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Haddow J.E.,Brown University | Haddow J.E.,Savjani Institute for Health Research | Craig W.Y.,Maine Medical Center Research Institute | Neveux L.M.,Brown University | And 48 more authors.
PLoS ONE | Year: 2016

Several studies have now reported associations between gestational diabetes mellitus (GDM) and low free thyroxine (fT4) during the second and third trimesters, but not in the first trimester. The present study further examines relationships between low fT4, maternal weight, and GDM among women in the FaSTER (First and Second Trimester Evaluation of Risk) trial, in an effort to determine the extent to which thyroid hormones might contribute to causality. The FaSTER cohort includes 9351 singleton, euthyroid women; 272 of these women were subsequently classified as having GDM. Thyrotropin (TSH), fT4, and thyroid antibodies were measured at 11-14 weeks' gestation (first trimester) and 15-18.9 weeks' gestation (second trimester). An earlier report of this cohort documented an inverse relationship between fT4 in the second trimester and maternal weight. In the current analysis, women with GDM were significantly older (32 vs. 28 years) and weighed more (75 vs. 64.5 kg). Maternal weight and age (but not TSH) were significantly associated univariately with fT4 (dependent variable), in the order listed. Second trimester fT4 odds ratios (OR) for GDM were 2.06 [95% CI1.37-3.09] (unadjusted); and 1.89 [95% CI1.26-2.84] (adjusted). First trimester odds ratios were not significant: OR 1.45 [95%CI 0.97-2.16] (unadjusted) and 1.11 [95% CI 0.74-1.62] (adjusted). The second trimester fT4/GDM relationship thus appeared to strengthen as gestation progressed. In FaSTER, high maternal weight was associated with both low fT4 and a higher GDM rate in the second trimester. Peripheral deiodinase activity is known to increase with high caloric intake (represented by high weight). We speculate that weight-related lowfT4 (the metabolically inactive prohormone) is a marker for deiodinase activity, serving as a substrate for conversion of fT4 to free triiodothyronine (fT3), the active hormone responsible for glucose-related metabolic activity. © 2016 Haddow et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Haddow J.E.,Brown University | Haddow J.E.,Savjani Institute for Health Research | Craig W.Y.,Foundation for Blood Research | Palomaki G.E.,Brown University | And 8 more authors.
Thyroid | Year: 2013

Background: Among euthyroid pregnant women in a large clinical trial, free thyroxine (FT4) measurements below the 2.5th centile were associated with a 17 lb higher weight (2.9 kg/m2) than in the overall study population. We explore this relationship further. Methods: Among 9351 women with second trimester thyrotropin (TSH) measurements between 1st and 98th centiles, we examine: (i) the weight/FT4 relationship; (ii) percentages of women in three weight categories at each FT4 decile; (iii) FT4 concentrations in three weight categories at each TSH decile; and (iv) impact of adjusting FT4 for weight-in the reference group and in 190 additional women with elevated TSH measurements. Results: FT4 values decrease steadily as weight increases (p<0.0001 by ANOVA) among women in the reference group (TSH 0.05-3.8 IU/L). TSH follows no consistent pattern with weight. When stratified into weight tertiles, 48% of women at the lowest FT4 decile are heavy; the percentage decreases steadily to 22% at the highest FT4 decile. Median FT4 is lowest in heaviest women regardless of the TSH level. In the reference group, weight adjustment reduces overall variance by 2.9%. Fewer FT4 measurements are at either extreme (below the 5th FT4 centile: 4.8% before adjustment, 4.7% after adjustment; above the 95th FT4 centile: 5.0% and 4.7%, respectively). Adjustment places more light weight women and fewer heavy women below the 5th FT4 centile; the converse above the 95th centile. Between TSH 3.8 and 5 IU/L, the FT4 percentage below the 5th FT4 centile is not elevated (3.8% before adjustment, 3.1% after adjustment). Percentage of FT4 values above the 95th centile, however, is lower (1.5% before adjustment, 0.8% after adjustment). Above TSH 5 IU/L, 25% of women have FT4 values below the 5th FT4 centile; weight adjustment raises this to 30%; no FT4 values remain above the 95th FT4 centile. Conclusions: During early pregnancy, TSH values are not associated with weight, unlike nonpregnant adults. Lower average FT4 values among heavy women at all TSH deciles partially explain interindividual differences in FT4 reference ranges. The continuous reciprocal relationship between weight and FT4 explains lower FT4 with higher weight. Weight adjustment refines FT4 interpretation. © 2013, Mary Ann Liebert, Inc.


