Iron metabolism in monochorionic twin pregnancies in relation to twin–twin transfusion syndrome

Rekha Bajoria1,2,5, Ed J.Lazda3, Stuart Ward1 and Suren R.Sooranna4

1 University of Manchester, Academic Unit of Obstetrics and Gynaecology, St Mary's Hospital, Manchester, Imperial College School of Medicine, 2 Institute of Obstetrics and Gynaecology, Queen Charlotte's and Hammersmith Hospital, 3 Department of Histopathology, Hammersmith Hospital, and 4 Department of Maternal & Fetal Medicine, Chelsea and Westminster Hospital, London, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Fetal iron metabolism was investigated in monochorionic (MC) twin pregnancies in relation to twin–twin transfusion syndrome (TTTS). Matched maternal and fetal blood samples were obtained both in utero and at birth from MC twins with TTTS (n = 23) and without TTTS (n = 18). In a second group of 30 twin pairs (15 with and 15 without TTTS), liver iron content was assessed by using archived paraffin wax-embedded blocks. Serum ferritin was determined by radioimmunoassay and values are given as gestation independent Z-scores and expressed as mean with 95% confidence intervals. Ferritin concentrations in the recipients were higher than in the donors both in utero (P < 0.01) and at birth (P < 0.01). Fetal serum ferritin in non-TTTS twins were similar to the recipient twins but higher than the donor twins (P < 0.05). A significant association was found between ferritin concentrations, the total red blood cell count and haemoglobin in the TTTS twin pairs (P < 0.01) and the non-TTTS twins as a group (P < 0.01). The total stainable liver iron was comparable between twin pairs in the TTTS and non-TTTS groups. This study fails to provide evidence of iron overload in the recipient and depletion in the donor twins and, thereby, questions the validity of the conventional theory of inter-twin transfusion as the cause of TTTS.

Key words: chorionicity/ferritin/liver iron/polyhydramnios/twin-twin transfusion syndrome


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Twin–twin transfusion syndrome (TTTS) occurs in 4–25% of monochorial (MC) multiple pregnancies and accounts for 17% of perinatal mortality in twins (Kingdom and Bajoria, 1998Go). Chronic TTTS presents in the early-mid-trimester of pregnancy with a characteristic discordance in fetal growth, amniotic fluid volume and fetal bladder size. The growth-restricted or `donor twin' is usually oliguric, with severe oligohydramnios, while the larger or `recipient twin' becomes hydropic and polyuric with gross polyhydramnios (Bajoria and Kingdom, 1997Go). If pregnancy continues, the recipient fetus may develop features indicating congestive cardiac failure, such as cardiac dilatation, hypertrophy, tricuspid regurgitation, ascites, pleural and pericardial effusions (Zosmer et al., 1994Go; Simpson et al., 1998Go).

The pathophysiology of TTTS is poorly understood. Traditionally, TTTS is thought to occur due to transfusion of blood via placental vascular anastomoses between the two circulations (Strong and Corney, 1966Go). Recent vascular anastomotic studies have developed the concept that TTTS may result from a paucity of compensatory concordant surface communications and, therefore, unidirectional arterio-venous (AV) transfusions remain unchecked (Bajoria et al., 1995Go; Machin et al., 1996Go; Bajoria, 1998Go). This chronic `unbalanced' inter-twin transfusion may result in iron overload in the recipient twin, while the donor twin may suffer from depletion of iron stores. In the absence of an active mechanism for iron excretion from the fetus, the recipient twin is likely to be at a higher risk of iron overload. It is well established that patients with iron overload are susceptible to multi-organ damage, especially the heart and liver, either from excessive iron deposition in the parenchymal cells or from an increase in non-protein-bound iron free radicals (Berger et al., 1990Go; Piperno, 1998Go). The donor twin is also at risk of iron deficiency anaemia because of chronic blood loss.

Information relating to iron metabolism in MC twin pregnancy with or without TTTS is sparse. Demonstration of iron overload in the recipient and depletion in the donor twin may strengthen the vascular imbalance theory and improve our understanding of the pathophysiology of this enigmatic condition. Iron is stored predominantly in the reticuloendothelial cells of the liver, spleen, and bone marrow as the water soluble intracellular protein ferritin (Iancu, 1990Go). Various investigators have shown that measurement of serum ferritin reliably reflects the total body iron stores in both the adult and the newborn (Walters et al., 1973Go; Lipschitz et al., 1974Go; Forman and Vye, 1980Go).

