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research paper

Indian Pediatr 2014;51: 32-36

Cord Blood Thyroid Stimulating Hormone Level – Interpretation in Light of Perinatal Factors


Amit Gupta, Smita Srivastava and Anjoo Bhatnagar

From Department of Pediatrics and Neonatology, Fortis Hospital and Research Centre, Faridabad, Haryana, India.

Correspondence to: Dr Amit Gupta, Consultant, Department of Pediatrics and Neonatology, Fortis Hospital and Research Centre, Faridabad 121 001, Haryana, India.
Email: [email protected]

Received: April 11, 2013;
Initial review: May 05, 2013;
Accepted: August 29, 2013.
Published online: September 05, 2013.

 PII: S097475591300371




Objectives:
To study the influence of perinatal factors on cord blood TSH (CB TSH) levels.

Design: Cross-sectional study.

Setting: Tertiary care private hospital.

Methods: CB TSH levels were measured in 952 live-born infants using electrochemiluminescence immunoassay. The effect of perinatal factors on the CB TSH levels was analyzed statistically.

Results: The median CB-TSH was 8.75 microIU/mL (IQR = 6.475 – 12.82) with 11.5% neonates having values more than 20. CB TSH was significantly raised in first order neonates (P <0.01) and in babies delivered by assisted vaginal delivery and normal delivery (P <0.01). Neonates who had fetal distress or non-progress of labour had significantly higher CB TSH than those who were delivered by elective caesarean section. Requirement of resuscitation beyond the initial steps and low Apgar scores at 1 minute also resulted in significantly raised CB TSH (both P <0.01). Maternal hypothyroidism, maternal hypertension and neonates’ weight appropriateness for gestation, gestational age and birth weight did not have significant effect.

Conclusions: The incidence of high cord blood TSH (>20 microU/mL) is 11.45%. On multivariate analysis, requirement of resuscitation, mode of delivery and fetal distress as indication for LSCS were significant factors affecting CB TSH values. Hence, these values need to be interpreted in light of perinatal factors.

Keywords: Cord blood, Newborn screening, Perinatal factors, Thyroid stimulating hormone.

 


C
ongenital Hypothyroidism is the most common preventable cause of mental retardation with an incidence of 1:2500 to 1:2800 live births in India [1, 2]. Clinical diagnosis is difficult at birth and the time of initiation of therapy is a critical determinant of outcome. In view of paramount importance of early diagnosis and treatment, various screening programs were initiated [3,4]. In India, ICMR introduced congenital hypothyroidism screening program in neonates at various centers in 2007 [5,6]. Neonatal screening methods measure Thyroid Stimulating Hormone level in either cord blood sample or that obtained from heel prick sample at 3 to 4 days of life. When cord blood Thyroid Stimulating Hormone (CB TSH) is measured for congenital hypothyroidism screening, it has a high sensitivity but with a high false positive rates [7].

Various maternal and perinatal factors are known to affect the CB TSH levels [8]. There is a scarcity of Indian data on the effects of various factors on CB TSH levels. This study presents an analysis of various maternal and perinatal factors on CB TSH level.

Methods

This cross-sectional study was conducted in the neonatology unit of department of pediatrics at Fortis Escorts hospital, Faridabad, a tertiary-care hospital in Delhi NCR region. Priori calculation of sample size to study 10 factors in multiple regression model with a small (0.02) effect size and type 1 error of 5% (P<0.05) and power of 80% yielded a minimum sample size of 818. The study was planned to include consecutive 1000 live born neonates delivered at our hospital from July 2009 onwards to account for a maximum 20% drop out/ consent withdrawal or sample processing issues. We planned to include all live births in the hospital from July 2009 onwards. Exclusion criteria were: neonates with major life threatening malformations; those with antenatally detected central nervous system malformations; and neonates whose mothers were on any antithyroid drugs.

An informed consent was obtained from either of the parents. Antenatal and intra-partum information was noted from mother’s medical record. Blood samples were drawn for blood group and TSH assay as per unit’s protocol, through a 5 mL syringe from the maternal end of the cord immediately after the cord was cut. The sample thus collected was kept at room temperature of around 25°C and was transported to laboratory within one hour. Neonates whose blood samples were not processed for technical reasons were excluded from final analysis (commonly due to inadequate amount hemolyzed sample). The sample was analyzed within 3 hours using electrochemiluminescence immunoassay on Cobas e 411 analyser with functional sensitivity of 0.014 microIU/mL All neonates who had CB TSH values more than 20 were advised repeat TSH assessment within 14 days of life.