Haddow J.E.,Brown University | Haddow J.E.,Savjani Institute for Health Research
Expert Review of Obstetrics and Gynecology | Year: 2013

Despite the lack of consensus among groups issuing recent guidelines, it is possible to identify options that are available for prenatal practitioners. Examples include the following: iodine supplements to protect against hypothyroidism; adjusting l-thyroxine dosage upward in women with previously diagnosed hypothyroidism to account for increased pregnancy needs; and screening for undetected thyroid deficiency via targeted questions and/or thyroid-stimulating hormone testing. Decision-making about thyroid status requires access to reliable, trimester-specific normative data for both thyroid-stimulating hormone and free thyroxine, as well as an understanding of the impact of human chorionic gonadotropin on thyroid function, especially during the first trimester. Continuity of care is enhanced by systematic follow-up postpartum, including attention to postpartum thyroid dysfunction that often occurs among women with raised antibody levels. © 2013 2013 Expert Reviews Ltd.


March M.I.,Beth Israel Deaconess Medical Center | Geahchan C.,Beth Israel Deaconess Medical Center | Wenger J.,Harvard University | Raghuraman N.,Beth Israel Deaconess Medical Center | And 12 more authors.
PLoS ONE | Year: 2015

Objective: Angiogenic factors are strongly associated with adverse maternal and fetal outcomes among women with preterm preeclampsia (PE) in developed countries. We evaluated the role of angiogenic factors and their relationship to adverse outcomes among Haitian women with PE. Material and Methods: We measured plasma antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and proangiogenic placental growth factor (PlGF) levels in women with PE (n=35) compared to controls with no hypertensive disorders (NHD) (n=43) among subjects with singleton pregnancies that delivered at Hospital Albert Schweitzer (HAS) in Haiti. We divided the preeclamptic women into two groups, early onset (≤ 34 weeks) and late onset (>34 weeks) and examined relationships between sFlt1/PlGF ratios on admission and adverse outcomes (abruption, respiratory complications, stroke, renal insufficiency, eclampsia, maternal death, birth weight <2500 grams, or fetal/neonatal death) in women with PE subgroups as compared to NHD groups separated by week of admission. Data are presented as median (25th-75th centile), n (%), and proportions. Results: Among patients with PE, most (24/35) were admitted at term. Adverse outcome rates in PE were much higher among the early onset group compared to the late onset group (100.0% vs. 54.2%, P=0.007). Plasma angiogenic factors were dramatically altered in both subtypes of PE. Angiogenic factors also correlated with adverse outcomes in both subtypes of PE. The median sFlt1/PlGF ratios for subjects with early onset PE with any adverse outcome vs. NHD <=34 weeks with no adverse outcome were 703.1 (146.6, 1614.9) and 9.6 (3.5, 58.6); P<0.001). Among late onset group the median sFlt1/PlGF ratio for women with any adverse outcome was 130.7 (56.1, 242.6) versus 22.4 (10.2, 58.7; P=0.005) in NHD >34 weeks with no adverse outcome. Conclusion: PE-related adverse outcomes are common in women in Haiti and are associated with profound angiogenic imbalance regardless of gestational age at presentation. © 2015 March et al.


Palomaki G.E.,Brown University | Palomaki G.E.,Savjani Institute for Health Research | Haddow J.E.,Brown University | Haddow J.E.,Savjani Institute for Health Research | And 17 more authors.
Prenatal Diagnosis | Year: 2015

