Molecular Human Reproduction, Vol. 7, No. 4, 387-395,
April 2001
© 2001 European Society of Human Reproduction and Embryology
Genes or placenta as modulator of fetal growth: evidence from the insulin-like growth factor axis in twins with discordant growth
1 Academic Unit of Obstetrics and Gynaecology, University of Manchester, St Mary's Hospital, Manchester, 2 Chelsea and Westminster Hospital, London and 3 University of Liverpool, Liverpool Women's Hospital, Liverpool, UK
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Abstract |
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To determine whether fetal growth is regulated by placental and/or fetal factors, we measured maternal and fetal concentrations of insulin-like growth factor-I (IGF-I), IGF-II and insulin-like growth factor binding protein-1 (IGFBP-1) (total and non-phosphorylated) in dichorionic (DC) and monochorionic (MC) twins with (DC, n = 13; MC, n = 12) or without (DC, n = 13; MC, n = 12) discordant birth weight. In the discordant MC pregnancy, growth-restricted (IUGR) twins had lower IGF-II concentrations (P < 0.001) but similar IGF-I concentrations compared to the appropriate for gestational age (AGA) co-twin. The differences in IGF-II concentrations showed a positive association with percentage birth weight discordance (r = 0.60; P < 0.05) in MC twins. In contrast, IUGR DC twins had lower IGF-I concentrations (P < 0.05) but similar IGF-II concentrations compared to the AGA co-twins. There was a positive correlation between IGF-I concentrations and birth weight (r = 0.47; P < 0.05) in DC twins. Total IGFBP-1 concentrations were higher in both MC and DC IUGR twins (P < 0.05) compared to AGA twins. A negative association was found between total IGFBP-1 concentrations and birth weight of both MC (r = 0.47; P < 0.05) and DC (r = 0.58; P < 0.01) twins. No such differences in IGF concentrations were found between concordant MC and DC twin pairs. The maternal IGF concentrations were comparable between the MC and DC groups. These data suggest that growth discordances of twins exposed to the same maternal environment may be due to variations in either IGF-I or IGF-II/IGFBP-1, depending upon the functioning of the placenta.
fetal growth/IGF-I/IGF-II/IGFBP-1/twins
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Introduction |
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The insulin-like growth factors (IGF) and their binding proteins (IGFBP) are essential for fetal growth and development. This is evidenced by studies using mice (DeChiara et al., 1990
; Baker et al., 1993; Liu et al., 1993) in which ablation of either the IGF-I or IGF-II gene resulted in embryonic and neonatal mice becoming 40% smaller than their normal littermates. The IGF-II-deficient mice also had reduced placental growth but survived normally, whereas the mice lacking IGF-I had increased neonatal death. The evidence from human pregnancies is conflicting. All tissues in the human fetus express IGF-I/IGF-II mRNA, though significantly higher levels of IGF-II mRNA are detected, leading to the suggestion that this is the IGF which mediates growth and differentiation in developing tissues (Scott et al., 1985; Han et al., 1987, 1988; Brice et al., 1989). Most studies, but not all (Giudice et al., 1995), have failed to show an association between serum IGF-II concentrations and fetal weight (Samaan et al., 1990; Reece et al., 1994; Osorio et al., 1996). Instead, birth weight has been reported to correlate with serum IGF-I concentrations (Lassarre et al., 1991; Klauwer et al., 1997). Furthermore, IGF-I concentrations are decreased in utero and at birth in intrauterine growth-restricted (IUGR) fetuses (Giudice et al., 1995; Ogilvy-Stuart et al., 1998) and are increased in large for gestational age newborns (Giudice et al., 1995).
Although the association between fetal IGF and birth weight is well established, little information is available on the underlying mechanisms by which circulating IGF concentrations are altered in fetal life. Evidence of reduced placental amino acid transporter activity in singleton IUGR pregnancies (Godfrey et al., 1998) has led to the suggestion that maternal undernutrition may influence the fetal IGF axis and thereby intrauterine growth. However, there is a possibility that the influence of IGF on fetal growth may be the result of interaction between maternal physical constraints, placental function, several fetal regulatory systems, and genotype. Therefore, on the assumption that intrauterine fetal growth restriction has in-utero programming implications for health status in later life, it is crucial to appreciate the independent role of fetal genome, maternal variables and placental factors on the fetal IGF axis. This information may be pertinent to the proposal for a large scale implementation of an altered maternal diet as a means of preventing the fetal origins of adult disease (Campbell et al., 1996).
