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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 2 601-603
Copyright © 2001 by The Endocrine Society

Original Studies

Follow-Up Examination at the Age of 15 Months of Extremely Preterm Infants after Postnatal Estradiol and Progesterone Replacement

Andreas Trotter, Birgit Bokelmann, Wolfgang Sorgo, Doris Bechinger-Kornhuber, Hilde Heinemann, Gesine Schmücker, Margarethe Oesterle, Brigitte Köhntop, Karl-Heinz Brisch and Frank Pohlandt

Section of Neonatology and Pediatric Critical Care Medicine, Children’s Hospital; and Section of Pediatric Neurology, Department of Neurology (D.B.-K., H.H.) and Outpatient Department of Child and Adolescent Psychiatry, Department of Psychotherapy and Psychosomatic Medicine (G.S., M.O., B.K., K.-H.B.), University of Ulm, 89075 Ulm, Germany

Address all correspondence and requests for reprints to: Dr. Andreas Trotter, Section of Neonatology and Pediatric Critical Care Medicine, Children’s Hospital, University of Ulm, Prittwitzstrasse 43, 89075 Ulm, Germany. E-mail: andreas.trotter{at}medizin.uni-ulm.de


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
A randomized controlled pilot study was performed with a sample of extremely preterm infants to evaluate the impact of postnatal estradiol and progesterone replacement on postnatal bone mineral accretion. Twenty-five of 30 infants in the pilot study survived, and of these, 24 infants were available for the follow-up examination at a median chronological age of 18.1 months (minimum-maximum, 17.0–20.6) corresponding to a corrected age of 14.8 months (minimum-maximum, 12.9–17.4). Somatic growth data and bone mineralization showed no differences between the hormone-treated and control group infants. The deviation of the skeletal age from the corrected age was 0.0 months (minimum-maximum, -7.7 to 7.4) for hormone-treated infants compared with -1.7 months (minimum-maximum, -7.5 to 5.9) for the control group. The Bayley scales mental and psychomotor developmental indexes were 89 (minimum-maximum, 71–107) and 101 (minimum-maximum, 49–121) for the hormone-treated infants and 93 (minimum-maximum, 49–111) and 71 (minimum-maximum, 49–121) for the control group infants, respectively (mental developmental index, P = 1.0; psychomotor developmental index, P = 0.14). The normal psychomotor development in the hormone-treated infants compared with the below average development in the control group infants is encouraging and indicates the potentially important integrative role of sex steroids for the developing brain. Larger studies on the effects of the postnatal replacement of estradiol and progesterone in extremely preterm infants are warranted.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
EXTREMELY PRETERM infants suffer from osteopenia even given the presence of adequate vitamin D intake and supplementation with calcium and phosphorus (1). Estrogen deficiency has been identified as a risk factor for postmenopausal osteoporosis (2), and progesterone (P) has been recognized to be a bone-trophic hormone (3). Because the fetus is exposed to increasing amounts of estradiol (E2) and P during pregnancy (4), deprivation of E2 and P after preterm birth may contribute to osteopenia of prematurity. Postnatal replacement of E2 and P in extremely preterm infants had the aim of maintaining the hormonal environment present in utero. We conducted a randomized controlled pilot study in extremely preterm infants to evaluate the impact of E2 and P replacement on postnatal bone mineral accretion (5). We found a trend toward improved bone mineral accretion in those infants that received hormone replacement and a sufficient supply of calcium and phosphorus. A trend toward a lower incidence of bronchopulmonary dysplasia in the hormone replacement group was an encouraging additional result.

The follow-up examination of the preterm infants in the pilot study aimed at exploring the potential midterm effects of postnatal E2 and P replacement on the bone mineral accretion, skeletal age, and neurological development.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects

From the 30 infants enrolled in the randomized controlled pilot study, 25 infants survived (E2 and P replacement group, n = 13; control group, n = 12). The parents of 24 infants agreed to the follow-up examination. Gestational age, body weight, body length, and head circumference at birth and at the end of the E2 and P replacement showed no statistical differences between the groups (5). The follow-up examination was performed at a median chronological age of 18.1 months (minimum-maximum, 17.0–20.6) corresponding to a corrected age of 14.8 months (minimum-maximum, 12.9–17.4).