Introduction: Preeclampsia (PE) is a pregnancy-specific syndrome associated with adverse maternal and fetal outcomes. Patient-specific risks based on angiogenic factors might better categorize those who might have a severe adverse outcome. Methods: Women evaluated for suspected PE at a tertiary hospital (2009-2012) had pregnancy outcomes categorized as 'referent' or 'severe', based solely on maternal/fetal findings. Outcomes that may have been influenced by a PE diagnosis were considered 'unclassified'. Soluble fms-like tyrosine kinase (sFlt1) and placental growth factor (PlGF) were subjected to bivariate discriminant modeling, allowing patient-specific risks to be assigned for severe outcomes. Results: Three hundred twenty-eight singleton pregnancies presented at ≤34.0weeks' gestation. sFlt1 and PlGF levels were adjusted for gestational age. Risks above 5:1 (10-fold over background) occurred in 77% of severe (95% CI 66 to 87%) and 0.7% of referent (95% CI <0.1 to 3.8%) outcomes. Positive likelihood ratios for the modeling and validation datasets were 19 (95% CI 6.2-58) and 15 (95% CI 5.8-40) fold, respectively. Conclusions: This validated model assigns patient-specific risks of any severe outcome among women attending PE triage. In practice, women with high risks would receive close surveillance with the added potential for reducing unnecessary preterm deliveries among remaining women. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.


Pinar H.,Brown University | Palomaki G.E.,Brown University | Haddow H.R.M.,Savjani Institute for Health Research | Rowles A.,Brown University | Torabi R.,Brown University
Pediatric and Developmental Pathology | Year: 2014

Identifying growth abnormalities in stillbirths is clinically useful but complicated by maceration. This is an observational study of consecutive postmortem examinations in which femur lengths and gestational age at delivery were collected, along with associated congenital anomalies and extent of fetal maceration. Between 2005 and 2012, 1530 consecutive postmortem examinations were performed and the information recorded. Fragmented fetuses (417), live-born fetuses that survived for more than 24 hours (134), fetuses with any signs of maceration (419), fetuses with known anomalies (98), and records with missing data (249) were excluded. The analyses focused on the remaining 265 nonmacerated stillborn fetuses and infants that survived for less than 24 hours after birth. The relationship between gestational age at delivery and femur length was computed, and a quadratic equation fit the data well between 12 and 40 weeks' gestation (R 5 0.944). Gestational age-specific reference ranges for radiographic femur measurements in stillbirths are equivalent to those for ultrasound-determined measurements in ongoing pregnancies. These reference data may be useful in identifying growth abnormalities in nonmacerated stillborn fetuses. © 2014 Society for Pediatric Pathology.


Palomaki G.E.,Women and Infants Hospital | Palomaki G.E.,Brown University | Palomaki G.E.,Savjani Institute for Health Research | Kloza E.M.,Women and Infants Hospital | And 11 more authors.
Prenatal Diagnosis | Year: 2015

Objective: The proportion of circulating cell free DNA derived from the feto-placental unit (fetal fraction or FF) correlates with test success and interpretation reliability. Some fetal disorders are associated with systematically lower FF, sometimes resulting in noninformative results. Methods: We analyzed results from pregnancies tested in a nested case/control study derived from a cohort of 4664 high-risk pregnancies. Low FF was defined before and after adjusting for maternal weight and gestational age. Results: Compared with euploid pregnancies, the median FF was significantly higher in Down syndrome pregnancies (ratio 1.17) and significantly lower in trisomy 18 and triploid pregnancies (ratios 0.71 and 0.19, respectively). Among 2157 pregnancies tested, 13 (0.6%) had FF <3.0% (all noninformative), including three trisomy 18 and three triploidy fetuses. After adjustment, 16 pregnancies (0.7%) had FF <0.3 multiples of the median (six informative), including one trisomy 18 and three triploidy fetuses. Modeled positive predictive values for low and high-risk populations were 7% and 30%, respectively. Conclusion: Among women with noninformative results attributable to low FF, trisomy 18 and/or triploidy risk are sufficiently high to warrant offering additional assessments (e.g. ultrasound). If the testing indication is ultrasound abnormality, amniocentesis and karyotype/microarray should be considered. © 2014 John Wiley & Sons, Ltd.