Twin studies may be an alternative to animal experiments to resolve the debate as to whether environmental factors (maternal, placental) and/or fetal genes drive the association between fetal programming and intrauterine growth via IGF. Disparity in fetal growth within twin pairs cannot be attributed to confounding maternal variables such as nutrition, hypertension, diabetes, and smoking, as these factors are common to each member of a twin pair. Recently, we have shown that growth restriction in one of the MC twin pair may be due to impaired transfer of amino acids from maternal circulation (Bajoria et al., 2000), thereby raising the possibility that placental dysfunction may be the primary regulator of the fetal IGF axis. Nevertheless, the influence of genes to drive the association between fetal IGF and growth cannot be ruled out as evidence in fetal and adult life suggests that genetic factors influence circulating IGF concentrations (Kao et al., 1994; Harrela et al., 1996; Verhaeghe et al., 1996).
To test the hypothesis that growth restriction in twins occurs due to interaction between genetic, placental and hormonal factors, we investigated the IGF axis in monochorionic (monozygotic) and dichorionic (dizygotic) twins with or without discordant birth weight.
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Materials and methods |
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Patients
We studied 50 women with twin pregnancies. Chorionicity was established prenatally by ultrasound scan at 15–19 weeks (Bajoria and Kingdom, 1997
). Twins with concordant genitalia, a single placental mass and intra-fetal septal thickness of <2 mm were classed as monochorionic (MC; n = 24). Dichorionic (DC) placentation was diagnosed in the presence of discordant genitalia, separate placentae, membrane thickness >2 mm and the presence of twin peak sign (n = 26). In early pregnancy, the positive predictive value of the composite ultrasound scan parameters for determination of chorionicity is almost 100% (Bajoria and Kingdom, 1997). Chorionicity was confirmed at birth by histological examination of the placenta and membranes. None of the placentae studied had evidence of any significant degree of calcification and/or infarction.
The diagnosis of discordant growth was made when the difference in birth weight was 
20% with no polyhydramnios in the larger twin's sac; and the smaller twin had an abdominal circumference 
5th centile with abnormal umbilical artery Doppler waveforms (Bajoria, 1998). Fetal growth and amniotic fluid volume were monitored by fortnightly ultrasound scans. This constituted the study group.
Twins with differences in birth weight of 10% and normal amniotic fluid volumes in both sacs constituted the concordant/control group. All pregnancies were monitored by serial ultrasound scans for fetal growth, amniotic fluid volume and umbilical artery Doppler waveforms.
Pregnancies complicated by chronic and acute twin–twin transfusion syndrome, death of one or both twins in utero or at birth; fetal aneuploidy; and structural abnormalities were excluded. Chronic mid-trimester TTTS was excluded based on the prenatal sonographic criteria of: (i) monchorionic placenta; (ii) discordant birth weight of >20%; (iii) severe acute polyhydramnios in the larger twin's sac and severe oligohydramnios in the smaller twin's sac; (iv) discordant bladder dynamics with chronically distended bladder in the recipient twin and non-visualization of bladder in the donor twin; (v) increased cardiac/thoracic ratio in the larger twin with normal ratio in the growth-restricted twin; (vi) absence of structural and/or chromosomal abnormalities in both of the twins (Zosmer et al., 1994; Bajoria et al., 1995, 1999). We also excluded those MC pregnancies which were complicated by acute TTTS. The diagnosis of acute TTTS is usually made at birth in the presence of severe polycythaemia in one and anaemia in the other twin. Women who underwent embryo reduction and selective fetocide were also excluded. There were no cases of maternal diabetes, essential hypertension, pregnancy-induced hypertension, pre-eclampsia, renal or cardiac disease.
In the dichorionic twin pregnancies, there were 18 sets of twins with different and eight with same sex pairing. In same sex pairs, zygosity information obtained by DNA analysis was available for four cases. However, in the remaining four sets of twins zygosity was assigned by phenotype assessment by the parents (Bonnelykke et al., 1989).
Collection of blood samples
Maternal and umbilical venous cord bloods were obtained at birth from each twin. The samples were centrifuged, and the plasma stored at –70°C until assay. Additional umbilical arterial and venous samples from each twin were also obtained at birth for determination of haemoglobin and acid-base status. Maternal samples were not available in 16 cases. The study was conducted at St Mary's Hospital, Manchester. Samples were collected at the Institute of Obstetrics and Gynaecology, Hammersmith Hospitals NHS Trust, London (n = 32), Liverpool Women's Hospital (n = 2) and St Mary's Hospital, Manchester (n = 16). Informed consent was obtained from all women who were recruited for collection of maternal samples as required by the Local Hospital research ethics committee.
