1 Laboratory of Endocrinology and Metabolism, Department of Internal Medicine, 2 Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago and 3 Laboratory of Animal Physiology and Endocrinology, School of Veterinary Medicine, University of Concepción, Chillán, Chile
4 To whom correspondence should be addressed at: Laboratory of Endocrinology, Department of Medicine, W. Division, School of Medicine, Las Palmeras 299, Interior Quinta Normal, Casilla 33052, Correo 33, Santiago, Chile. Email: tsir{at}med.uchile.cl
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Abstract |
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Key words: birth weight/macrosomia/metformin/polycystic ovary syndrome/small for gestational age
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Introduction |
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The aim of the present study was to establish the birth weight in newborns of PCOS mothers compared with a control group of newborns of normal women matched by age and weight at the beginning of pregnancy.
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Material and methods |
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All women had been anovulatory as indicated by progesterone measurements and ultrasound examinations. Hyperprolactinaemia, androgen-secreting neoplasm, Cushing's syndrome and attenuated 21-hydroxylase deficiency, as well as thyroid disease, were excluded by appropriate tests.
We selected 180 normal pregnant women of similar age, socio-economic level and BMI with singleton pregnancies as a control group. The control women had a history of regular 28- to 32- day menstrual cycles, absence of hirsutism and other manifestations of hyperandrogenism, and were not receiving any drug therapy. These women were recruited from the prenatal care unit of our hospital from the 12th week of gestation during the same time period.
Only non-smoking and non-alcohol or drug abusing PCOS and control pregnant women were included in the study. All subjects had given their written consent to their participation in the study, which was approved by the local ethics committee.
Study protocol
Both groups of pregnant women were followed in the same prenatal care unit. Duration of gestation, initial BMI, BMI in the third trimester, weight gain during pregnancy and blood pressure were recorded.
During gestational week 2228 the women were admitted to the Clinical Research Center in the morning (08:3009:00) after an overnight fast of between 8 and 12 h and a 2 h, 75 g oral glucose tolerance test was performed in accordance with published criteria (World Health Organization, 1999). Pregnancy-induced hypertension was defined as gestational hypertension (blood pressure
140/90 mm Hg without proteinuria at a gestational age >20 weeks on two or more occasions) or pre-eclampsia (blood pressure
140/90 mm Hg with proteinuria >0.3 g/24 h after 20 weeks gestation).
Immediately after delivery, a physical examination of the newborn was performed. Anthropometric measurements at birth were recorded, including weight, length and head circumference. Weight and length were transformed into standard deviation score (SDS) using local normative data for newborns (Juez et al., 1989; Soto et al., 2003
), adjusting for differences in gestational age and gender. SDS were calculated using the formula SDS=(xmean)/SD. Infants were defined as small for gestational age (SGA) infants (birth weight <5th percentile), appropriate for gestational age (AGA) infants (birth weight >5th and <90th percentile) and large for gestational age (LGA) infants (birth weight >90th percentile) (de Rooy and Hawdon, 2002
; Das and Sysyn, 2004
). Infants showing evidence of malformations or genetic disorders were excluded from the study.
Statistical evaluation
Data are expressed as means and SD when normally distributed, and as medians and interquartile ranges when not normally distributed. Prevalence of SGA or LGA in PCOS and control groups was assessed by chi-square (2). Differences in the pregnancy characteristics of control and PCOS mothers and in the respective newborns were assessed by Student's t-test and differences between SGA and LGA infants born to PCOS and control mothers were assessed by the MannWhitney test. The potential confounding effects of continuous variables related to birth weight such as maternal height, were assessed by analysis of co-variance (ANCOVA). Logistic regression techniques were used to assess the association between the PCOS status and SGA and for adjusting by the possible confounding effects of covariates such as maternal height, parity and gestational diabetes. Statistical analysis was performed using the statistical package for Social Science Software (SPSS 10.0). A P value of less than 0.05 was considered to be statistically significant.
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Results |
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The clinical characteristics of the LGA newborns are given in Table IV. Birth length SDS was greater, but head circumference was smaller in LGA newborns of PCOS mothers compared to those of controls (P<0.05). However, the prevalence of LGA infants was similar in both groups (Control: 11.1% versus PCOS: 17.0%, P=0.396) (Figure 1 LGA/control bar seems higher than 11.1%). Nevertheless, weight gain during pregnancy in PCOS mothers with LGA infants was significantly higher compared to control mothers [(17.64 (12.025.0) versus 13.08 (5.6020.20) kg; P=0.036)]. The incidence of gestational diabetes in the mothers was also similar, with one mother in each group.