The aim of this study was to determine iron stores in MC twin pregnancies with or without TTTS, as assessed by the fetal serum ferritin concentrations and liver iron content in those twin pairs who died at birth.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients
A total of 41 MC twin pregnancies were studied. Monochorionicity was established ultrasonically prior to 18 weeks gestation by demonstration of (i) concordant genitalia, (ii) interfetal membrane thickness <2.0 mm, and (iii) single placental mass, and was confirmed by histological examination of placenta at birth (Bajoria and Kingdom, 1997Go). Of these, 23 cases were complicated by TTTS. The diagnosis of TTTS in MC pregnancies was made on the ultrasound scan criteria of: growth discordance of >15% with polyhydramnios [amniotic fluid index (AFI) of >40 cm] in the larger twin and anhydramnios or oligohydramnios (single deepest pool of <2 cm) in the smaller twin (Bajoria et al., 1995Go). The control group (n = 18) included uncomplicated MC twins with growth discordance of <15% and normal amniotic fluid volumes in both sacs (AFI of <24 cm) confirmed on fortnightly ultrasound scans from 18 weeks gestation.

Collection of samples
In the TTTS group, matched maternal and fetal blood samples were collected from 15 women undergoing fetal blood sampling (FBS) for clinical reasons at Queen Charlotte's Hospital, London. Intrauterine FBS was performed for clinical indications to establish fetal well-being and to exclude major haematological discordance. FBS was performed from the intrahepatic vein or the umbilical vein, and an additional 1 ml fetal blood sample was obtained for estimation of ferritin and full blood count. The fetal source of blood was confirmed from separate mean cell volume peaks on a Coulter Channelyzer (Coulter Electronics, Luton, UK) and by using the standard Kleihauer-Betke method where the blood film is stacked to detect red cells containing adult haemoglobin in a blood sample obtained by fetal blood sampling in utero. Of 15 cases who underwent FBS, cord blood samples from both twins were available at birth in only eight cases. In a further group of seven women with TTTS who did not undergo FBS in utero, cord blood samples from twins were collected at birth.

In the non-TTTS group, maternal and fetal blood samples were collected from seven cases undergoing FBS for various clinical reasons. The indications for FBS were suspected aneuploidy due to fetal growth discordance with normal liquor volume (n = 3), the presence of chromosomal markers on ultrasound (n = 2), and maternal age (n = 2). Of seven cases who underwent FBS, maternal and cord blood samples were also collected in only four cases at birth. In a further group of 11 women with uncomplicated MC pregnancies, maternal and cord blood samples were collected from both twins at birth. In all cases, women gave written informed consent for collection of additional research samples as approved by the Hospital Ethical Committee. Maternal peripheral venous blood was collected immediately prior to FBS. All samples were collected by R.B. at Queen Charlotte's and Hammersmith Hospitals.

Ferritin assay
Aliquots of fetal blood were centrifuged at 3000 g for 15 min and serum stored at –70°C until batch assays were performed. The concentration of ferritin was measured using a commercially available radioimmunoassay system (Amersham International, Amersham Bucks, UK).

Measurement of liver iron content
From a second group of MC twins with (n = 15) or without (n = 15) TTTS who underwent autopsy, 3 µm thick tissue sections were cut and plated on to poly-L-lysine coated slides from the wax-embedded archived blocks of fetal liver. Tissue sections were stained using Perls' method for haemosiderin (Silver et al., 1993Go). A perinatal pathologist (E.J.L.) who was blind to the corresponding clinical and biochemical data performed the histological examinations. The iron content was assessed using a previously published scale (Deugnier et al., 1992Go) in which the haemosiderin content of hepatocytes in each of the microcirculatory zones of Rappaport, sinusoidal lining cells, and biliary epithelium, stroma and vessel walls in the portal tract, were semiquantitatively assessed and summated to give an overall score for liver iron.

Statistical methods
Ferritin concentrations and haematological parameters were expressed as Z-scores of published reference ranges for singleton pregnancies as the ranges for twins were not available (Nicolaides et al., 1989Go; Abbas et al., 1994aGo). All values were expressed as mean and 95% confidence interval (CI). Clinical data were expressed as medians and ranges. 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. Differences between twin pairs were calculated by subtracting the value of the recipient/larger from that of the donor/smaller twin. For non-parametric data, correlations were sought using the Spearman coefficient and comparison made between groups by the Mann-Whitney test. Percentage growth discordance was defined as the difference in growth expressed as a proportion of the birthweight of the larger twin. In the control group, the larger fetuses were labelled as twin 1 and the smaller as twin 2.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Clinical features and haematological indices for the MC twins with or without TTTS at the time of fetal blood sampling are given in Table IGo. All patients in the TTTS group were treated by amnioreduction.


