scholarly journals Exposure to Perflouroalkyl acids and foetal and maternal thyroid status: a review

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Sophie A. H. Boesen ◽  
Manhai Long ◽  
Maria Wielsøe ◽  
Vicente Mustieles ◽  
Mariana F. Fernandez ◽  
...  
Keyword(s):  
Thyroid Stimulating Hormone ◽  
Inverse Association ◽  
Postnatal Exposure ◽  
Free Triiodothyronine ◽  
Perfluorodecanoic Acid ◽  
Pubmed Database ◽  
Thyroid Disruption ◽  
Total Thyroxine ◽  
Maternal Thyroid ◽  
Perfluorinated Alkyl Acids

Abstract Background Exposure to perfluorinated-alkyl-acids (PFAAs) is ubiquitous. PFAAs are hormone-disrupting compounds that are strongly suspected to affect mother-child-health such as fetal growth. Thyroid disruption is a plausible mechanism of action. We aim to summarize the epidemiological evidence for the relation between prenatal and postnatal exposure to PFAAs and disruption of thyroid homeostasis in mothers and/or infants. Method Fifteen original publications on PFAAs concentrations and thyroid hormones (TH) in pregnant women and/or infants were found upon a literature search in the PubMed database. Information on exposure to seven PFAAs congeners [Perfluorooctane sulfonate (PFOS), Perfluorooctanoate (PFOA), Perfluorohexane sulfonate (PFHxS), Perfluorononanoic acid (PFNA), Perfluorodecanoic acid (PFDA), Perfluoroundecanoic acid (PFUnA), and Perfluorododecanoic acid (PFDoA)] and thyroid stimulating hormone (TSH), free and total thyroxine (FT4 and TT4), free and total triiodothyronine (FT3 and TT3), T3RU (Free triiodothyronine resin uptake) and FT4-index (FT4I) levels were recorded. We evaluated sampling of maternal TH by trimester, and infant TH by sex stratification. Reported associations between mother or infant PFAAs and TH were not uniformly assessed in the selected studies. Results Ten out of the fifteen studies examined maternal PFAAs concentration and TSH level. Seven studies showed significant associations between TSH and exposure to six PFAAs congeners, most of them were positive. Maternal T4 and T3 were investigated in nine studies and five studies found inverse associations between exposure to six PFAAs congeners and TH (TT3, TT4, FT3, FT4 and FT4I) levels. Eight of the fifteen studies investigated PFAAs concentrations and infant TSH. Infant TSH level was significantly affected in four studies, positively in three studies. Nine studies investigated infant T4 and T3 and seven studies found significant associations with PFAAs exposure. However, both inverse and positive significant associations with infant TH were found eliciting no clear direction. Conclusion Results indicate a mainly positive relationship between maternal PFAAs concentrations and TSH levels, and suggestion of an inverse association with T4 and/or T3 levels. Associations of infant TH with PFAAs concentration were less consistent.

scholarly journals Impact of thyroid hormones on asthma in older adults

2019 ◽  
Vol 47 (9) ◽  
pp. 4114-4125 ◽  
Author(s):  
Zhan Bingyan ◽  
Wei Dong
Keyword(s):  
Respiratory Failure ◽  
Thyroid Hormones ◽  
Pulmonary Function ◽  
Correlation Coefficients ◽  
Forced Expiratory Volume ◽  
Thyroid Stimulating Hormone ◽  
Type I ◽  
Free Triiodothyronine ◽  
Specific Effects ◽  
Total Thyroxine