The data were entered in Excel sheet and percentages of various outcome measures were calculated using SPSS for Windows version 12. The effect of various perinatal factors on the CB TSH levels was analyzed using independent Kruskal Wallis and Mann Whitney tests to define differences between groups and a P value of <0.05 was defined as significant. The relationship between variables was first analyzed using univariate analysis and all the variables were then taken to multivariate regression along with demographic factors. The study was approved by the hospital ethics committee.

Results

Of 1000 newborns enrolled, one was excluded on clinical grounds (mother on anti thyroid dugs) while another 47 cord blood samples could not be processed. Thus the study population comprised of 952 subjects (Table I). The CB-TSH values ranged between 1.01- 63.74 microIU/mL with median at 8.75 (IQR = 6.475-12.82). 109 out of 952 neonates (11.45%) had CB-TSH values >20 microIU/mL and 44 (4.6%) had values >30. CB TSH values were found to be significantly raised in neonates delivered as first order compared to multiparous mothers (higher order births) (P=0.005) and in babies delivered by assisted vaginal delivery and normal delivery compared to caesarean section (P<0.001). Also, neonates who had fetal distress or non-progress of labour had significantly higher CB TSH than those who were delivered by elective caesarean section; (P<0.001). Requirement of resuscitation beyond the initial steps and low Apgar scores of <7 at 1 minute also resulted in significantly raised CB TSH (P<0.001). Male neonates had slightly increased CB TSH than their female counterparts (P =0.031). It was noticed that maternal hypothyroidism, maternal hypertension and neonates’ weight appropriateness for gestation do not significantly affect the CB TSH value (Table II). No correlation was found between CB TSH, gestational age (r= -0.009) (Fig. 1) and birth weight (r= -0.004) (Fig. 2). On multivariate analysis- requirement of resuscitation, mode of delivery and fetal distress as indication for lower segment cesarean section (LSCS) were found to be significant factors.

TABLE I Profile of Subjects included in the Study
Characteristic No (%) No (%)
Birth Order
  First   544 57.1
  Second 342 35.9
  Third or Higher 66 6.9
Mode of Delivery
  Normal Vaginal Delivery 438 46.0
  Assisted Vaginal Delivery 60 6.3
  Caesarean Section 454 47.7
Indication of Caesarean Section
  Elective 301 31.6
  For Fetal Distress 91 9.6
  For Non Progress Of Labour 53 5.6
  Other 9 0.9
Hypothyroid mother 48 5.0
Euthyroid mother 904 95.0
Maternal Pregnancy Induced Hypertension
  PIH 67 7.0
  Normotensive 885 93.0
Weight Appropriateness for Age
  Small For Gestation 31 3.3
  Appropriate For Gestation 873 91.7
  Large For Gestation 48 5.0
Male sex 510 53.6
Resuscitation Required
  Routine Care 802 84.2
  Beyond Initial Steps 150 15.8
APGAR Scores
  Less Than 5 28 2.9
  5 or 6 84 8.8
  7 or More 840 88.2
Gestational Age
  Term (37-41 weeks) 769 80.8
  Preterm (<37 weeks) 182 19.1
  Preterm (<32 weeks) 25 2.6
TABLE II Comparison of Cord Blood TSH Values in Accordance with Subject Characteristics 

Characteristic Number  Median Interquartile P value  
  (microIU/mL) range
First order birth 544 9.03 6.58 – 15.4 0.005
Higher order birth 408 7.47 4.83 – 10.56
Normal & assisted vaginal delivery 498 9.33 5.94 – 15.41 <0.001
Caesarean section 454 7.56 5.82 – 9.81
LSCS for fetal distress and non progress 153 7.69 5.3 – 11.05 <0.001
Elective LSCS 301 7.56 5.99 – 9.52
Hypothyroid mother 48 8.76 6.47 -12.06 0.220
Euthyroid mother 904 8.05 5.47 – 11.72
PIH In mother 67 9.6 7.28 – 12.41 0.584
Normotensive mother 885 8.67 6.45 – 13.07
Male baby 510 9.26 6.63 – 13.35 0.031
Female baby 442 8.22 6.21 – 12.48
Small for gestation 31 8.73 6.60 – 12.17 0.506
Appropriate for gestation 873 8.8 6.51 – 12.87
Large for gestation 48 7.68 5.43 – 14.65
Resuscitation beyond initial steps 150 13.78 8.92 – 21.02 <0.001
Routine care 802 8.25 6.22 – 11.67
Apgar less than 7 112 12.42 8.18 – 19.23 <0.001
Apgar 7 or more 840 8.42 6.4 – 12.08
 

Fig. 1 Correlation between gestational age and CB TSH value.

Fig. 2 Correlation between birth weight and CB TSH value.