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Table I. Clinical features of pregnancies with mid-trimester twin–twin transfusion syndrome (TTTS) compared with the control group
 
In utero
Fetal ferritin concentration
Gestation independent ferritin Z-scores in the recipient fetus were higher than the donor (mean 1.9; CI 1.4 to 2.5 versus mean 0.6, CI 0.1 to 1.1; P < 0.01). In the control group ferritin concentrations were comparable between the twin pairs (mean 1.7, CI 1.1 to 2.2 versus mean 1.4, CI 0.5 to 2.2). In the recipient twin, ferritin Z-scores were comparable with those in the non-TTTS twins as a group (mean 1.4, CI 0.9 to 1.8). In contrast, ferritin concentrations in the donor twin were lower than the non TTTS fetuses as a group (P < 0.05). (Figure 1Go). The inter-twin differences were comparable between TTTS and non-TTTS twins (mean 1.3, CI 0.5 to 2.0 versus mean 0.4, CI 0.1 to 0.7).



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Figure 1. Ferritin concentrations in monochorionic twins with or without twin-twin transfusion syndrome (TTTS) at the time of (a) fetal blood sampling in utero and, (b) at birth. All values are expressed as gestational age independent Z-scores. There was no significant difference between the two groups.

 
There was no statistically significant difference between recipient fetuses with and without hydrops (mean 2.2, CI 1.8 to 2.6 versus mean 1.7, CI 0.6 to 2.8) (Figure 2Go). Inter-twin differences were comparable between hydropic and non-hydropic recipient twins (mean 1.5, CI 1.1 to 2 versus mean 1.1, CI –0.4 to 2.7)



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Figure 2. Concentrations of ferritin in the recipient twins with and without hydrops. All values are expressed as gestational age independent Z-scores. There was no significant difference between the two groups.

 
Fetal haematological parameters
Fetal haematological parameters are given in Figure 3Go and Table IGo. In the recipient twin, Z-scores of total red blood cell (RBC) count (mean 1.5, CI 0.6 to 2.4 versus mean –0.6, CI –1.7 to 0.5; P < 0.05) and haemoglobin concentration (mean 3.4, CI 2.5 to 4.3 versus mean 0.5, CI –0.8 to 1.7; P < 0.01) were higher than in the donor twin. However, no significant difference in total RBC (mean 0.3, CI –0.6 to 1.7 versus mean 0.3, CI –0.5 to 1.4) and haemoglobin (mean 1.5, CI –0.6 to 2.0 versus mean 1.1, CI –0.3 to 1.0; P = 0.26) concentrations was found between the twin pairs in the control group. Delta haemoglobin (mean 3.0, CI 1.1 to 5 versus mean 1.0, CI –0.2 to 0.7; P = 0.7) and RBC (mean 2.1, CI 0.7 to 3.5; versus mean 0.5, CI –0.2 to 0.6; P = 0.07) were comparable in the TTTS and non-TTTS groups.



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Figure 3. The top panel shows the correlations between fetal ferritin and total red blood cell count in the recipient twin (y = 0.53x + 1.15; r = 0.84), donor twin (y = 0.34x + 0.74; r = 0.75) and the control monochorionic (MC) twins (y = 0.58x + 1.3; r = 0.77) at the time of fetal blood sampling. Bottom panel shows the correlations between fetal ferritin and haemoglobin in the recipient twin (y = 0.49x + 0.26; r = 0.82), donor twin (y = 0.30x + 0.40; r = 0.76) and control group (y = 0.54x + 0.73; r = 0.82) at the time of fetal blood sampling. All values are expressed as gestational age independent Z-scores.

 
A significant association was found between ferritin concentrations and the total RBC count in the recipient twin (y =0.53x + 1.15; n = 15, r = 0.84, P < 0.01), the donor twin (y = 0.34x + 0.74; n = 15, r = 0.75, P < 0.01) and the non-TTTS twins as a group (y = 0.58x + 1.3; n = 14, r = 0.77, P < 0.01) (Figure 3Go). A similar relationship was also noted between serum ferritin and haemoglobin in the recipient twin (y = 0.49x + 0.26; n = 15, r = 0.82; P < 0.001), donor twin (y = 0.3x + 0.40; n = 15, r = 0.76, P < 0.01) and the non-TTTS twins as a group (y = 0.54x + 0.73; n = 14, r = 0.82, P < 0.01) (Figure 3Go). No association was found between the fetal serum ferritin concentrations and the acid-base status.

