Jon M. Nakamoto

National Status of Testing for Hypothyroidism during Pregnancy and Postpartum

CONTEXTnHypothyroidism, overt or subclinical, is associated with adverse outcomes for pregnant women and their offspring. Knowledge of current national thyroid testing rates and positivity during pregnancy is limited.nnnOBJECTIVEnThe aim of the study was to estimate thyroid testing rate and positivity during pregnancy and postpartum, including testing and positivity rates of thyroperoxidase antibody (TPO Ab) and free T(4) tests in pregnant women with elevated TSH levels (hypothyroid), and in pregnant women having TSH within range (euthyroid).nnnDESIGN AND SETTINGnRecords from a large, national sample of pregnant women screened from June 2005 through May 2008 were examined.nnnPARTICIPANTSnThe study included 502,036 pregnant women, for whom gestational age information was available.nnnMAIN MEASURESnTesting rates and the prevalence of hypothyroidism during pregnancy and postpartum were measured using assay-specific, trimester-specific reference intervals. Screening and positivity rates of TPO Ab and free T(4) tests were also measured.nnnRESULTSnOf women ages 18 to 40 yr, 23% (117,892 of 502,036) were tested for gestational hypothyroidism (defined as both subclinical and overt hypothyroidism). Of these, 15.5% (18,291 of 117,892) tested positive for gestational hypothyroidism. Twenty-four percent (22,650 of 93,312) of women with TSH within range and 33% (6,072 of 18,291) of women with elevated TSH were also tested for gestational hypothyroxinemia. Gestational hypothyroxinemia was seen in 0.2% (47 of 22,650) of the tested women with TSH within range and was seen in 2.4% (144 of 6,072) of the tested women having elevated TSH; 0.3% (276 of 93,312) of women with TSH within range received a TPO Ab test, and of these, 15% (41 of 276) tested positive; 0.66% (120 of 18,291) of women with elevated TSH received a TPO Ab test, and of these, 65% (78 of 120) tested positive. Only 20.7% (1873 of 9063) of hypothyroid women received thyroid screening within 6 months postpartum; of these, 11.5% (215 of 1873) were diagnosed with postpartum hypothyroidism.nnnCONCLUSIONnGestational hypothyroidism is more common than generally acknowledged. Testing is not common, and test selection is variable. There is a low rate of postpartum follow-up.

Gaps in diabetes screening during pregnancy and postpartum.

OBJECTIVE: To estimate the screening rate and prevalence of gestational diabetes mellitus (GDM) and the screening rate and prevalence of postpartum diabetes, in a large, national sample of pregnant women. We also estimated the potential effects of the new International Association of Diabetes and Pregnancy Study Groups recommendations, which replace the 100-g oral glucose tolerance test (OGTT) with the 75-g OGTT, on GDM prevalence and gestational plasma glucose testing practices. METHODS: We identified pregnant women who used the laboratory services of Quest Diagnostics and who were screened for GDM and were tested postpartum. Gestational diabetes mellitus prevalence was calculated according to the current American Diabetes Association/ Carpenter-Coustan criteria, and the new International Association of Diabetes and Pregnancy Study Groups criteria. RESULTS: Sixty-eight percent (632,820/924,873) of pregnant women aged 25 to 40 (ie, those not in a low-risk age group) who utilized the services of Quest Diagnostics during this study were screened for GDM. Of the entire adult pregnant population (ages 18–40) who received GDM screening, 5% (40,955/842,993) had positive test results under the current criteria. Nineteen percent (4,486/23,299) of those with GDM received postpartum diabetes testing within a 6-month period. Ninety percent (148,749/166,085) of all confirmatory GDM tests performed on pregnant women at Quest Diagnostics were the 100-g OGTT. The number of women with GDM after receiving the 75-g OGTT would have doubled under the International Association of Diabetes and Pregnancy Study Groups criteria. CONCLUSION: Many women may not be receiving GDM screening during pregnancy. Postpartum diabetes screening rates after pregnancy remain low. Adoption of the new International Association of Diabetes and Pregnancy Study Groups criteria would require a significant change in current clinical practice. LEVEL OF EVIDENCE: III

Validation and Clinical Application of a Locus- Specific Polymerase Chain Reaction- and Minisequencing-Based Assay for Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)

Congenital adrenal hyperplasia is an autosomal recessive disorder caused by defective adrenal steroid biosynthesis, resulting in reduced glucocorticoid and increased androgen production. The majority of cases are due to inactivation of the 21-hydroxylase gene (CYP21A2), most commonly caused by genomic rearrangements with the adjacent, highly homologous pseudogene CYP21A. The most common deletions and gene conversion events have been defined and are typically detected by Southern hybridization detection of CYP21 rearrangements and/or polymerase chain reaction (PCR). However, Southern hybridization is laborious, and allele-specific PCR results may be difficult to interpret. We have therefore developed a locus-specific, PCR-based, minisequencing method for detecting the 12 most common CYP21A2 mutations. We validated the assay using a panel of 20 previously genotyped samples obtained from individuals who collectively have a broad spectrum of mutations causing 21-hydroxylase deficiency. We also used 19 control samples having no CYP21 mutations. All validation samples were correctly typed, and we identified haplotypes that may be useful for clinical diagnosis. Results from 102 clinical samples demonstrate that this assay is a rapid, reliable, and robust method for locus-specific identification of mutations and is suitable for routine clinical use and prenatal diagnosis.