Discussion

Though the Screening for congenital hypothyroidism will decrease the burden of mentally retarded children in the society, the method of screening is not uniform [3]. Some countries use T4 while others prefer TSH as the tool since maternal diseases affecting placental dynamics influence T4 levels [9,10]. Few others use both T4 and TSH. Technically, using both T4 and TSH will be superior but would increase the cost of screening. Most of the countries have accepted TSH either through heel prick or through cord-blood as the screening method for congenital hypothyroidism. Cord blood collection of sample is preferred for its ease of collection of sample, lower rates of follow up losses, more practical for mothers with short hospital stay following delivery and its utility as an indicator of the prevalence of iodine deficiency disorders [11,12].

Researchers have studied different CB TSH cut off levels varying between 20-90 for recall with an objective to keep cost of rescreening low and making it more cost effective. In Indian setup, cord blood TSH value of >20µIU/mL is seen as safe cut off for recall [13,14]. We, in the setting of tertiary care referral hospital, found that 11.5% of all samples had values more than 20 µIU/mL which reflected that a high recall rate is associated with CB TSH assessment. The only other comparable study from a near similar geographical area [15] though does not provide the numbers of patients with TSH levels more than 20 microU/mL, but reports the mean CB TSH as 10.6 +/- 6.7 microU/mL and that their high risk patients (>6 % population) had a mean TSH above 20 microU/mL.

Changes in TSH levels in response to T3 and T4 blood levels forms the basis of screening for congenital hypothyroidism through CB TSH estimation. However, other factors may also influence TSH levels. Various authors have correlated an increase in TSH values with factors like birth asphyxia and difficult deliveries [15], perinatal stress events [8], birth weight, male infant sex and instrumental delivery [16], and negatively with cesarean sections as mode of delivery [17]; but the mechanism are poorly understood.

The postnatal surge in TSH levels, common to all newborns, is considered to be mediated through alpha adrenergic stimulation following the cold stress [18]. In a study on neonatal rats, it was demonstrated that perinatal hypoxia increases the secretion of catecholamines [19]. Similarly, a surge in catecholamine secretion was seen in human neonates during parturition; and this was more in asphyxiated newborns and in vaginally delivered newborns compared to those born by elective caesarean section [20]. Others too observed that with perinatal hypoxia there is an increase in endogenous catecholamine [21], which is more pronounced when the scalp PH is less than 7.26 [22]. This alpha adrenergic stimulation in turn might be responsible for the observed increase in CB TSH in our subjects who had low Apgar scores, required active resuscitation after birth, were born through vaginal delivery or non-elective LSCS, and to primiparous mother. However, in our study, no significant difference was found in CB TSH values in male and female neonates; nor any positive correlation found with the birth weight.

Unlike authors who observed a negative correlation of serum TSH with gestational age [23], we did not find it to be significant. At our center, we commonly give antenatal steroids before premature deliveries and Dexamethasone has been shown to blunt the release of catecholamine [24,25], which might have an effect on TSH levels.

Perinatal stress factors and mode of delivery have a significant impact on cord-blood TSH levels and any rise in cord blood TSH should be seen in the light of these factors. The proportion would be higher where high-risk pregnancies are delivered. Larger studies should factor this impact and work out a correction in TSH cut off in accordance to influencing factors if present. Many repeat evaluations of thyroid function can thus be avoided, and would not only save the cost but also would allay the anxiety of parents of neonates undergoing a repeat/confirmatory test.

Contributors: AG and AB: conceived and designed the study and revised the manuscript; SS: contributed through collection of data, analysis and manuscript writing; AG: monitored the process, helped in manuscript writing and provided for important intellectual content. He will act as guarantor of the study.

Funding: None; Competing interests: None stated.


What is Already Known?

• Cord blood TSH assessment is a useful screening tool for congenital hypothyroidism but with high false positive rates.

What Does This Study Add?

• Perinatal stress factors and mode of delivery significantly impact cord-blood TSH levels and should be accounted for while interpreting the results.

References

1. Desai MP, Colaco MP, Ajgaonkar AR, Mahadik CV, Vas FE, Rege VV, et al. Neonatal screening for congenital hypothyroidism in a developing country: problems and strategies. Indian J Pediatr. 1987;54:571-81.

2. Desai MP, Upadhye P, Colaco MP, Mehre M, Naik SP, Vaz FE, et al. Neonatal screening for congenital hypothyroidism using the filter paper thyroxine technique. Indian J Med Res. 1994;100:36-42.

3. Newborn screening for congenital hypothyroidism: recommended guidelines: American Academy of Pediatrics Section on Endocrinology and Committee on Genetics and American Thyroid Association Committee on Public Health. Pediatrics 1993;91:1203-9.

4. Nanayakkaral D, Wijekoon A, Jiffry N, Mudiyanse R, Nilam J, Perera K, et al. Screening for congenital hypothyroidism in government hospitals in Sri Lanka. Proceedings of the Peradeniya University Research Sessions, Sri Lanka. 2007;12: 133-4.