At birth
Similar to in-utero data, ferritin concentrations in the venous cord blood of recipient twins were higher than in donors (mean 1.4, CI 0.8 to 1.9 versus mean 0.5, CI 0.2 to 0.7; P < 0.01) (Figure 1Go). In the non- TTTS pregnancies ferritin concentrations were comparable between the twin pairs (mean 0.9, CI 0.7 to 1.1 versus mean 1.0, CI 0.6 to 1.3). Cord ferritin concentrations in the donor twin were lower than the non-TTTS twin pairs as a group (P < 0.05). However, umbilical venous concentration of ferritin in the recipient twin was comparable with that of the control group. The inter-twin ferritin concentrations in TTTS and non-TTTS groups were comparable (mean 0.9, CI 0.4 to 1.5 versus mean 0.5, CI 0.4 to 0.9).

The maternal ferritin concentrations were similar in TTTS (mean 30, CI 21 to 38 µg/l), and non-TTTS (mean 29, CI 23 to 36 µg/l) pregnancies but were lower than in fetal blood (P < 0.01).

Iron quantification (Figures 4 and 5GoGo)
The median gestational age at delivery was similar in the TTTS and non-TTTS twin groups (median 24; range 16–29 weeks versus median 22; range 14–30.5 weeks). The total iron score in the recipient's liver was similar to that of the donor twin (mean 6, CI 3 to 9 versus mean 4, CI 2 to 6) (Figure 4Go). Liver iron score in the hydropic recipient twin was comparable with non-hydropic cases (mean 7, CI 2 to 12, n = 7 versus mean 5, CI 3 to 7; n = 8). Similarly, the iron score in the twin 1 was comparable to that of twin 2 (mean 5, CI 3 to 7 versus mean 4, CI 2 to 6). The liver iron contents of the donor and the recipient twin were similar to that of the non-TTTS twins as a group (Figure 5Go). The inter-twin differences in the TTTS and non-TTTS groups were similar (mean 2, CI –0.5 to 4.3 versus mean 2.5, CI 1.5 to 3.5).



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Figure 4. Liver iron score in monochorionic twins (A) with twin-twin transfusion syndrome (TTTS) and, (B) without TTTS. NS = non significant.

 


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Figure 5. Liver section from monochorionic twins with and without twin-twin transfusion syndrome (TTTS). Iron is depicted in blue as rough aggregates throughout the liver parenchymal cells. Top panel compares the liver section of the (A) recipient and (B) donor twin of TTTS, while the bottom panel shows sections of the (C) twin 1, and (D) twin 2 of the non-TTTS twins. Original magnification x250.

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study suggests that serum ferritin concentrations in the recipient twin of the TTTS are higher than in the donor twin. However, ferritin concentrations between the non-TTTS twin pairs were comparable and similar to those of the recipient twin.

Despite comparable maternal ferritin concentrations between TTTS and non-TTTS groups, ferritin concentrations in the donor twin were different from those of recipient and non-TTTS twins. Human and animal experiments have yielded conflicting results regarding the influence of maternal iron balance on fetal iron stores (Hussain et al., 1977Go; Krawinkel et al., 1990Go). Although fetal ferritin concentrations were higher than the maternal concentrations, there was no correlation between these two variables in the TTTS and non-TTTS groups. This may be attributed to an active mechanism of iron transport across the placenta which allows the fetus to maintain a normal haemoglobin concentration even if the mother is iron deficient (Okuyama et al., 1985Go; Knisely et al., 1989Go). Correlations between fetal ferritin concentrations, total RBC count and haemoglobin in MC twins with or without TTTS further supports this assumption.

An obvious explanation for discordant ferritin concentrations in the TTTS group seems to be the transfusion of blood from the donor to the recipient twin along the unidirectional AV anastomoses. If this were true, then the recipient twin is likely to be iron overloaded, while the donor would show signs of depletion. Instead, the data presented here fail to provide evidence for iron overload and/or depletion in TTTS twin pairs. Serum ferritin concentrations of >1000 µg/l with increased total liver iron stores are considered to be the hallmark of iron overload in fetal and adult life (Piperno, 1998Go). In the current study, recipient twins had serum ferritin concentrations well below the concentrations suggestive of iron overload. Similarly, ferritin concentrations in the donor twin were within the normal range reported for the singleton intrauterine growth retardation (IUGR) fetuses (Abbas et al., 1994bGo), Notwithstanding this, similar ferritin concentrations in recipient and the non-TTTS twins also indicate that differences in ferritin concentrations between TTTS twin pairs cannot be simply due to inter-twin transfusion.