Objective Thyroid hormones affect airway contraction, but the specific effects of thyroid hormones on airways are controversial. Methods We divided 78 advanced-age men with asthma into 3 groups: type I respiratory failure (RF1), type II respiratory failure (RF2), and no respiratory failure (NRF). Pulmonary function was measured after asthma stabilization. Results The free triiodothyronine (FT3) level was significantly higher in the RF1 than RF2 group, but the free thyroxine (FT4), total thyroxine (TT4), and thyroid-stimulating hormone (TSH) levels were not significantly different. In the RF1, RF2, and NRF groups, the correlation coefficients between FT3 and the forced expiratory volume in1 s (FEV1) were 0.317, 0.627, and 0.213; those between FT3 and the FEV1/forced vital capacity (FVC) ratio were 0.287, 0.412, and 0.156; those between FT4 and FEV1 were 0.214, 0.231, and 0.167; and those between FT4 and the FEV1/FVC ratio were 0.211, 0.215, and 0.218, respectively. In the RF1 and RF2 groups, the correlation coefficients between the sum activity of peripheral deiodinases (SPINA-GD) and the FEV1/FVC ratio were 0.164 and 0.421, and those between SPINA-GD and FEV1 were 0.284 and 0.491, respectively. Conclusion The correlation between FT3 and pulmonary function is likely caused by changes in thyroid enzymology.

scholarly journals Marked Biological Variance in Endocrine and Biochemical Markers in Childhood: Establishment of Pediatric Reference Intervals Using Healthy Community Children from the CALIPER Cohort

2013 ◽  
Vol 59 (9) ◽  
pp. 1393-1405 ◽  
Author(s):  
Dana Bailey ◽  
David Colantonio ◽  
Lianna Kyriakopoulou ◽  
Ashley H Cohen ◽  
Man Khun Chan ◽  
...  
Keyword(s):  
Reference Values ◽  
Biochemical Markers ◽  
Troponin I ◽  
Reference Intervals ◽  
Thyroid Stimulating Hormone ◽  
Healthy Children ◽  
Free Triiodothyronine ◽  
Laboratory Test Results ◽  
Total Triiodothyronine ◽  
Total Thyroxine

BACKGROUND Reference intervals are indispensable in evaluating laboratory test results; however, appropriately partitioned pediatric reference values are not readily available. The Canadian Laboratory Initiative for Pediatric Reference Intervals (CALIPER) program is aimed at establishing the influence of age, sex, ethnicity, and body mass index on biochemical markers and developing a comprehensive database of pediatric reference intervals using an a posteriori approach. METHODS A total of 1482 samples were collected from ethnically diverse healthy children ages 2 days to 18 years and analyzed on the Abbott ARCHITECT i2000. Following the CLSI C28-A3 guidelines, age- and sex-specific partitioning was determined for each analyte. Nonparametric and robust methods were used to establish the 2.5th and 97.5th percentiles for the reference intervals as well as the 90% CIs. RESULTS New pediatric reference intervals were generated for 14 biomarkers, including α-fetoprotein, cobalamin (vitamin B12), folate, homocysteine, ferritin, cortisol, troponin I, 25(OH)-vitamin D [25(OH)D], intact parathyroid hormone (iPTH), thyroid-stimulating hormone, total thyroxine (TT4), total triiodothyronine (TT3), free thyroxine (FT4), and free triiodothyronine. The influence of ethnicity on reference values was also examined, and statistically significant differences were found between ethnic groups for FT4, TT3, TT4, cobalamin, ferritin, iPTH, and 25(OH)D. CONCLUSIONS This study establishes comprehensive pediatric reference intervals for several common endocrine and immunochemical biomarkers obtained in a large cohort of healthy children. The new database will be of global benefit, ensuring appropriate interpretation of pediatric disease biomarkers, but will need further validation for specific immunoassay platforms and in local populations as recommended by the CLSI.

scholarly journals Relationship between Different Psoriasis Types and Thyroid Dysfunction: A Retrospective Analysis

Scanning ◽  
2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
Juan Du ◽  
Chunyue Ma ◽  
Runnan Wang ◽  
Lanmei Lin ◽  
Luhui Gao ◽  
...  
Keyword(s):  
Psoriatic Arthritis ◽  
Thyroid Function ◽  
Thyroid Dysfunction ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Peroxidase ◽  
Thyroid Function Tests ◽  
Free Triiodothyronine ◽  
Hormone Levels ◽  
Significant Difference ◽  
Total Thyroxine