Body weight, body length, and head circumference were measured. The current values were subtracted from the values obtained at the end of the E2 and P replacement period 6 weeks postnatally to calculate the monthly increases in somatic growth data.

Bone mineral content (BMC) was measured as described previously (6) using single photon absorption densitometry (model 278/C, Norland Corp., Fort Atkinson, WI). Because the BMC is highly correlated to the body weight (BW) (6), the BMC/BW ratio was calculated to compare the two groups. The bone mineral accretion (milligrams per cm per 100 g wt gain) was calculated as the difference between the two BMC measurements at the follow-up examination and at 6 weeks postnatally divided by the corresponding weight gain.

A radiograph of the left hand and wrist (distance to the cathode, 100 cm; voltage, 40 kV; amperage, 1.4 mAS) was performed to determine skeletal age according to the criteria defined by Greulich and Pyle (7). The age of each ossification center (distal epiphysis of the ulna and radius, carpal and meta-carpo-phalangeal bones, and phalanges) was determined, and the individual average skeletal age was calculated. This was performed by an experienced pediatric endocrinologist (W.S.).

The Bayley scales of infant development were used (8). The test was performed by a psychologist experienced in examining preterm infants. Using the corrected age, the raw scores of the mental and motor developmental tests were determined. These were then converted to index scores [mental developmental index (MDI) and psychomotor developmental index (PDI)] in which 100 represents the 50th percentile of a normative collective. Because MDI and PDI scores below 50 are not defined, they were recorded as a value of 49. The raw scores were extrapolated to a mental developmental age and a psychomotor developmental age, and the corrected age was subtracted from them.

A pediatric neurologist evaluated the function of the cranial nerves (II–XII), muscle tone, motor abilities, motor reflexes, coordination of movements, and brainstem functions. Based on a scoring system, the infants were classified into five groups that were defined as normal, questionably pathological, minor, moderate, or showing severe neurological deficit. The examiners for skeletal age, the Bayley test of infant development, and the neurological status were blind to the infant’s postnatal treatment.

Statistical analysis

The Mann-Whitney U test was used to compare the results of the study groups. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Body weight, body length, and head circumference showed no significant difference between the groups at the follow-up examination. The median BMC/BW ratios 6 weeks postnatally were 53.1 mg/cm·kg (minimum and maximum, 45.7–70.5) and 51.2 mg/cm·kg (minimum and maximum, 34.5–58.8) in the E2 and P replacement and control groups, respectively. At the follow-up examination, the median BMC/BW ratios were 38.5 mg/cm·kg (minimum and maximum, 24.6–50.5) and 40.9 mg/cm·kg (minimum and maximum, 31.8–58.8). The bone mineral accretion values were 3.53 mg/cm·100 g wt gain (minimum and maximum, 2.03–5.04) and 3.92 mg/cm·100 g wt gain (minimum and maximum, 3.01–5.59), respectively. No variable showed a statistically significant difference between the groups.

The parents of one infant in the control group did not agree to a radiograph of the left hand. Table 1Go shows the skeletal age of each group. The median deviation of the skeletal age from the corrected age of 1.7 months in the control group indicates a delayed skeletal maturation. The median skeletal age of the replacement group infants exactly fitted the corrected age (P = 0.64).


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  		Table 1. Skeletal age and its deviation from the corrected age at the follow-up examination of the infants in the E2 and P replacement group (n = 13) and the control group (n = 10)

 
In 2 infants in the E2 and P replacement group (1 with a grade IV intraventricular hemorrhage on both sides and 1 with a normal cerebral ultrasound) and in 1 infant in the control group (normal brain scan), the Bayley test was not representative due to visual impairment (retinopathia of prematurity), anxiety of the examiner, or tiredness of the infant. In the remaining 21 infants, the MDI of the groups equaled each another (Table 2Go). For the E2 and P replacement group, the median PDI was 101 and therefore can be said to be within normal limits (normal range, 85–114) (8). For the control group, the median PDI was 71, corresponding to a mildly delayed performance.