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Discussion |
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Individual variability in growth rates during infancy is dependent on both genetic and environmental factors. Genetically determined insulin resistance results in impaired insulin-mediated growth (Hattersley and Tooke, 1999). For example, fetuses with monogenic disorders affecting insulin secretion or insulin sensitivity exhibit intrauterine growth retardation, which strongly supports the fetal insulin hypothesis (Temple et al., 1995
, 1996
; Thomas et al., 1995
; Hattersley et al., 1998
).
In addition, it has been proposed that the endocrine, nutritional and metabolic milieu of the fetus may have a programming effect, which may persist into adult life (Barker, 1994; Holemans et al., 1998
; Tchernitchin et al., 1999
; Rhind et al., 2001
). Intrauterine growth retardation is associated with several adult disorders such as cardiovascular disease, type 2 diabetes, obesity and hypertension (Barker et al., 1993
; Hoffman et al., 1997
; Bavdekar et al., 1999
; Jaquet et al., 2000
; Gray et al., 2002
; Ong and Dunger, 2002
). In addition, low birth weight has been related with reproductive disorders (de Bruin et al., 1998
; Rhind et al., 2001
; Ibañez et al., 2002a
,b
, 2003
; Davies and Norman, 2002
) including PCOS (Ibáñez et al., 1998
.
Recently, it has been proposed that fetal growth retardation may be related to prenatal exposure to sex steroids. In sheep, testosterone treatment during pregnancy may lead to growth-retarded male and female offspring (Manikkam et al., 2004). We have recently demonstrated that pregnant women with PCOS exhibit a significant increase in androgen concentrations during pregnancy, which could provide a potential source of androgens to the fetus, and is perhaps another mechanism to explain the higher prevalence of low birth weight newborns in PCOS mothers (Sir-Petermann et al., 2002
). We should point out that, in the present study, the low birth weight of only two newborns could be attributed to preterm induction of labour due to pre-eclampsia. Therefore, both the fetal programming hypothesis proposed by Barker and Osmond (1986)
and the fetal insulin hypothesis proposed by Hattersley and Tooke (1999)
, and later supported by Hübinette et al. (2001)
, provide plausible mechanisms to help explain the higher prevalence of SGA newborns in PCOS mothers independently of pregnancy complications and maternal determinants of birth weight such as parity and maternal height (Hindmarsh et al., 2002
).
Thus, the offspring of PCOS mothers may represent a high-risk group with a great potential for early clinical intervention. In this regard, a treatment programme, including diet, exercise and insulin sensitising agents before pregnancy in those PCOS women who desire fertility, and diet and exercise in those who become pregnant, may constitute a timely therapeutic approach. Following this approach, the incidence of pregnancy complications such as gestational diabetes and pregnancy-induced hypertension observed in our PCOS patients was lower than that reported in the literature (Lesser and Garcia, 1997; Urman et al., 1997
). Moreover, as previously reported (Urman et al., 1997
), the incidence of pregnancy complications is higher in obese PCOS patients and obese control women than in lean women, indicating that obesity itself is a risk factor for the above complications. Nevertheless, the incidence of pregnancy complications in the same study was not greater among obese PCOS patients compared to lean PCOS patients, suggesting that PCOS itself may be the primary risk factor associated with an increased incidence of gestational diabetes and pregnancy-induced hypertension.
Another potential therapeutic intervention might be the use of metformin during pregnancy. According to the studies of Glueck et al. (2004), the benefits of continuing metformin through pregnancy could limit weight gain, improve insulin sensitivity and reduce androgen levels. These effects might prevent the development of pregnancy complications such as intrauterine growth retardation and exposure of the fetus to androgen excess. However, there is insufficient evidence to support the use of metformin during pregnancy at this time.
A relationship between PCOS and neonatal macrosomia was suggested many years ago (Wortsman et al., 1991), but this potential relationship has been controversial (Urman et al., 1997
). In the present study, the prevalence of macrosomic infants in the PCOS group was 17% and in the control group 11%, this difference was not statistically significant. However, weight gain during pregnancy for PCOS mothers with LGA newborns was significantly greater compared to control mothers, therefore, the same therapeutic approach may be desirable for these patients.
In summary, PCOS mothers showed a significantly higher prevalence of SGA newborns which cannot be completely attributed to pregnancy complications or maternal determinants of birth weight and seems to be more related to the PCOS condition of the mother.