Objective. The aim of this study was to investigate the relationship between different psoriasis types and thyroid dysfunction. Methods. The data of patients diagnosed with psoriasis between January 2013 and October 2018 who underwent thyroid function tests were collected. Free triiodothyronine (FT3), free thyroxine (FT4), total triiodothyronine (TT3), total thyroxine (TT4), thyroid-stimulating hormone (TSH), thyroglobulin antibody (TGAb), and thyroid peroxidase antibody (TPOAb) were measured. The thyroid function of patients with psoriasis vulgaris, pustular psoriasis, erythrodermic psoriasis, and psoriatic arthritis was evaluated, and the differences in hormone levels and antibodies in the pituitary-thyroid axis with psoriasis type were analyzed. Results. The data of a total of 468 patients were analyzed in this study. The proportion of normal hormone levels was higher among vulgaris patients ( P < 0.001 ), while the erythrodermic patients were more likely to have decreased FT3 or FT4 but normal TSH ( P < 0.001 ). FT3 levels were lower in pustular patients ( P < 0.05 ), FT4 levels were lower in erythrodermic patients ( P < 0.05 ), and TSH levels were higher in patients with psoriatic arthritis ( P < 0.05 ). TPOAb levels were higher than normal in all patients, but there was no significant difference in the levels of TPOAb and TGAb among 4 types of the patients. Conclusion. Psoriasis is related to thyroid dysfunction, especially in patients with atypical psoriasis types. The possibility of complications should be considered in erythrodermic patients.

NO LONGTERM SEVERE THYROID DYSFUNCTION SEEN IN PATIENTS WITH PREEXISTING REDUCED SERUM TT3 CONCENTRATIONS AFTER A SINGLE LARGE DOSE OF IODINATED CONTRAST

2020 ◽  
Vol 26 (8) ◽  
pp. 840-845
Author(s):  
Si Hai-Long ◽  
Qin Qin ◽  
Liu Yuan-Yuan ◽  
Zhao Bing-Rang
Keyword(s):  
Thyroid Dysfunction ◽  
Coronary Intervention ◽  
Thyroid Stimulating Hormone ◽  
World Health ◽  
Thyroid Peroxidase ◽  
Free Triiodothyronine ◽  
Iodinated Contrast ◽  
Total Triiodothyronine ◽  
Total Thyroxine ◽  
Health Organization

Objective: After an intravenous bolus injection of 100 mL of iodinated contrast agent (370 mgI/mL), the amount of iodine atoms entering the blood is tens of thousands of times the daily dose of iodine recommended by the World Health Organization. However, the effect of iodinated contrast in patients with nonthyroidal illness, manifested as reduced serum total triiodothyronine (TT3) concentrations, is unclear. We studied the effect of iodinated contrast on thyroid function and auto-antibodies in patients with reduced TT3 after diagnosis and treatment of coronary heart disease. Methods: This was a prospective cohort study. One hundred and fifty-four stable angina pectoris patients with reduced TT3 and normal thyroid-stimulating hormone (TSH), free thyroxine (FT4), and reverse triiodothyronine (rT3) were enrolled from January, 2017, to June, 2018. All subjects had no history of thyroid dysfunction and had no recent infections, tumors, trauma, or other critical illnesses. Fourty-one patients underwent coronary angiography and 113 patients underwent coronary intervention. Results: There were 6 patients (3.9%) with hypothyroidism and 30 patients (19.5%) developed subclinical hypothyroidism (SCHypo) on the first day after surgery. There were 6 patients (3.9%) with hypothyroidism, 6 patients (3.9%) with SCHypo, and 18 patients (11.7%) with subclinical hyperthyroidism (SCHyper) at the first month postsurgery. There were 23 patients (14.9%) with SCHyper and 6 patients (3.9%) with SCHypo at the sixth month after surgery. No patient with longterm severe thyroid dysfunction occurred during follow-up. The levels of free triiodothyronine, FT4, TT3, total thyroxine, and TSH showed statistically significant changes at 1 day, and 1, 3, and 6 months postoperative ( P<.005). The level of rT3 showed no statistically significant change at 1, 3, and 6 months postoperative ( P>.05). The levels of thyroglobulin antibody and thyroid peroxidase antibody decreased at 6 months postoperative ( P<.001). Conclusion: The risk of subclinical thyroid dysfunction and transient hypothyroidism occurred with a single large dose of iodinated contrast in the diagnosis and treatment of coronary heart disease, but no longterm severe thyroid dysfunction occurred. Patients with preoperative thyroid antibody elevation were more likely to have subclinical thyroid dysfunction after surgery. Abbreviations: FT3 = free triiodothyronine; FT4 = free thyroxine; PCI = percutaneous coronary intervention; rT3 = reverse triiodothyronine; SCHyper = subclinical hyperthyroidism; SCHypo = subclinical hypothyroidism; TGAB = thyroglobulin antibody; TPOAB = thyroid peroxidase antibody; TT3 = total triiodothyronine; TT4 = total thyroxine; TSH = thyroid-stimulating hormone; WHO = World Health Organization

