Acta Padiatr Scand [Suppl] 370: 115-120, 1990

Birth Data for Patients Who Later Develop Growth Hormone Deficiency: Preliminary Analysis of a National Register K. ALBERTSSON-WIKLAND on behalf of the Executive Scientific Committee of the Kabi International Growth Study and the Swedish Paediatric Study Group for Growth Hormone Treatment, A. NIKLASSON and P. KARLBERG From the Departments of Paediarrics. Universiry of Gothenburg, Gothenburg. Sweden

ABSTRACT. Albertsson-Wikland, K. on behalf of the Executive Scientific Committee of the Kabi International Growth Study and the Swedish Paediatric Study Group for Growth Hormone Treatment, Niklasson, A., and Karlberg, P. (Departments of Paediatrics, University of Gothenburg, Gothenburg, Sweden). Birth data for patients who later develop growth hormone deficiency: preliminary analysis of a national registry. Acta Paediatr Scand [ S ~ p p l 3] 7 0 115-120, 1990. This study analyses gestational age, mode of delivery and size a t birth in children who later developed idiopathic or organic growth hormone deficiency (GHD). A data register of children on growth hormone (GH) treatment in Sweden was compared with the Swedish Medical Birth Register during a 14-year period (1973-1986) comprising 1.4 million newborn children. Size a t birth was evaluated using a new Swedish reference standard based on data from around 500,OOO newborn children. It was found that the children who later develop idiopathic GHD (IGHD) were born with a normal distribution of gestational age. They were more often born with breech delivery (7.1% versus 2.8%) or caesarean section (16.6% versus 10.4%) compared with normal children. The children's condition at birth was poorer than normal, as shown by the frequency of Apgar scores below 7 at 5 minutes (5.2% versus 1.2%). Finally, it was found that children who later develop IGHD (n = 220) had a median birth length of 0.87 SDS below the mean and a median birth weight of 0.60 SDS below the mean of the standard. In contrast, both the birth length and weight of the children who later develop organic GHD (OGHD) (n = 92) did not differ from that of the reference. Key words: Idiopafhic growfh hormone deficiency, birth length, birth weighf, gesm-onal age.

It has previously been suggested that small size at birth is associated with the subsequent development of growth hormone deficiency (GHD). However, studies conducted in the 1960s and 1970s led to the conclusion that children who develop GHD have a normal weight and length at birth (1-3). Hence, it was believed that growth hormone (GH) did not influence fetal growth, despite the fact the fetal plasma GH levels are high (4). These conclusions can be challenged, however, because there were inconsistencies in the results of the studies (2). There has also been speculation about the influence of delivery problems on subsequent development of GHD. This study aims to explore both of these issues, based on around 500,000 children with GHD and normal subjects. There is a national register of birth data for Swedish children receiving GH treatment, as well as a Medical Birth Register covering all births in Sweden since 1973 (5). Size at birth has been evaluated using a new Swedish reference standard based on data from 475,588 newborn children (6).

PATIENTS AND METHODS Register of Swedish children wirh GHD. Voluntary registration of children on GH treatment was started in Sweden in 1988, and the children receiving Genotropin' form the Swedish part of the Kabi International Growth Study (KIGS). Although voluntary, this register is known to be almost complete because in 1989 it was compared by the National Board of Health and Welfare with all prescriptions of GH in Sweden (7).

'Genotropin, trademark KabiVitrum AB. Sweden for recombinant somatropin; Genotonorm in Belgium, France and Spain.

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Table 1. Details of children with IGHD or OGHD.

Number of patients (n) Sex ratio (ma1e:female) Age at start of GH treatment (years) (median)

IGHD

OGHD

220

92

3. I

9.5

Height SDS at start (median)

-2.5

Target height SDS (median)