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Acknowledgements |
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References |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
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Barker DJP (1994) Programming the baby. In Mothers, Babies, and Disease in Later Life. BMJ Publishing Group, London, pp. 1436.
Barker DPJ and Osmond C (1986) Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1, 10771081.[Medline]
Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K and Clark PM (1993) Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidemia (Syndrome X): relation to reduced fetal growth. Diabetologia 36, 6267.[CrossRef][ISI][Medline]
Bavdekar A, Yajnik CS, Fall CH, Bapat S, Pandit AN, Deshpande V, Bhave S, Kellingray SD and Joglekar C (1999) Insulin resistance syndrome in 8 year-old Indian children: small at birth, big at 8 years, or both? Diabetes 48, 24222429.[Abstract]
Benitez R, Sir-Petermann T, Palomino A, Angel B, Maliqueo M, Perez F and Calvillan M (2001) Prevalence of metabolic disorders among family members of patients with polycystic ovary syndrome. Rev Med Chil 129, 707712.[ISI][Medline]
Das UG and Sysyn GD (2004) Abnormal fetal growth: intrauterine growth retardation, small for gestational age, large for gestational age. Pediatr Clin North Am 51, 639654.[CrossRef][ISI][Medline]
Davies MJ and Norman RJ (2002) Programming and reproductive functioning. Trends Endocrinol Metab 13, 386392.[CrossRef][ISI][Medline]
de Bruin JP, Dorland M, Bruinse HW, Spliet W, Nikkels PG and Te Velde ER (1998) Fetal growth retardation as a cause of impaired ovarian development. Early Hum Dev 51, 3946.[CrossRef][ISI][Medline]
de Rooy L and Hawdon J (2002) Nutritional factors that affect the postnatal metabolic adaptation of full-term small- and large-for-gestational-age infants. Pediatrics 109, E42.[CrossRef][Medline]
Dunaif A (1997) Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 18, 774800.
Dunaif A, Graf M, Mandeli J, Laumas V and Dobrjansky A (1987) Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 65, 499507.[Abstract]
Dunaif A, Segal KR, Futterweit W and Dobrjansky A (1989) Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38, 11651174.[Abstract]
Ehrmann DA, Barnes RB and Rosenfield RL (1995) Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev 16, 322353.[CrossRef][ISI][Medline]
Franks S (1995) Polycystic ovary syndrome. N Engl J Med 333, 853861.
Glueck CJ, Goldenberg N, Wang P, Loftspring M and Sherman A (2004) Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy. Hum Reprod 19, 510521.
Gray P, Cooper PA, Cory BJ, Toman M and Crowter NJ (2002) The intrauterine environment is a strong determinant of glucose tolerance during the neonatal period, even in prematurity. J Clin Endocrinol Metab 87, 42524256.
Hattersley AT and Tooke JE (1999) The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 353, 17891792.[CrossRef][ISI][Medline]
Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R and Ellard S (1998) Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet 19, 268270.[CrossRef][ISI][Medline]
Hindmarsh PC, Geary MP, Rodeck CH, Kingdom JC and Cole TJ (2002) Intrauterine growth and its relationship to size and shape at birth. Pediatr Res 52, 263268.
Hoffman PL, Cutfield WS, Robinson EM, Bergman RN, Menon RK, Sperling MA and Gluckman PD (1997) Insulin resistance in short children with intrauterine growth retardation. J Clin Endocrinol Metab 82, 402406.
Holemans K, Aerts L and Van Assche FA (1998) Fetal growth and long-term consequences in animal models of growth retardation. Eur J Obstet Gynecol Reprod Biol 81, 149156.[CrossRef][ISI][Medline]
Holte J (1996) Disturbances in insulin secretion and sensitivity in women with the polycystic ovary syndrome. Baillieres Clin Endocrinol Metab 10, 221247.[CrossRef][ISI][Medline]
Hübinette A, Cnattingius S, Ekbom A, de Faire U, Kramer M and Lichtenstein P (2001) Birthweight, early environment, and genetics: a study of twins discordant for acute myocardial infarction. Lancet 357, 19901997.[CrossRef][ISI][Medline]
Hull MG (1987) Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. Gynecol Endocrinol 1, 235245.[Medline]
Ibáñez L, Potau N, Francois I and de Zegher F (1998) Precocious pubarche, hyperinsulinism and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J Clin Endocrinol Metab 83, 35583562.
Ibáñez L, Potau N, Ferrer A, Rodriguez-Hierro F, Marcos MV and de Zegher F (2002b) Reduced ovulation rate in adolescent girls born small for gestational age. J Clin Endocrinol Metab 87, 33913393.