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  		Table 2. The MDI and PDI of the E2 and P replacement group (n = 11) and the control group (n = 10)

 
The results of the neurological examination are presented in Fig. 1Go. All infants were included. Three infants in the E2 and P replacement group, but none of the control group infants, were classified as normal after the neurological examination. The two infants from the control group with major neurological deficit had combined grade III and IV intraventricular hemorrhage. The infant in the E2 and P replacement group with a two-sided grade IV intraventricular hemorrhage was classified as having minor neurological deficits.



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  		Figure 1. Result of the neurological examination of 24 extremely low birth weight infants with or without postnatal E2 and P replacement at a median corrected age of 14.8 months. IVH, Intraventricular hemorrhage grade III or IV.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
After postnatal E2 and P replacement, the median skeletal age exactly fitted the corrected age, whereas the median skeletal age was delayed for 1.7 months in the control group infants. This finding is in agreement with observations in primates delivered preterm that showed delayed skeletal maturation at term and at 6 months of age (9).

Neurological examination was normal in three infants in the E2 and P replacement group, but in none of the control group infants. For the control group infants, the median MDI and PDI scores were 93 and 71, corresponding to a median delay of 1.3 months for mental development and 3.7 months for motor development. The results are in accordance with previous findings in preterm infants and reflect the fact that preterm infants perform below their same postmenstrual age peers born at term (8). The median MDI score of the infants receiving postnatal E2 and P replacement was 89 and also lower than that of a normative sample. Interestingly, the replacement group achieved normal psychomotor development, with a median PDI score of 101. Estrogens have been discussed as possible trophic factors for developing neurons (10). They can promote axonal and dendritic growth and synapse formation (11) and thus can influence the development of neural networks.

No significant differences were found between the infants of the hormone replacement group and the control group infants, possibly due to the small sample size of the pilot study. Interestingly, normal PDI was found in the replacement group, whereas extremely preterm infants without hormone replacement most often showed a delay in psychomotor development. This preliminary data support the potentially important integrative role of sex steroids in the developing brain. Further studies of the effects of postnatal replacement of E2 and P in extremely preterm infants are warranted.

Received July 7, 2000.

Revised September 11, 2000.

Revised October 4, 2000.

Accepted October 19, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Pohlandt F. 1994 Prevention of postnatal bone demineralization in very low-birth-weight infants by individually monitored supplementation with calcium and phosphorus. Pediatr Res. 35:125–129.[Medline]
  2. Lindsay R. 1988 Sex steroids in the pathogenesis and prevention of osteoporosis. In: Melton LJ, Riggs L, eds. Osteoporosis: etiology, diagnosis and management. New York: Raven Press; 333–358.
  3. Prior JC. 1990 Progesterone as a bone-trophic hormone. Endocr Rev. 11:386–398.[Abstract]
  4. Hercz P. 1985 Quantitative changes in steroid and peptide hormones in the maternal-fetoplacental system between the 28th-40th weeks of pregnancy. Acta Med Hung. 42:29–39.[Medline]
  5. Trotter A, Maier L, Grill HJ, Kohn T, Heckmann M, Pohlandt F. 1999 Effects of postnatal estradiol and progesterone replacement in extremely preterm infants. J Clin Endocrinol Metab. 84:4531–4535.[Abstract/Free Full Text]
  6. Pohlandt F, Mathers N. 1989 Bone mineral content of appropriate and light for gestational age preterm and term newborn infants. Acta Paediatr Scand. 78:835–839.[Medline]
  7. Greulich W, Pyle S. 1959 Radiographic atlas of skeletal development of the hand and wrist, 2nd Ed. Stanford: Stanford University Press.
  8. Bayley N. 1993 Manual of the Bayley scales II of infants development, 2nd Ed. New York: Psychological Corp.
  9. Newell-Morris L, Carrol B, Covey A, Medley S, Sackett GP. 1991 Postnatal growth and skeletal maturation of experimental preterm macaques (Macaca nemestrina). J Med Primatol. 20:17–22.[Medline]
  10. Beyer C. 1999 Estrogen and the developing mammalian brain. Anat Embryol. 199:379–390.[CrossRef][Medline]
  11. Matsumoto A. 1991 Synaptogenic action of sex steroids in developing and adult neuroendocrine brain. Psychoneuroendocrinology. 16:25–40.[CrossRef][Medline]



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*ESTRADIOL
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Medline Plus Health Information
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*Premature Babies

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