5. Dutta R. ICMR to conduct first nationwide newborn screening for genetic disorders. Express Health Care Management; 1st –15th September 2005. 

6. Kapoor S, Kabra M. Newborn Screening: Current Perspectives. Indian Pediatr. 2010;47:219-24.

7. Kaur G, Srivastav J, Jain S,  Chawla D, Chavan BS, Atwal R, et al. Preliminary report on neonatal screening for congenital hypothyroidism, congenital adrenal hyperplasia and glucose-6-phosphate dehydrogenase deficiency: A Chandigarh experience. Indian J Pediatr. 2010;77:969–73. 

8. Kim EY, Park SK, Song CH, Lim SC. Perinatal factors affecting thyroid stimulating hormone (TSH) and thyroid hormone levels in cord blood. Korean J Pediatr. 2005;48:143-7.

9. Franklin RC, Carpenter LM, O’Grady CM. Neonatal thyroid function: influence of perinatal factors. Arch Dis Child. 1985;60:141-4.

10. Fuse Y, Wakae E, Nemoto Y,  Uga N, Tanaka M, Maeda M, et al. Influence of perinatal factors and sampling methods on TSH and thyroid hormone levels in cord blood. Endocrinol Japon. 1991;38:297-302.

11. Mu Li, Eastman CJ. Neonatal TSH Screening: is it a sensitive and reliable tool for monitoring iodine status in populations. Best Practice and Research Clinical Endocrinology and Metabolism. 2010;24;63-75. 

12. Kýslal F, Cetinkaya S, Dilmen U, Yasar H, Tezic T. Cord blood thyroid stimulating hormone (TSH) and free T4 (fT4) levels in Turkish neonates: Is iodine deficiency still a continuing problem? Pediatrics International October 2010;5:762-8.

13. Manglik AK, Chatterjee N, Ghosh G. Umbilical cord blood TSH levels in term neonates: A screening tool for congenital hypothyroidism. Indian Pediatr. 2005;42:1029-32.

14. Ogunkeye OO, Roluga AI, Khan FA. Resetting the Detection Level of Cord Blood Thyroid Stimulating Hormone (TSH) for the Diagnosis of Congenital Hypothyroidism. J Trop Pediatr. 2008;54:74-7.

15. Rashmi, Seth A, Sekhri T, Agarwal A. Effect of perinatal factors on cord blood thyroid stimulating hormone levels. J Pediatr Endocrinol Metab. 2007;20:59-64.

16. Chan LY,  Fok WY, Sahota D, Lau TK. Cord blood thyroid-stimulating hormone level and risk of acidosis at birth. European Journal of Obstet and Gyne and Reproductive Biol. 2006;124:173-7.

17. Chan LY, Leung TN, Lau TK. Influences of perinatal factors on cord blood thyroid-stimulating hormone level. Acta Obstetricia et Gynecologica Scandinavica. 2001;80:1014–8.

18. Lee MM, Moshang T Jr, Endocrine disorders of the newborn. In: MacDonald, Mhairi G, Seshia, Mary MK, Mullett, Martha D, ed. Avery’s Neonatology, 6th Edition; Philadelphia; Lippincott Williams and Wilkins. 2005;1828–95.

19. Rico AJ, Prieto-Lloret J, Gonzalez C, Rigual R. Hypoxia and acidosis increase the secretion of catecholamines in the neonatal rat adrenal medulla: an in vitro study. Am J Physiol Cell Physiol. 2005;289:C1417-C25.

20. Hugo. Stress, arousal and gene activation at birth. News Physiol Sci. 1996;11:214–8.

21. Gülmezoglu AM, Mahomed K, Hofmeyr GJ, Nikodem VC, Kramer T. Fetal and maternal catecholamine levels at delivery. J Perinat Med. 1996;24:687-91.

22. Bistoletti P, Nylund L, Lagercrantz H, Hjemdahl P, Ström H. Fetal scalp catecholamines during labor. Am J Obstet Gynecol. 1983;147:785-8.

23. Desai M, Dabholkar C, Colaco MP. Thyroid function in fullterm and preterm newborns. Indian J Pediatr. 1985;52:599-607.

24. Fletcher AJ, Gardner DS, Edwards CM, Fowden AL, Giussani DA. Cardiovascular and endocrine responses to acute hypoxaemia during and following dexamethasone infusion in the ovine fetus. J Physiol. 2003;549(Pt. 1): 271-87.

25. Jellyman JK, Gardner DS, Edwards CM, Fowden AL, Giussani DA. Fetal cardiovascular, metabolic and endocrine responses to acute hypoxaemia during and following maternal treatment with dexamethasone in sheep. J Physiol. 2005;567(Pt. 2):673-88.

 

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