Ibáñez L, Potau N, Enriquez G, Marcos MV and de Zegher F (2003) Hypergonadotrophinaemia with reduced uterine and ovarian size in women born small-for-gestational-age. Hum Reprod 18, 15651569.
Ibáñez L, Valls C, Cols M, Ferrer A, Marcos MV and De Zegher F (2002a) Hypersecretion of FSH in infant boys and girls born small for gestational age. J Clin Endocrinol Metab 87, 19861988.
Jaquet D, Gaboriau A, Czernichow P and Levy-Marchal C (2000) Insulin resistance early in adulthood in subjects born with intrauterine growth retardation. J Clin Endocrinol Metab 85, 14011406.
Juez G, Lucero E, Ventura-Junca P, Gonzalez H, Tapia JL and Winter A (1989) Intrauterine growth in Chilean middle class newborn infants. Rev Chil Pediatr 60, 198202.[Medline]
Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR and Azziz R (1998) Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 83, 30783082.
Lesser KB and Garcia FA (1997) Association between polycystic ovary syndrome and glucose intolerance during pregnancy. J Matern Fetal Med 6, 303307.[CrossRef][Medline]
Manikkam M, Crespi EJ, Doop DD, Herkimer C, Lee JS, Yu S, Brown MB, Foster DL and Padmanabhan V (2004) Fetal programming: prenatal testosterone excess leads to fetal growth retardation and postnatal catch-up growth in sheep. Endocrinology 145, 790798.
Ong KK and Dunger DB (2002) Perinatal growth failure: the road to obesity, insulin resistance and cardiovascular disease in adults. Best Pract Res Clin Endocrinol Metab 16, 191207.[CrossRef][ISI][Medline]
Rhind SM, Rae MT and Brooks AN (2001) Effects of nutrition and environmental factors on the fetal programming of the reproductive axis. Reproduction 122, 205214.
Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 19, 4147.
Sir-Petermann T, Devoto L, Maliqueo M, Peirano P, Recabarren SE and Wildt L (2001) Resumption of ovarian function during lactational amenorrhoea in breastfeeding women with polycystic ovary syndrome: endocrine aspects. Hum Reprod 16, 16031610.
Sir-Petermann T, Maliqueo M, Angel B, Lara HE, Perez-Bravo F and Recabarren SE (2002) Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum Reprod 17, 25732579.
Soto N, Bazaes RA, Pena V, Salazar T, Avila A, Iniguez G, Ong KK, Dunger DB and Mericq MV (2003) Insulin sensitivity and secretion are related to catch-up growth in small-for gestational-age infants at age 1 year: results from a prospective cohort. J Clin Endocrinol Metab 88, 36453650.
Tchernitchin AN, Tchernitchin NN, Mena MA, Unda C and Soto J (1999) Imprinting: perinatal exposures cause the development of diseases during the adult age. Acta Biol Hung 50, 425440.[ISI][Medline]
Temple IK, James RS, Crolla JA, Sitch FL, Jacobs PA, Howell WM, Betts P, Baum JD and Shield JP (1995) An imprinted gene(s) for diabetes? Nat Genet 9, 110112.[CrossRef][ISI][Medline]
Temple IK, Gardner RJ, Robinson DO, Kibirige MS, Ferguson AW, Baum JD, Barber JC, James RS and Shield JP (1996) Further evidence for an imprinted gene for neonatal diabetes localised to chromosome 6q22-q23. Hum Mol Genet 5, 11171124.
Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF and Bryan J (1995) Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 286, 426429.
Urman B, Sarac E, Dogan L and Gurgan T (1997) Pregnancy in infertile PCOD patients. Complications and outcome. J Reprod Med 42, 501505.[ISI][Medline]
World Health Organization (1999) Report of a WHO consultation: definition, diagnosis and Classification of Diabetes Mellitus and its complications. In Part I: Diagnosis and classification of diabetes mellitus. World Health Organization, Department of Noncommunicable Disease Surveillance, Geneva.
Wortsman J, de Angeles S, Futterweit W, Singh KB and Kaufmann RC (1991) Gestational diabetes and neonatal macrosomia in the polycystic ovary syndrome. J Reprod Med 36, 659661.[ISI][Medline]
Zawadzki JK and Dunaif A (1992) Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In Hershmann JM (ed.) Current Issues in Endocrinology and Metabolism. Blackwell, Boston, pp. 377384.
Submitted on December 28, 2004; resubmitted on February 25, 2005; accepted on March 3, 2005.