Immunoassays
Plasma IGF-I was determined by an IGF-II blocked radioimmunoassay (Gill et al., 1997) with an intra- and inter-assay coefficient of variation (CV) of 4.0–5.7% and 5.2–7.4% respectively.
Plasma IGF-II was measured after acid-ethanol extraction using the previously reported two-site immunoradiometric assay (Crosby et al., 1993). This assay has a sensitivity of 30 µg/l and a CV of <10% between 200 and 4500 ng/ml both within and between assays.
IGFBP-1 was determined by two radioimmunoassays (RIA 6303 and 6305) to allow assessment of IGFBP-1 phosphorylation status as well as measurement of concentrations (Westwood et al., 1994). The assays utilize human recombinant IGFBP-1 for standards and radiolabel, and either monoclonal antibody 6303 or 6305 (generously provided by Medix Biochemica, Kauniainen, Finland). RIA 6303 recognizes all isoforms of IGFBP-1, including the phosphoform characteristic of normal plasma (hpIGFBP-1), whereas RIA 6305 only detects the non- and lesser-phosphorylated isoforms (lpIGFBP-1). RIA 6303 has a detection limit of 5 µg/l whereas that of RIA 6305 is 2 µg/l. The inter-assay CV are 8 and 10% respectively, while RIA 6303 has an intra-assay CV of 6.8%, and that of RIA 6305 is 7.6%.
Data analysis
Clinical data are expressed as medians and ranges, while peptide concentrations are expressed as mean ± SEM. For parametric data, the paired t-test was used to compare values within twin pairs and the Student's t-test between groups. Fisher's exact test was used for blocked comparisons. For non-parametric data, Mann-Whitney test was used to compare data between groups. Percentage growth discordance was defined as the difference in birth weight expressed as a proportion of the birth weight of the larger twin. In the control group, the heavier twin was labelled as twin 1 and lighter as twin 2.
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Results |
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In the discordant group, there were 12 sets of MC and 13 sets of DC twins, while the concordant group also had 12 sets of MC and 13 sets of DC twin pregnancies. In the DC group, all measured values of IGF were comparable between same and different sex twin pairs and there were no differences between female and male twins. Therefore, in DC pregnancies, data for same and different sex twin pairs are grouped together according to their differences in birth weight. The clinical parameters for concordant and discordant MC and DC twins are given in Table I
. In the discordant monochorionic (for pH, median 7.35, range 7.22-7.43 versus median 7.18, range 7.01-7.25; P < 0.001; for pO2 median 35, range 29–47 versus median 25, range 17–32 mmHg; P < 0.001) and dichorionic (for pH median 7.36, range 7.13–7.43 versus median 7.19, range 7.05–7.31; P < 0.001; for pO2 median 43, range 35–57 versus median 26, range 15–33 mmHg; P < 0.001) pregnancies, IUGR twins were significantly more hypoxic and acidaemic than the AGA co-twins.
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Monochorionic pregnancies
Maternal IGF concentrations
Measured concentrations of maternal IGF-I, IGF-II, total IGFBP-1 and lpIGFBP were comparable between discordant and concordant growth groups (Table II
).
Fetal IGF concentrations
In the concordant twins, fetal IGF-I, IGF-II, total and lpIGFBP-1 concentrations were comparable between twin pairs (Table II). Fetal IGF-I concentrations within each twin pair were positively correlated (r = 0.73; P < 0.01) (Table III). However, there were no associations between birth weight and fetal IGF-I, IGF-II, total and/or lpIGFBP-1 concentrations.
In the discordant group, fetal IGF-I (r = 0.79; P < 0.01), IGF-II (0.59; P < 0.05), IGFBP-1 (r = 0.73; P < 0.01) and lp-IGFBP-1 (r = 0.86; P < 0.001) concentrations within each twin pair were positively correlated (Table III), but only IGF-I and lpIGFBP-1 concentrations were similar between twin pairs (Table II). However, fetal IGF-II concentrations in IUGR twins were lower than in AGA co-twins (P < 0.001) and in concordant twin pairs (Table II and P < 0.01) (Figure 1). No such differences were found between discordant AGA twins and concordant twins (Table II). Fetal IGFBP-1 concentrations in IUGR twins were higher than in the AGA twins (P < 0.05), and in the twins-1 (P < 0.05) and twins-2 (P < 0.01) of the concordant group. This difference in IGFBP-1 concentrations might be attributed to differences in the hpIGFBP-1, as the concentrations of lpIGFBP-1 were comparable between twin pairs.