0

1.1

9.9 -1.5

0.5

For this analysis, the register was closed on 1 February 1990. At that time, it comprised 248 children with idiopathic GHD (IGHD) and 100 with organic GHD (OGHD). The criterion for the diagnosis of GHD was a GH response to provocative tests of less than 20 mU/I. Six children with septo-optic dysplasia were excluded. For consistency, children with birth trauma as the suggested cause of GHD were classified as having IGHD. Birth data were available in 220 out of the 248 children with IGHD (89%) and in 92 of the 100 children with OGHD (92%); this analysis is therefore based on data from a total of 3 12 children. The causes of OGHD were craniopharyngioma (n = 22). treatment for CNS tumour (n = 51) and treatment for leukaemia (n = 18). Descriptive information is found in Table I . For parental heights, the Swedish reference standard was used (8). Swedish Medical Einh Registrarion. Medical birth registration was instituted throughout Sweden in 1973 ( 5 ) . It is compulsory to report medical birth data on a registration form, and this constitutes part of the standardized record system for maternal health care, obstetric care and newborn infant health care. The registration form allows rapid exchange of information between these health care units. facilitating adequate clinical care of the mother and child. The National Board of Health and Welfare also receives registration forms for all newborn babies, stillborn as well as living. The primary goals of this register are to describe birth events, and to monitor the perinatal mortality and factors influencing this mortality. Data from the Swedish Medical Birth Register used in this analysis are weight, length and gestational age at birth, mode of delivery and Apgar score. Within this 14-year period (1973-1986). the annual birth rate was about 100.000, to give a total of 1.4 million births. The newborns surviving at least I week form the reference for the present analysis. The total population in Sweden today is approximately 8.5 million. Reference values for size ar birth. Reference values for length and weight at birth were established from the Medical Birth Register for all ‘healthy’ singletons of estimated gestational age 28-43 weeks who were born in Sweden during the years 1977-1981 (3). In order to obtain a healthy population from which standards could be established, approximately 20% of cases were excluded from the total population of around 500,000 newborn children. There were a variety of reasons for exclusion associated with factors that were thought to have affected intrauterine growth, such as: multiple births and stillbirths. defined maternal illnesses including diabetes, and certain congenital malformations. In almost all cases. two separate assessments of gestational age were available: one based on the dates of the last menstrual period reported by the mother, and the other on the obstetric assessment made by the physician. These reference values have been validated for all children born in Sweden in 1986.

RESULTS Gestational age. No statistically significant difference in gestational age was detected for either the children with IGHD or OGHD, when compared with the 100,OOO newborn babies on the Medical Birth Register for 1986 (Fig. 1). Mode of delivery and Apgar score. The condition of newborn children can be expressed using the Apgar score (9). A rating of below 7 at 5 minutes after delivery occurs much more frequently in children who later develop IGHD ( 5 . 2 % ) than in the total Swedish newborn population (1.2%). As stated earlier, children who later develop IGHD are more often born in the breech position (7.1% versus 2.8%) However, delivery by caesarean section is also more common in children who later develop IGHD (16.6% versus 10.4%) (Fig. 2 ) . Length and weight at birth. Fig. 3 shows the distribution of birth length of the children with IGHD and OGHD in relation to their gestational age. The values are expressed as SDS, calculated using the Swedish reference values (mean and SD) for size at birth. For the

Acta Paediatr Scand [Suppl] 370

Birth data for GHDpatients Swedish Medical Birth Register

40

0 IGHD

t n

5

Z

Gestationalage (weeks)

Fig. 1. Frequency distribution of gestational age for children who later develop IGHD (n = 220) or OGHD (n = 92). Swedish data compared with the whole newborn population in the Swedish Medical Birth Register (n = 1.4 million). No significant difference was detected.

Swedish Medical Birth Register

14 151

IGHD

11

OGHD

-

section

Fig. 2. Types of delivery in children who later develop IGHD and OGHD, compared with the frequency of type of delivery in the whole newborn population in the Swedish Medical Birth Register (n = 1.4 million). In children who later develop IGHD, breech delivery and section were significantly more frequent than in the normal population (7.1 4% versus 2.896, and 16.6% versus 10.4%. respectively).

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Acta Pardialr Scand [Suppl] 370

OGHD

IGHD

Fig. 3. Distribution of standardized birth length of children who later develop IGHD (n = 220) and OGHD (n = 92). in relation to gestational age. The values are standardized in SDS for the new Swedish reference values for size at birth (6).

children who later develop IGHD, the median birth length SDS is -0.87 SDS ( p < 0.001 Wilcoxon signed rank test), whereas the corresponding value for the children with OGHD is -0.08 SDS (not significant). The corresponding values for weight are shown in Fig. 4. The children with IGHD are also significantly lighter at birth, having a median SDS of -0.60 ( p < 0.001). The birth weight of the children with OGHD did not differ significantly from the reference population (-0.22 SDS). The target height of children who later developed IGHD was normal (Table I ) . The short children with IGHD do not always have short parents.

IGHD

51

4l 3

Gestational age (weeks)

."F

OGHD

3t

Gestational age (weeks)

Fig. 4. Distribution of standardized birth weight of children who later develop IGHD (n = 220) and OCHD

(n = 92) in relation to their gestational age. The values are standardized in SDS for the new Swedish reference valucs for size at birth ( 6 ) .