Haemosiderin deposition was also quantified both in the parenchymal and the mesenchymal zones of the liver of MC twins with or without TTTS to seek for further evidence of iron overload (Deugnier et al., 1992Go). A well-established method was used to calculate the total liver iron stores. This technique has been shown to be well correlated with the the previously used method of direct quantification of total liver iron (Barry and Sherlock, 1971Go). Data showing similar total liver iron in TTTS twin pairs also fail to provide evidence for iron overload and raise the possibility that discordant serum ferritin concentrations may be due to factor(s) other than inter-twin transfusion of blood.

However, it is possible that discordant ferritin concentrations in the TTTS group may be attributed to the indirect consequences of inter-twin transfusion of blood. Computer modelling studies also lend credence to this hypothesis and suggest that in the early stages of the disease, the donor twin compensates for the blood loss to the recipient twin by haemodilution as a result of transfer of water from maternal to the fetal vasculature, while the recipient develops haemoconcentration as a consequence of atrial natriuretic peptide-driven polyuria (Talbert et al., 1996Go). It is therefore possible that lower ferritin concentrations in the donor twin may be due to haemodilution effect, while relatively raised ferritin concentrations in the recipient twin are a reflection of haemoconcentration.

The underlying cause for the discrepancy between ferritin concentrations and liver iron stores in the TTTS group may also be simply due to the lack of robust correlation between serum ferritin concentrations and the total liver iron. Some investigators consider serum ferritin to be the most sensitive index for the detection of iron reserves (Walters et al., 1973Go; Lipschitz et al., 1974Go; Forman and Vye, 1980Go). It appears that no studies have systematically evaluated the relationship between circulating ferritin and stainable liver iron. However, comparable ferritin and iron stores in the non-TTTS group suggest that, in pregnancies complicated by TTTS, ferritin is not a robust index of iron reserves, and that there may be an alternative explanation for inter-pair differences in serum ferritin concentrations.

Higher ferritin concentrations may be due to increased production by the recipient twin. Serum ferritin is also considered to be an acute phase protein. Increased concentrations are found in the presence of hepatocellular damage due to infection or toxins, systemic infections, and trauma (Bobbio-Pallavicini et al., 1989Go). Hence, it is possible that ferritin concentrations in the recipient twin are raised because of hepatic congestion secondary to circulatory overload or hydrops. No data are available on the relationship between fetal hydrops and ferritin. Anecdotal data from two sets of twins suggest that ferritin concentrations are markedly higher in the twins with hydrops than those without (Caglar and Kollee, 1989Go). In the current study, however, it was not possible to find any differences in serum ferritin concentrations between hydropic and non-hydropic recipient twins.

Alternatively, the difference in the serum ferritin concentrations between TTTS fetuses may be due to discordance in placental transport of iron. Although, the mechanism of maternal-fetal iron transport is not fully understood, in normal pregnancy iron is transported unidirectionally from the mother to the fetus against a concentration gradient (Okuyama et al., 1985Go; Knisely et al., 1989Go). The number of transferrin receptors expressed on the placenta (Georgieff et al., 1999Go) regulates the uptake of iron from the maternal to the fetal circulation. It is conceivable that the recipient twin with a larger placental mass acquires more iron from the maternal compartment than the donor twin who has a relatively much smaller placenta (Bajoria, 1998Go). The fetal-to-maternal ratio of serum ferritin in gestationally matched IUGR fetuses is significantly less than the appropriately grown fetuses, probably as a consequence of impaired placental perfusion (Abbas et al., 1994bGo). Data regarding placental transport function of iron in the MC twins or in twin pregnancies are sparse. Our preliminary data on the essential amino acids in TTTS fetuses suggests that placental transport function in the donor differs markedly from that of the recipient twin (Bajoria et al., 2000Go). In sum, this indicates that impaired transfer of ferritin across the donor twins' placenta may be responsible for discordant ferritin concentrations in the TTTS group.

In conclusion, no biochemical/morphological evidence was found of iron overload/depletion in the recipient and/or donor twins of TTTS. Instead, fetal serum ferritin concentrations and liver iron content in the recipient twin were comparable with those of the control MC twins. These data therefore raise doubts regarding the validity of the traditional theory of inter-twin transfusion to be the principal cause of the clinical manifestation of TTTS. On the other hand, the higher ferritin concentrations in recipient fetuses could be interpreted as supporting the transfusion theory.


    Notes
 
5 To whom correspondence should be addressed at: St Mary's Hospital, Whitworth Park, Manchester M13 OJH, UK.E-mail: rekha.bajoria{at}man.ac.uk Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on December 6, 1999; accepted on November 30, 2000.





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