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There was a negative association between total IGFBP-1 concentrations and birth weight of discordant twin pairs (y = -0.41x +1145.5; r = 0.47; n = 24; P < 0.05). The percentage discordance in birth weight was related to the difference in IGF-II concentrations measured within each twin pair (y = 15.7x – 182.5; r = 0.60; n = 12; P < 0.05) (Figure 2
). However, there was no relationship between IGF-I and birth weight.
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Dichorionic pregnancies
Maternal fetal concentrations
There were no significant differences in the maternal concentrations of IGF-I, IGF-II, IGFBP-1 and lpIGFBP-1 between discordant and concordant DC twin pregnancies (Table II
).
Fetal IGF levels
There were no significant differences in IGF-I, IGF-II, IGFBP-1 and lpIGFBP-1 concentrations between concordant twins (Table II). Fetal IGF-I (r = 0.85; P < 0.001) and IGFBP-1 (r = 0.71; P < 0.01) within each concordant twin pair were positively correlated (Table III). This relationship was not apparent in twins with discordant birth weight, although, within each twin pair, the difference in birth weight was associated with the difference in their measured IGF-I concentrations.
In contrast to MC pregnancies, there were no differences in the IGF-II concentrations between discordant twin pairs (Table II). Fetal IGF-I was significantly lower in the IUGR than in the AGA twins of the discordant group (P < 0.05) and in twins-1 and twins-2 of the concordant group (P < 0.01) (Table II and Figure 3). In keeping with the MC twins, IGFBP-1 concentrations in the IUGR twins were higher than in the AGA twins (P < 0.05), and also than in the control twin pairs (P < 0.01) (Table II and Figure 3). The concentrations of lpIGFBP-1 were similar between discordant growth twin pairs.
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In the discordant growth group, IGF-I (y = 0.02x + 0.79; r = 0.47; n = 26; P < 0.05) and IGFBP-I concentrations (y = -1.08x + 2919.2; r = 0.58; n = 26, P < 0.01) showed a positive and negative association with birth weight respectively (Figure 4
). No such associations were found in the concordant group.
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Comparison of the IGF axis between MC and DC twins
The IGF-I, IGF-II, total IGFBP-1 and lpIGFBP-1 concentrations were similar between concordant MC and DC twins. Similarly, all the measured IGF in the AGA/larger DC twins were comparable to that in the MC twins. The concentrations of IGF-I in the IUGR twin of the discordant MC group were higher than in the DC IUGR twins (58 ± 7 versus 30 ± 5; P < 0.05). Similarly, fetal concentrations of IGF-II in the MC IUGR twins were lower than the DC IUGR twins (456 ± 57 versus 594 ± 58; P < 0.05) (Table II
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Discussion |
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In our study, the intra-pair IGF-I concentrations correlated in both concordant and discordant MC twins, thereby supporting evidence from previous concordant twin studies that endogenous circulating IGF-I concentrations are genetically determined (Kao et al., 1994
; Harrela et al., 1996; Verhaeghe et al., 1996). Data from studies in mice suggest that genetically determined IGF-I gene expression regulates growth in the fetus (Gluckman et al., 1992). Accordingly, the comparable circulating IGF-I concentration in MC twin pairs with discordant birth weight is in direct variance with our data from discordant DC twin pregnancies. In DC twins who are dizygotic with a difference in genetic make-up, only the twins with concordant growth had matching IGF-I concentrations. In contrast, the discordant DC twins had significantly different IGF-I concentrations, which were lower in the smaller twin. Furthermore, birth weights also correlated with IGF-I concentrations, thereby supporting the data of singleton pregnancies.
Comparable IGF-I concentrations between discordant MC twins could be a consequence of inter-twin transfusion of blood (Bajoria et al., 1995). Strong inter-twin correlations with IGF-I, IGF-II or IGFBP-I raise the possibility of some degree of intermingling of the two circulations. This model in turn may also provide an explanation for increased IGF-II concentrations in the larger twin as IGF-II might also be transferred in this way. However, configuration of placental vascular anastomoses in growth discordant twins is such that under a steady state, no net flux of blood occurs (Bajoria et al., 1995; Bajoria, 1998). Furthermore, decreased IGFBP-1 concentrations in the AGA twin along with the marked inter-pair differences between acid-base status and similar haematological parameters cannot be accounted for by this model of inter-twin transfusion.