scholarly journals Thyroxine Supplementation in Pregnant Women After Thyroidectomy for Thyroid Cancer and Neonatal Birth Weight

2021 ◽  
Vol 12 ◽  
Author(s):  
Zheng Ding ◽  
Fei Guo ◽  
Yulai Zhou ◽  
Xiaoyi Huang ◽  
Zhiwei Liu ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Birth Weight ◽  
Pregnant Women ◽  
Early Pregnancy ◽  
Late Pregnancy ◽  
Thyroid Stimulating Hormone ◽  
Control Group ◽  
Inverse Association ◽  
Neonatal Birth Weight ◽  
Maternal Thyroid

Patients are often supplemented with a sufficient dose of thyroxine after thyroidectomy for thyroid cancer. However, the influence of thyroxine supplementation on fetal growth in pregnant women after thyroidectomy for thyroid cancer remains unclear. The aim of this study was to investigate the effect of thyroxine supplementation on neonatal birth weight. This cohort study included 49,896 pregnant women (278 patients with a history of thyroidectomy for thyroid cancer and 39,363 control cases after exclusion). Thyroid parameters were examined in pregnant women and their newborns. The associations between maternal thyroid function and neonatal birth weight and small for gestational age were studied using regression analyses. In the levothyroxine supplementation group, free thyroxine (FT4) levels were significantly higher in both early pregnancy (P &lt; 0.001) and late pregnancy (P &lt; 0.001) groups than in the control group. Furthermore, levels of neonatal thyroid stimulating hormone (P = 0.032) and birth weight (P = 0.043) were significantly lower than those in the control group. We also observed a significant inverse association between maternal FT4 levels in early pregnancy and neonatal birth weight (P=0.028), especially in male newborns (P=0.036). In summary, after thyroidectomy for thyroid cancer, a sufficient dose of thyroxine supplementation in early pregnancy is significantly associated with reduced birth weight and may need to be monitored.

scholarly journals Recurrent Graves’ hyperthyroidism after prolonged radioiodine-induced hypothyroidism

2017 ◽  
Vol 8 (7) ◽  
pp. 111-115 ◽  
Author(s):  
Fariha Salman ◽  
Hooman Oktaei ◽  
Solomon Solomon ◽  
Ebenezer Nyenwe
Keyword(s):  
Unusual Case ◽  
Cost Effective ◽  
Thyroid Stimulating Hormone ◽  
Free Triiodothyronine ◽  
Laboratory Findings ◽  
Total Thyroxine ◽  
Ventricular Response ◽  
History Of ◽  
Irregular Pulse ◽  
Recurrent Hyperthyroidism

Background: Radioactive iodine (RAI) is the most cost effective therapy for Graves’ disease (GD). Patients with GD who have become hypothyroid after therapeutic RAI, rarely develop recurrence of disease. Herein we describe a case of recurrence of thyrotoxicosis after 2 years of hypothyroidism. Methods: We present the clinical features, laboratory findings, imaging and management of an unusual case of recurrent hyperthyroidism. Results: A 48-year-old male presented to the emergency room with a 2-day history of palpitation, chest discomfort and 30 pounds of weight loss. Examination was remarkable for rapid and irregular pulse, diffuse thyromegaly and brisk deep tendon reflexes but no eye changes or tremors. Laboratory tests showed thyroid-stimulating hormone (TSH) of <0.004 (0.3–5.6 mIU/ml), free thyroxine (FT4) 4.96 (0.9–1.8 ng/dl), free triiodothyronine (FT3) >20 (1.8–4.7 pg/ml), total thyroxine >800 (80–200 ng/dl). Electrocardiogram showed atrial fibrillation with rapid ventricular response. RAI uptake and scan showed a homogenous gland with 54% uptake in 6 h and 45% in 24 h. He was treated with propranolol and propylthiouracil with some clinical improvement. He subsequently underwent RAI therapy and developed hypothyroidism after 8 weeks. Hypothyroidism was treated with levothyroxine. At 2 years after RAI ablation, he again developed symptoms of hyperthyroidism and had suppressed TSH. The levothyroxine dose was stopped, 3 weeks after discontinuing levothyroxine, he remained hyperthyroid with TSH of 0.008 and FT4 of 1.62 and FT3 of 4.8. RAI uptake demonstrated 17% uptake at 24 h. Conclusion: Recurrent hyperthyroidism in GD is uncommon after development of post-ablative hypothyroidism. Our case illustrates the need for continued surveillance.

