks group 4.1% versus 8.4%, RR: 0.49, 95% CI: 0.24–0.98. After adjusting for possible confounders, there was no statistical difference associated with PPROM latency ≥4 weeks versus <4 weeks for death or moderate-to-severe CP. Conclusion: Prolonged exposure to an intrauterine environment of PPROM does not increase risk for CP.