Monochorionic twins, being monozygotic, have a similar growth potential (Bajoria and Kingdom, 1997) due to their comparable IGF-I concentrations. In the discordant growth MC pregnancy, growth failure in one twin is perhaps the effect of the placental factors which may override the genetic growth potential. IGF bioavailability is a reflection of integrated endocrine, autocrine and paracrine interactions between IGF, IGFBP and IGFBP proteases (Rosen and Pollack, 1999) and it is possible that ligand availability at the receptor level may differ between twin pairs with discordant weight. IGFBP-1 is thought to be the most important of the binding proteins during fetal life (Drop et al., 1984; Wang and Chard, 1992). It is produced at the maternal-fetal interface and concentrations are also altered in disorders of fetal growth. In accord with results from singleton pregnancies (Wang et al., 1991; Verhaeghe et al., 1993; Giudice et al., 1995; Ogilvy-Stuart et al., 1998), our data also suggest that the concentrations of total IGFBP-1 are negatively associated with birth weight as concentrations were increased in the growth-restricted MC and DC twins.
Higher total IGFBP-1 concentrations in the growth-restricted twins could be due to hypoxia. Our data also suggest that IUGR twins are more hypoxic and acidaemic than their co-twins, perhaps due to impaired placental gaseous exchange consequent upon placental dysfunction. Recent evidence from in-vitro studies using HepG2 cells suggests that chronic hypoxia up-regulates IGFBP-1 gene expression and protein (Tazuke et al., 1998). It is therefore possible that placental dysfunction with resultant fetal hypoxia and acidaemia stimulates production of total IGFBP-1, which is an important regulator of fetal growth through regulation of the bioavailability of genetically determined circulating IGF-I and substrate availability.
The phosphorylation status of IGFBP-1 determines its effect on IGF-I bioavailability. Phosphorylated IGFBP-1 (hpIGFBP-1) has a high affinity for IGF and is thought to inhibit IGF actions (Jones et al., 1991; Westwood et al., 1997), whereas the non-phosphorylated isoform, present in fetal serum (Westwood et al., 1994) and at the fetal-maternal interface (Westwood et al., 1998), has a lower affinity for IGF-I and can enhance IGF actions on trophoblast cells. In comparison with larger/AGA twins, the phosphorylated isoforms of IGFBP-1 are increased in smaller/IUGR twins. Similar data have been reported in singleton pregnancies (Iwashita et al., 1998). Our in-vitro data (Westwood et al., 1998), suggest that the presence of lpIGFBP-1 at the fetal-maternal interface is the result of preferential production of these isoforms in response to both IGF-II, another placental product, and the action of placental alkaline phosphates on the highly phosphorylated variants. Monochorionic IUGR twins in this study has reduced IGF-II concentrations compared to AGA co-twins and this could explain the reduced capacity of the fetal-maternal unit to produce non-phosphorylated IGFBP-1 and therefore suggests the possibility that a trophoblast-driven paracrine mechanism is the key regulator of fetal growth. Indeed in-vitro studies suggest that phosphorylated IGFBP-1 inhibits IGF-I-stimulated [3H]
-amino isobutyric acid uptake by human trophoblast cells (Yu et al., 1998). We have recently observed reduced essential amino acid concentrations in the growth-restricted MC twin (Bajoria et al., 2000). We appreciate that this may not be the sole mechanism for inter-pair differences in hpIGFBP-1 concentrations in the discordant DC twin pairs who had similar IGF-II concentrations. Instead, higher total IGFBP-1 concentrations in the DC IUGR twins may have a direct inhibitory effect on early placental development. Further work is required to explain the cause for the relatively higher concentrations of hpIGFBP-1 in the growth-restricted DC twins.