Performance Criteria for Testosterone Measurements Based on Biological Variation in Adult Males: Recommendations from the Partnership for the Accurate Testing of Hormones

BACKGROUNDnTestosterone measurements that are accurate, reliable, and comparable across methodologies are crucial to improving public health. Current US Food and Drug Administration-cleared testosterone assays have important limitations. We sought to develop assay performance requirements on the basis of biological variation that allow physiologic changes to be distinguished from assay analytical errors.nnnMETHODSnFrom literature review, the technical advisory subcommittee of the Partnership for the Accurate Testing of Hormones compiled a database of articles regarding analytical and biological variability of testosterone. These data, mostly from direct immunoassay-based methodologies, were used to specify analytical performance goals derived from within- and between-person variability of testosterone.nnnRESULTSnThe allowable limits of desirable imprecision and bias on the basis of currently available biological variation data were 5.3% and 6.4%, respectively. The total error goal was 16.7%. From recent College of American Pathologists proficiency survey data, most currently available testosterone assays missed these analytical performance goals by wide margins. Data from the recently established CDC Hormone Standardization program showed that although the overall mean bias of selected certified assays was within 6.4%, individual sample measurements could show large variability in terms of precision, bias, and total error.nnnCONCLUSIONSnBecause accurate measurement of testosterone across a wide range of concentrations [approximately 2-2000 ng/dL (0.069-69.4 nmol/L)] is important, we recommend using available data on biological variation to calculate performance criteria across the full range of expected values. Additional studies should be conducted to obtain biological variation data on testosterone from women and children, and revisions should be made to the analytical goals for these patient populations.

A Longitudinal Study of Estrogen-Responsive Tissues and Hormone Concentrations in Infants Fed Soy Formula

PurposenChemicals with hormonelike activity, such as estrogenic isoflavones, may perturb human development. Infants exclusively fed soy-based formula are highly exposed to isoflavones, but their physiologic responses remain uncharacterized. Estrogen-responsive postnatal development was compared in infants exclusively fed soy formula, cow-milk formula, and breast milk.nnnMethodsnWe enrolled 410 infants born in Philadelphia-area hospitals between 2010 and 2014; 283 were exclusively fed soy formula (n = 102), cow-milk formula (n = 111), or breast milk (n = 70) throughout the study (birth to 28 or 36 weeks for boys and girls, respectively). We repeatedly measured maturation index (MI) in vaginal and urethral epithelial cells using standard cytological methods, uterine volume and breast-bud diameter using ultrasound, and serum estradiol and follicle-stimulating hormone levels. We estimated MI, organ-growth, and hormone trajectories by diet using mixed-effects regression splines.nnnResultsnMaternal demographics did not differ between cow-milk-fed and soy-fed infants but did differ between formula-fed and breastfed infants. Vaginal-cell MI trended higher (P = 0.01) and uterine volume decreased more slowly (P = 0.01) in soy-fed girls compared with cow-milk-fed girls; however, their trajectories of breast-bud diameter and hormone concentrations did not differ. We observed no significant differences between boys fed cow-milk vs soy formula; estradiol was not detectable. Breastfed infants differed from soy-formula-fed infants in vaginal-cell MI, uterine volume, and girls estradiol and boys breast-bud diameter trajectories.nnnConclusionsnRelative to girls fed cow-milk formula, those fed soy formula demonstrated tissue- and organ-level developmental trajectories consistent with response to exogenous estrogen exposure. Studies are needed to further evaluate the effects of soy on child development.

Adrenoleukodystrophy: Guidance for Adrenal Surveillance in Males Identified by Newborn Screen.

ContextnAdrenoleukodystrophy (ALD) is a peroxisomal disorder associated with neurologic decompensation and adrenal insufficiency. Newborn screening for ALD has recently been implemented in five states with plans to expand to all 50 states in the United States. Adrenal insufficiency ultimately develops in most males with ALD, but the earliest age of onset is not well established.nnnObjectivenThese clinical recommendations are intended to address screening for adrenal insufficiency in boys identified to have ALD by newborn screen.nnnParticipantsnSeven members of the Pediatric Endocrine Society Drug and Therapeutics/Rare Diseases Committee, with clinical experience treating children with ALD and adrenal insufficiency, and a pediatric endocrinologist and laboratory director were selected to be on the working committee.nnnConsensus ProcessnThe authors comprised the working group and performed systematic reviews of the published literature regarding adrenal insufficiency and ALD. The recommendations were reviewed and approved by the larger Pediatric Endocrine Society Drug and Therapeutics/Rare Diseases Committee and then by the Pediatric Endocrine Society Board of Directors.nnnConclusionsnThere is limited literature evidence regarding monitoring of evolving adrenal insufficiency in male infants and children with ALD. The recommendations suggest initiating assessment of adrenal function at diagnosis with ALD and regular monitoring to identify boys with adrenal insufficiency in a timely manner and prevent life-threatening adrenal crisis. These recommendations are intended to serve as an initial guide, with the understanding that additional experience will inform future guidelines.