Scott Sullivan

Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline

OBJECTIVE The aim was to update the guidelines for the management of thyroid dysfunction during pregnancy and postpartum published previously in 2007. A summary of changes between the 2007 and 2012 version is identified in the Supplemental Data (published on The Endocrine Societys Journals Online web site at http://jcem.endojournals.org). EVIDENCE This evidence-based guideline was developed according to the U.S. Preventive Service Task Force, grading items level A, B, C, D, or I, on the basis of the strength of evidence and magnitude of net benefit (benefits minus harms) as well as the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS The guideline was developed through a series of e-mails, conference calls, and one face-to-face meeting. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocrine Society, Asia and Oceania Thyroid Association, and the Latin American Thyroid Society. A second draft was reviewed and approved by The Endocrine Society Council. At each stage of review, the Task Force received written comments and incorporated substantive changes. CONCLUSIONS Practice guidelines are presented for diagnosis and treatment of patients with thyroid-related medical issues just before and during pregnancy and in the postpartum interval. These include evidence-based approaches to assessing the cause of the condition, treating it, and managing hypothyroidism, hyperthyroidism, gestational hyperthyroidism, thyroid autoimmunity, thyroid tumors, iodine nutrition, postpartum thyroiditis, and screening for thyroid disease. Indications and side effects of therapeutic agents used in treatment are also presented.

Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum

Pregnancy has a profound impact on the thyroid gland and thyroid function. The gland increases 10% in size during pregnancy in iodine-replete countries and by 20%– 40% in areas of iodine deficiency. Production of thyroxine (T4) and triiodothyronine (T3) increases by 50%, along with a 50% increase in the daily iodine requirement. These physiological changes may result in hypothyroidism in the later stages of pregnancy in iodine-deficient women who were euthyroid in the first trimester. The range of thyrotropin (TSH), under the impact of placental human chorionic gonadotropin (hCG), is decreased throughout pregnancy with the lower normal TSH level in the first trimester being poorly defined and an upper limit of 2.5 mIU/L. Ten percent to 20% of all pregnant women in the first trimester of pregnancy are thyroid peroxidase (TPO) or thyroglobulin (Tg) antibody positive and euthyroid. Sixteen percent of the women who are euthyroid and positive for TPO or Tg antibody in the first trimester will develop a TSH that exceeds 4.0 mIU/L by the third trimester, and 33%–50% of women who are positive for TPO or Tg antibody in the first trimester will develop postpartum thyroiditis. In essence, pregnancy is a stress test for the thyroid, resulting in hypothyroidism in women with limited thyroidal reserve or iodine deficiency, and postpartum thyroiditis in women with underlying Hashimoto’s disease who were euthyroid prior to conception. Knowledge regarding the interaction between the thyroid and pregnancy/the postpartum period is advancing at a rapid pace. Only recently has a TSH of 2.5 mIU/L been accepted as the upper limit of normal for TSH in the first trimester. This has important implications in regards to interpretation of the literature as well as a critical impact for the clinical diagnosis of hypothyroidism. Although it is well accepted that overt hypothyroidism and overt hyperthyroidism have a deleterious impact on pregnancy, studies are now focusing on the potential impact of subclinical hypothyroidism and subclinical hyperthyroidism on maternal and

Iodine Supplementation During Pregnancy and Lactation

DIETARY IODINE INTAKE IS OBLIGATORY FOR THE PROduction of thyroid hormones. Despite substantial public health advances over the past 3 decades, iodine deficiency currently affects 1.92 billion people globally. Dietary iodine requirements are increased during pregnancy due to increased thyroid hormone production, increased renal iodine losses, and fetal iodine requirements. Dietary requirements remain increased in lactation due to the concentration of iodine in breast milk. Adverse effects of iodine deficiency in pregnancy, when the deficiency leads to severe decreases in maternal thyroxine (T4), include maternal and fetal goiter, cretinism, intellectual impairments, neonatal hypothyroidism, and increased pregnancy loss and infant mortality. Decreases in maternal T4 associated with even mild iodine deficiency may have adverse effects on the cognitive function of offspring, and iodine deficiency remains the leading cause of preventable intellectual disability worldwide.

N-acetylcysteine attenuates the maternal and fetal proinflammatory response to intrauterine LPS injection in an animal model for preterm birth and brain injury