scholarly journals Association between thyroid-stimulating hormone (TSH) and proteinuria in relation to thyroid cyst in a euthyroid general population

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yuji Shimizu ◽  
Yuko Nabeshima-Kimura ◽  
Shin-Ya Kawashiri ◽  
Yuko Noguchi ◽  
Shigeki Minami ◽  
...  
Keyword(s):  
General Population ◽  
Positive Association ◽  
Thyroid Stimulating Hormone ◽  
Inverse Association ◽  
Normal Range ◽  
Free Triiodothyronine ◽  
Significant Positive Association ◽  
Cross Sectional ◽  
Thyroid Cyst ◽  
Stimulating Hormone

Abstract Background High normal levels of thyroid-stimulating hormone (TSH) have been reported to be associated with chronic kidney disease (CKD) among euthyroid individuals. However, there has been only limited research on the association between TSH and proteinuria, a major risk factor for the progression of renal disease. Methods A cross-sectional study of 1595 euthyroid individuals was conducted. All participants were within the normal range for free triiodothyronine (T3), free thyroxine (T4), and TSH. Analyses were stratified by thyroid cyst status to test the hypothesis that the absence of thyroid cysts, an indicator of latent thyroid damage, is associated with declining ability to synthesis thyroid hormone. Results For participants with thyroid cysts, a significant inverse association between TSH and proteinuria was observed (adjusted odds ratio (95% confidence intervals) of log-transformed TSH for proteinuria 0.40 (0.18, 0.89)). In participants without thyroid cysts, a significant positive association between those two factors was observed (2.06 (1.09, 3.90)). Conclusions Among euthyroid individuals in the general population, being in the normal range of TSH was found to have an ambivalent association with proteinuria. Thyroid cyst status could be an effect modifier for those associations.

scholarly journals Infant neurocognitive development is independent of the use of iodised salt or iodine supplements given during pregnancy

2013 ◽  
Vol 110 (5) ◽  
pp. 831-839 ◽  
Author(s):  
Piedad Santiago ◽  
Inés Velasco ◽  
Jose Antonio Muela ◽  
Baltasar Sánchez ◽  
Julia Martínez ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Thyroid Function ◽  
Urinary Iodine ◽  
Thyroid Volume ◽  
First Trimester ◽  
Thyroid Stimulating Hormone ◽  
Neurological Development ◽  
Free Triiodothyronine ◽  
Iodised Salt ◽  
Maternal Thyroid

The benefits of iodine supplements during pregnancy remain controversial in areas with a mild-to-moderate iodine deficiency. The aim of the present study was to determine the effect of improving iodine intakes, with iodised salt (IS) or iodine supplements, in pregnant Spanish women. A total of 131 pregnant women in their first trimester were randomly assigned to three groups: (1) IS in cooking and at the table, (2) 200 μg potassium iodide (KI)/d or (3) 300 μg KI/d. No differences were found in thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3) or thyroid volume (TV) between the three groups. Regardless of the group in which women were included, those who had been taking IS for at least 1 year before becoming pregnant had a significantly lower TV in the third trimester (P= 0·01) and a significantly higher urinary iodine in the first (173·7 (sd81·8)v. 113·8 (sd79·6) μg/l,P= 0·001) and third trimesters (206·3 (sd91·2)v. 160·4 (sd87·7) μg/l,P= 0·03). Also, no differences were seen in TSH, FT4 or FT3. Children's neurological development was not significantly associated with the consumption of IS for at least 1 year before becoming pregnant and no differences were found according to the treatment group. In conclusion, in pregnant women with insufficient iodine intake, the intake of IS before becoming pregnant was associated with a better maternal thyroid function. The form of iodide intake was not associated with maternal thyroid function or children's neurological development.