Acta Paediatr Scand [Suppl] 370

Birth data for CHD patients

DISCUSSION This study shows that children with IGHD have a reduced weight and length at birth, which is in contrast to most published reports (1). This difference could be due to the large number of GHD children in this study and the use of standardized size, expressed in SDS. A better resolution of data variability is thus achieved, reducing ‘noise’ due to gender or gestational age variations. That the OGHD group showed no difference in size at birth compared with the reference standard strengthens the findings that the IGHD group is shorter and lighter at birth. The study also highlights the importance of using good reference values for size at birth in relation to gestational age. Children with IGHD also have more delivery problems and more often have an impaired general condition postnatally, as shown by the frequency of Apgar scores below 7 at 5 minutes. These findings are in agreement with the literature (3), where an over-representation of breech deliveries in children with GHD has previously been described. Goodman et af. showed that out of 35 children with GHD, 1 1 % had breech deliveries (lo), Bierich that out of 45 GHD children, 62% had breech deliveries (1 l), Job that out of 31 children, 52% had breech delivery (12) and Rona found breech deliveries in 11 % of 140 GHD children (3). It has been proposed that GHD in such patients is due to the trauma caused by breech delivery. However, it has also been speculated that the mechanism causing the failed vertex position at labour, which leads to breech delivery, might also be related to damage of the hypothalamic-pituitary region. It is known that children born in the breech position have a three times higher incidence of malformations than normal, and a decreased birth weight for the placenta weight (3). In this respect, it is of interest to note the finding of this report that not only breech deliveries, but also the frequency of caesarean section deliveries, were increased in children who later developed GHD. Since the deliveries of these children were compared with those of all the children born in Sweden during the same period, the increase in the frequency of section cannot just be due to the change in clinical practice. It will therefore be of interest to explore the reasons for caesarean section further; for example, breech presentation may account for many of the elective sections and birth complications caused by breech presentations may account for some acute caesarean sections. The interesting new findings presented in this preliminary report have been possible to obtain because of the existence of a national register of children receiving GH. The Kabi International Growth Study (KIGS) offers the possibility of pooling data on a great number of children on GH treatment in different countries, and will therefore provide an even greater opportunity to gain more knowledge about GHD in the future.

ACKNOWLEDGEMENTS The members o f the Swedish Paediatric Study Group for Growth Hormone Treatment are: Kerstin AlbertssonWikland. Stefan Aronsson, Jan Gustafsson. Lars Hagenas. Anders Hager, Sten Ivarsson, Christian Moell. Karl-Olof Nilsson. Martin Ritztn, Torsten Tuvemo. Ulf Westgren and Otto Westphal.

REFERENCES 1 . Falkner F, Tanner JM (eds). Human growth. Vol. I . Developmental biology. Prenatal growth, 2nd ed.

New York. London: Plenum Press, 1986. 2 . Laron Z . Pertzelaw A . Somatotrophin in antenatal and perinatal growth and development. Lance1 1969: i: 680-81. 3. Rona R. An epidemiological and genetic study o f idiopathic growth hormone deficiency. Department o f Growth and Development, Institute o f Child Health, University o f London. Thesis, 1976. 4. Jost A . Fetal hormones and fetal growth. Contrib Gynaecol Obstetr 1979; 5: 1-20.

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5. Medical Birth Registry 1973-1986. Statistics of the National Board of Health and Welfare. Statistical Reports HS 1977: 16; 1980: 2; 1981: 2; 1983: 5; 1984: 2. National Central Bureau of Statistics, Stockholm, Sweden. 6. Niklasson A, Ericson A. Fryer J , Karlberg J , Lawrence C, Karlberg P. An update of the Swedish Reference Standards for weight, length and head circumference at birth for given gestational age (1977-1981; n = 475.588). Acta Paediatr Scand (in press). 7. Ritztn EM, Albertsson-Wikland K (eds). Growth hormone treatment of short stature. State-of-the-art in 1989. Proceedings of a meeting held in Stockholm October 19-20, 1989. Acta Paediatr Scand [Suppl] 1989: 362. 8. Karlberg P. Taranger J , Engstrom I. Lichtenstein H, Svennberg-Redegren 1. The somatic development of children in a Swedish urban community. Acta Paediatr Scand [Suppl] 1976; 258: 1-148. 9. Apgar V, James LS. Further observations on the newborn scoring system. Am J Dis Child 1962: 104: 419-28. 10. Goodman HG, Brumbach MM. Kaplan SL. Growth and growth hormone: 11. A comparison of isolated growth hormone deficiency and multiple pituitary deficiencies in 35 patients with idiopathic hypopituitary dwarfism. New Engl J Med 1968; 278(2): 57. I I , Bierich JR. On the aetiology of hypopituitary dwarfism. In: Pecile A. Miiller EE, eds. Growth and growth hormone. Proceedings of the Second International Symposium on Growth Hormone. Amsterdam: Excerpta Medica Foundation, 1972. 12. Job JG. Lejeune C , Canlorbe P, Rossier A. Le nanisme par insuffisance hypophysaire sporadique idiopathique. Etude d’une sCrie de 31 cas. Arch Fr P d i a t r 1972; 29: 2. (K.A.-W.) Department of Paediatrics I1 Gothenburg University East Hospital S-416 85 Gothenburg Sweden

Birth data for patients who later develop growth hormone deficiency: preliminary analysis of a national register. The Executive Scientific Committee of the Kabi International Growth Study and the Swedish Paediatric Study Group for Growth Hormone Treatment.

This study analyses gestational age, mode of delivery and size at birth in children who later developed idiopathic or organic growth hormone deficienc...
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