Objective. Maternal immune activation (MIA) is associated with preterm birth (PTB) and abnormal neurologic outcome. We hypothesized that N-acetylcysteine (NAC) would decrease PTB and neonatal brain injury acting as an anti-inflammatory. Methods. Pregnant CD-1 mice received intrauterine LPS or saline on day 15/20. They received NAC or saline and were monitored until delivery. Pups were followed and sacrificed on postnatal days 1/30 and brains were collected. Immunostaining for heavy-chain neurofilament protein (NF-H), myelin basic protein (MBP), and proteolipid protein (PLP) was performed. In another group, animals were sacrificed 6 h after treatment, and fetal brain, placenta, and myometrium were collected. Il-6, Il-1β, Il-10, and tumor necrosis factor (TNF)-α mRNA expression was determined. Nonparametric analysis was used for analysis, and pairwise comparisons were performed when appropriate. Results. Lipopolysaccharide (LPS) caused PTB (79 vs. 0%, p < 0.005), and this was reduced by NAC [0.45 (95% CI: 0.26–0.83), p < 0.008]. LPS increased IL-6 expression in myometrium and placenta. This was attenuated by NAC in myometrium. IL-1β, IL-6, and TNF-α expression increased in the fetal brain with LPS. LPS produced altered NF-H, MBP, and PLP staining, and these effects were attenuated by NAC. Conclusion. NAC attenuates inflammation in this MIA model and reduces PTB and white matter injury. It is an interesting candidate for study for prevention of PTB and neurologic injury.

Development and validation of a spontaneous preterm delivery predictor in asymptomatic women.

BACKGROUND Preterm delivery remains the leading cause of perinatal mortality. Risk factors and biomarkers have traditionally failed to identify the majority of preterm deliveries. OBJECTIVE To develop and validate a mass spectrometry-based serum test to predict spontaneous preterm delivery in asymptomatic pregnant women. STUDY DESIGN A total of 5501 pregnant women were enrolled between 17(0/7) and 28(6/7) weeks gestational age in the prospective Proteomic Assessment of Preterm Risk study at 11 sites in the United States between 2011 and 2013. Maternal blood was collected at enrollment and outcomes collected following delivery. Maternal serum was processed by a proteomic workflow, and proteins were quantified by multiple reaction monitoring mass spectrometry. The discovery and verification process identified 2 serum proteins, insulin-like growth factor-binding protein 4 (IBP4) and sex hormone-binding globulin (SHBG), as predictors of spontaneous preterm delivery. We evaluated a predictor using the log ratio of the measures of IBP4 and SHBG (IBP4/SHBG) in a clinical validation study to classify spontaneous preterm delivery cases (<37(0/7) weeks gestational age) in a nested case-control cohort different from subjects used in discovery and verification. Strict blinding and independent statistical analyses were employed. RESULTS The predictor had an area under the receiver operating characteristic curve value of 0.75 and sensitivity and specificity of 0.75 and 0.74, respectively. The IBP4/SHBG predictor at this sensitivity and specificity had an odds ratio of 5.04 for spontaneous preterm delivery. Accuracy of the IBP4/SHBG predictor increased using earlier case-vs-control gestational age cutoffs (eg, <35(0/7) vs ≥35(0/7) weeks gestational age). Importantly, higher-risk subjects defined by the IBP4/SHBG predictor score generally gave birth earlier than lower-risk subjects. CONCLUSION A serum-based molecular predictor identifies asymptomatic pregnant women at risk of spontaneous preterm delivery, which may provide utility in identifying women at risk at an early stage of pregnancy to allow for clinical intervention. This early detection would guide enhanced levels of care and accelerate development of clinical strategies to prevent preterm delivery.

N-acetylcysteine prevents preterm birth by attenuating the LPS-induced expression of contractile associated proteins in an animal model

Objective: Intrauterine infection is associated with maternal immune activation (MIA) leading to preterm birth through upregulation of contractile associated proteins (CAPs). We hypothesized that N-acetylcysteine would decrease NF-κB activation and CAP expression in a MIA model for preterm birth. Methods: Pregnant CD-1 mice were given intrauterine LPS or saline on day 15/20. They received NAC or saline prior to injection and were monitored until delivery. The rate of preterm birth in the control, LPS, and LPS + NAC animals was determined. In another group, animals were sacrificed 6 h after treatment and myometrium was collected. COX-2, connexin 43, and oxytocin receptor expression was determined. Results: LPS administration resulted in preterm birth and this effect was attenuated by NAC. LPS increased COX-2, connexin 43, and oxytocin receptor expression. NAC significantly decreased COX-2 expression. LPS increased NF-κB activation; this was attenuated by NAC. Conclusion: NAC may be beneficial in prevention of MIA-related preterm birth through attenuation of NF-κB activation and COX-2 upregulation.

South Carolina Partners for Preterm Birth Prevention: a regional perinatal initiative for the reduction of premature birth in a Medicaid population