scholarly journals European Biological Variation Study (EuBIVAS): within- and between-subject biological variation estimates for serum thyroid biomarkers based on weekly samplings from 91 healthy participants

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Michela Bottani ◽  
Aasne K. Aarsand ◽  
Giuseppe Banfi ◽  
Massimo Locatelli ◽  
Abdurrahman Coşkun ◽  
...  
Keyword(s):  
Large Scale ◽  
Thyroid Stimulating Hormone ◽  
Biological Variation ◽  
Healthy Individuals ◽  
Serum Samples ◽  
Free Triiodothyronine ◽  
Performance Specifications ◽  
Study Population ◽  
Variance Homogeneity ◽  
Healthy Participants

Abstract Objectives Thyroid biomarkers are fundamental for the diagnosis of thyroid disorders and for the monitoring and treatment of patients with these diseases. The knowledge of biological variation (BV) is important to define analytical performance specifications (APS) and reference change values (RCV). The aim of this study was to deliver BV estimates for thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), thyroglobulin (TG), and calcitonin (CT). Methods Analyses were performed on serum samples obtained from the European Biological Variation Study population (91 healthy individuals from six European laboratories; 21–69 years) on the Roche Cobas e801 at the San Raffaele Hospital (Milan, Italy). All samples from each individual were evaluated in duplicate within a single run. The BV estimates with 95% CIs were obtained by CV-ANOVA, after analysis of variance homogeneity and outliers. Results The within-subject (CV I ) BV estimates were for TSH 17.7%, FT3 5.0%, FT4 4.8%, TG 10.3, and CT 13.0%, all significantly lower than those reported in the literature. No significant differences were observed for BV estimates between men and women. Conclusions The availability of updated, in the case of CT not previously published, BV estimates for thyroid markers based on the large scale EuBIVAS study allows for refined APS and associated RCV applicable in the diagnosis and management of thyroid and related diseases.

Impact of maternal thyroid disease on neonatal thyroid status

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Lakshmi Venugopalan ◽  
Aishwarya Rajan ◽  
Hemchand. K. Prasad ◽  
Anupama Sankaran ◽  
Gnanabalan Murugesan ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Thyroid Stimulating Hormone ◽  
Study Group ◽  
Thyroid Status ◽  
Case Identification ◽  
Group I ◽  
Group Ii ◽  
Maternal Thyroid ◽  
Heel Prick ◽  
Stimulating Hormone

AbstractObjectivesPrevalence of Maternal and congenital hypothyroidism is on the rise. To present the thyroid stimulating hormone screening results in babies born to hypothyroid mothers and assess the burden, aetiology of hypothyroidism in these babiesMethodsAll antenatal mothers attending our hospital during the study period were enrolled into the study. Group I includes 249 term babies born to hypothyroid mothers and group II comprises 2154 newborns born to mothers who are euthyroid. Heel prick thyroid stimulating hormone was done for all newborns on day 3 for both groups. Confirmatory venous testing was done for all for babies in group I and screen positives belonging to group II. Evaluation and therapy done as per standard guidelines.ResultsThyroid stimulating hormone values in the two groups are presented. There was significant correlation between peak maternal thyroid stimulating hormone and neonatal day 3 heel prick in group I (r=0.7, P<0.05). The prevalence of positive screening test in groups I and II was 3.8 and 1.03% (p<0.05) whereas corresponding values for confirmed disease was 4.3 and 0.6%, respectively (p<0.05). Aetiological evaluation revealed both transient hypothyroidism (33.3%) and permanent hypothyroidism (66.6%).Conclusion4.3% of babies born to hypothyroid mothers develop congenital hypothyroidism; aetiology being both transient and permanent. A venous test by 3 weeks is helpful in these babies to improve case identification.

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