Haddow J.E.,Brown University | Haddow J.E.,Savjani Institute for Health Research | Haddow J.E.,Women and Infants Hospital | Neveux L.M.,Brown University | And 7 more authors.
Thyroid | Year: 2015

Background: Following treatment sufficient to normalize thyrotropin (TSH), nonpregnant hypothyroid adults display higher free thyroxine (FT4) concentrations than a reference population. Our aim is to determine whether FT4 concentrations are higher during pregnancy among women treated for hypothyroidism and whether their weight is associated with FT4 levels. Weight/FT4 relationships have not previously been reported in treated hypothyroid adults (either pregnant or nonpregnant). Methods: Thyroid-related measurements were available from over 10,000 women at two early pregnancy time periods from the FaSTER (First and Second Trimester Evaluation of Risk for Fetal aneuploidy) trial (1999-2002). All women were receiving routine prenatal care. Present analyses were restricted to 9267 reference women and 306 treated, hypothyroid women with TSH between the 2nd and 98th reference percentiles. We compared FT4 values between those groups at 11-14 and 15-18 weeks' gestation, using linear regression to estimate FT4/maternal weight relationships, after accounting for treatment and other potential covariates. Results: In comparison to reference women, median FT4 values and percent of FT4 values ≥95th reference percentile were significantly higher in treated women at both 11-14 and 15-18 weeks' gestation (p<0.001) overall and after stratification by weight into tertiles. Among both treated and reference women, median FT4 decreased monotonically with increasing weight, regardless of anti-thyroperoxidase antibody status. Maternal age, maternal weight, and treatment status were important predictors of FT4 levels (p<0.001, defined by partial r2 values of 1% or higher). Anti-thyroperoxidase antibody status, TSH values (after logarithmic transformation), and all interaction terms were well below an r2 of 1%. FT4 levels were 1.45 pmol/L higher in treated than reference women, independent of other factors. Maternal age and weight reduced FT4 levels by 0.0694 pmol/L/y and 0.0208 pmol/L/kg, respectively. Conclusions: FT4 concentrations are higher among treated hypothyroid pregnant women than among reference women, and higher maternal weight is associated with lower FT4 levels, regardless of treatment status. This inverse relationship is not associated with higher TSH levels. While no immediate clinical implications are attached to the current observations, increased peripheral deiodinase activity in the presence of higher weight might explain these findings. Further investigation appears worthy of attention. © Copyright 2015, Mary Ann Liebert, Inc.


Haddow J.E.,Brown University | Haddow J.E.,Savjani Institute for Health Research | Craig W.Y.,Foundation for Blood Research | Neveux L.M.,Brown University | And 8 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Lower birth weight has been reported in conjunction with high maternal free T4 (FT4) in euthyroid pregnancies, raising concerns for suboptimal outcomes. Objective: The objective of the study was to explore the relationships between high maternal FT4 and pregnancy complications in euthyroidwomenand to further examine the relationshipsamong maternal size, FT4, and birth weight. Design: This was an observational multicenter cohort study. Setting: The study was conducted at prenatal clinics. Study Subjects: A total of 9209 euthyroid women with singleton pregnancies participated in the study. Interventions: There were no interventions. Main Outcome Measures: Relationships between second-trimester high maternal FT4 and pregnancy/ delivery complications and, among FT4, maternal weight and birth weight were measured. Results: Women in the highest FT4 quintile are younger and weigh less than women in quintiles 1-4; gestational diabetes and preeclampsia occur less often (P = < .001, P < .001, P < .001, and P=.05, respectively). Lowest median birth weight occursamongwomenin the highest FT4 quintile (P = < .001), but deliveries less than 37 weeks' gestation are not increased. Labor/delivery complications do not differ by FT4 quintile. Restricting analyses to maternal weight-adjusted smallfor- gestational-age deliveries yields similar results, except for preeclampsia. In the highest maternal weight decile, adjusted median birth weight is 266 g higher (8.3%) than in the lowest weight decile; adjusted median FT4 is 0.91 pmol/L lower (6.8%). Among women in the highest FT4 decile, adjusted median birth weight is 46 g lower (1.3%) than in the lowest FT4 decile. All three relationships are statistically significant (P < .001, P < .001, and P = .004, respectively). Conclusions: Lower median birth weight among euthyroid women with high FT4 is not associated with adverse pregnancy outcomes. Further investigation is indicated to determine how the variations in thyroid hormone concentration influence birth weight. © 2014 by the Endocrine Society.

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