OBJECTIVE The objective of the study was to improve the distribution of preterm deliveries in a Medicaid population through a regional perinatal risk assessment and case management initiative. STUDY DESIGN An innovative public/private partnership was initiated in the 8 county Lowcountry (LC) perinatal region to reduce preterm birth (PTB) among Medicaid recipient women. Eligible women were identified and underwent telephonic risk assessment, education, and access to a 24 hours, 7 days per week perinatal hotline. Women with predetermined risk factors for PTB were offered patient-centered case management. Medicaid claims and birth certificate data were used to compare obstetric outcomes for 2006 (intervention) and 2004 (control) in both the Lowcountry (LC; program) and Midlands (ML; nonprogram) perinatal regions. RESULTS There were 6356 Medicaid deliveries in the LC in 2006. Of these, 2111 were referred for telephonic risk assessment; 317 had identifiable PTB risk factors and consented to case management. Compared with 2004, there was a significant improvement in the distribution of preterm birth (P = .05) in the LC region, primarily confined to deliveries less than 28 weeks (1.6% vs 1.1%; P = .029, relative risk [RR] 0.75, 95% confidence interval [CI], 0.51-0.96). There were also reductions in the frequency (6.7% vs 5.8%; RR 0.86, 95% CI, 0.75-0.98; P = .04) and mean duration (25.0 vs 20.6 days; 95% CI, 1.03-7.77; P = .01) of neonatal intensive care unit (NICU) admissions. No changes were identified in the ML region. CONCLUSION A regional initiative of telephonic risk assessment and case management of Medicaid recipient women significantly reduced deliveries less than 28 weeks and NICU care.

Blunt needles for the reduction of needlestick injuries during cesarean delivery: a randomized controlled trial.

OBJECTIVE: To compare the rate of glove perforation as a proxy for needlestick injuries between blunt and sharp needles used during cesarean-delivery closure and to survey physician satisfaction with blunt needles. METHODS: Patients requiring cesarean delivery were assigned randomly to receive closure with either blunt (study group) or sharp needles (control group). Patient demographics, operator experience, and other clinical variables were collected. Physicians reported any percutaneous injuries and were surveyed regarding satisfaction with the assigned needles. Glove perforation was determined using a validated water-test method. Differences between patient groups were tested using &khgr;2 and Fisher exact test for categorical variables and Student t-test or Wilcoxon rank-sum test for continuous variables. RESULTS: There were 194 patients enrolled in the trial: 97 in the control group and 97 in the study group. There were no statistical differences between groups in patient demographics. There were no differences between groups in clinical variables, type of cesarean delivery, or experience level of the surgeon. There was a significant reduction in total glove perforation rate for the primary surgeon with blunt needles (7.2%) compared with sharp needles (17.5%) (relative risk [RR] 0.66, 95% confidence interval [CI] 0.49–0.89) as well as for the assistant surgeon (RR 0.54, 95% CI 0.41–0.71). There was poor correlation between reported perforations and those detected by water test (R2=0.3). Physicians reported that they were not as satisfied with blunt needles compared with sharp needles (P=.001). CONCLUSION: There was a significant decrease in the rate of glove perforation for surgeons and assistants performing cesarean-delivery closure with blunt needles. Assistant surgeons had the greatest reduction in glove perforations. However, physicians reported decreased satisfaction performing the surgery with blunt needles. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00844636 LEVEL OF EVIDENCE: I

The use of blunt needles does not reduce glove perforations during obstetrical laceration repair

OBJECTIVE The objective of the study was to compare the rate of glove perforation for blunt and sharp needles used during obstetrical laceration repair. A secondary aim was to assess physician satisfaction with blunt needles. STUDY DESIGN This was an institutional review board-approved, randomized, prospective trial. Patients with obstetric lacerations were randomized to repair with either blunt or sharp needles. Patient demographics, operator experience, and other clinical variables were collected. Physicians reported any percutaneous injuries and were surveyed regarding satisfaction with the assigned needles. Glove perforation was determined using a validated water test method. RESULTS There were 438 patients enrolled in the trial: 221 in the control group and 217 in the study group. There was no statistical difference between groups in patient demographics, clinical variables, severity of laceration, or experience level of the surgeon. There was no difference in the glove perforation rate between blunt and sharp needles (risk ratio, 0.79; 95% confidence interval, 0.2-2.95). There was poor correlation between reported perforations and those detected by water test (R(2) = 0.33). The physicians reported that blunt needles were more difficult to use than sharp needles (P = .0001). CONCLUSION There was no difference in the rate of surgical glove perforation for blunt, compared with sharp, needles used during vaginal laceration repair. Physicians also reported increased difficulty performing the repair with blunt needles.

Severe hypercalcemia associated with uterine leiomyoma in pregnancy.

BACKGROUND: Uterine leiomyomas are the most common pelvic tumor, and a frequent indication of the need for gynecologic surgery. Although usually asymptomatic, life-threatening cases can occur. We present a case of critical hypercalcemia associated with a leiomyoma during pregnancy with the intention of highlighting the endocrinology of leiomyomas, features shared with malignant neoplasms, and the potential for effects on obstetric outcomes. CASE: A 32-year-old gravid woman with a large leiomyoma presented at 33 5/7 weeks of gestation with critical hypercalcemia requiring intensive care. Postpartum myomectomy cured her hypercalcemia, which was driven by parathyroid hormone-related protein (PTHrP) produced by the tumor. CONCLUSION: Obstetricians should be aware of the existence of humoral hypercalcemia related to leiomyomas and the potential effects on pregnancy.