Previous twin studies have used univariate genetic analysis to conclude that the regulation of IGF-II concentrations is complex and probably determined by both genetic and environmental factors (Verhaeghe et al., 1996). We found that concordant MC twins had similar IGF-II concentrations, whereas the discordant MC twins had significantly different IGF-II concentrations. IGF-II was lower in the smaller infant and the difference in their IGF-II concentrations correlated with the differences in their birth weights. IGF-II is present in placental chorionic villi and fetal membranes from as early as 6 weeks and its expression is most abundant in the trophoblastic columns of the anchoring villi, suggesting that IGF-II may be an important regulator of placental development and function (Irving and Lala, 1995). The IGF-II knockout mouse has a much smaller placenta in comparison to wild-type littermates and mice in whom the IGF-I gene has been ablated (Baker et al., 1993), and decreased placental weight and placental IGF-II mRNA are usually observed in animal fetuses with IUGR (Price et al., 1992). Since the growth-restricted twin has a small placenta and reduced microvasculature (Bruner et al., 1998), the decreased concentrations of IGF-II in MC IUGR twins supports the hypothesis that placental IGF-II influences fetal growth and development. However, our data showing comparable IGF-II concentrations in the discordant DC twins are at odds with those from MC twins and may reflect differences in the underlying placental pathology between the two groups.
The observed differences in various IGF analytes between concordant and discordant growth twins cannot be attributed to maternal IGF concentrations. In singleton pregnancies, a significant association has been reported between maternal IGFBP-1 and birth weight by some (Baldwin et al., 1993; Hills et al., 1996) but not all investigators (Whittaker et al., 1990). In singleton IUGR pregnancies, higher maternal IGFBP-1 concentrations have been reported, perhaps as a consequence of hypoxia due to poor development of the placenta (Langford et al., 1994; Larsen et al., 1996; Holmes et al., 2000). In our study, maternal IGFBP-1 concentrations were similar between discordant and concordant growth twin pairs. This is not altogether surprising as circulating maternal IGFBP-1 concentrations in twin pregnancies reflects protein production from both twins' placenta. Notwithstanding this, in twin gestation, the relatively greater increase in maternal circulating blood volume, weight gain and larger placental mass is likely to mask the subtle rise in IGFBP-1 concentrations as a consequence of growth restriction of one twin.
The differences in the IGF data between discordant monozygotic and dizygotic twins observed in this study suggest that the aetiology of growth restriction in these two groups is different. In MC twins with similar maternal environment and genetic make-up, the cause of growth restriction could be abnormal placentation. Discordant placental development in MC twins can be explained by the theory of trophotrophism whereby simultaneous proliferation of placental villi on one edge of the placenta into regions of favourable blood supply may be accompanied by atrophy and/or partial degeneration of villi in the poorly perfused area (Finberg, 1993). Such trophotrophism may be a result of asymmetrical physiological transformation of maternal spiral arteries (Matijevic and Bajoria, 2000) with an abnormal placental mass of the IUGR twin compared with the AGA co-twin (Bajoria, 1998). Similar to singleton preterm IUGR fetuses, we also have found that the passage of certain amino acids across the smaller twin's placenta is markedly impaired. These results taken together suggest that in MC twins with similar growth potential, the IGF axis at maternal-fetal interface is perhaps the key regulator of fetal growth. In contrast, regulation of fetal growth in DZ twins is complex, and may be influenced by discordant placentation, paternal genetic influences, and intrauterine environment. This may perhaps explain the reduced IGF-I concentrations along with the high circulating IGFBP-1 which may further reduce the availability of IGF-I, and thereby explain the effect on fetal growth.
The functional significance of alterations in IGF axis of IUGR twins is not clear. Nutrition is considered to be an important regulator of the IGF system during fetal life (Straus et al., 1991). Chronic hypoxia and undernutrition (Bajoria et al., 2000) may be one mechanism operating in the growth-restricted twin to cause fetal IGF deficiency and mediate, in part, the influence of placental supply of nutrients on fetal growth. Alternatively, changes in the IGF axis in the growth-restricted twin may be for the benefit of the fetus in that by minimizing the rate of energy expenditure for growth it may favour survival and the development of vital organs.
In summary, our data are consistent with the hypothesis that when the placenta is functioning adequately, the endogenous IGF-I primarily regulates fetal growth, as concentrations within concordant twin pairs were positively correlated. If, however, placental function is compromised then the IGF axis at the maternal-fetal interface becomes more important in determining fetal outcome. This study raises the possibility of intrauterine fetal therapy with IGF to ameliorate growth restriction in one twin.
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The authors gratefully thank The Royal Society and Research and Graduate Support Unit of the University of Manchester for financial support.
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4 To whom correspondence should be addressed at: St Mary's Hospital, Whitworth Park, Manchester M13 0JH, UK. E-mail: rekha.bajoria{at}man.ac.uk
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References |
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Submitted on November 10, 2000; accepted on February 2, 2001.
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