Placenta
Volume 31, Issue 5 , Pages 380-386, May 2010

Placental characteristics of selective birth weight discordance in diamniotic-monochorionic twin gestations

  • M.E. De Paepe

      Affiliations

    • Department of Pathology, Women and Infants Hospital, 101 Dudley Street, Providence, RI 02905, USA
    • Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University, Providence, RI, USA
    • Corresponding Author InformationCorresponding author at: Department of Pathology, Women and Infants Hospital, 101 Dudley Street, Providence, RI 02905, USA. Tel.: +1 401 274 1122x1544; fax: +1 401 453 7681.
    • ,
  • S. Shapiro

      Affiliations

    • Department of Pathology, Women and Infants Hospital, 101 Dudley Street, Providence, RI 02905, USA
    • ,
  • L. Young

      Affiliations

    • Department of Pathology, Women and Infants Hospital, 101 Dudley Street, Providence, RI 02905, USA
    • ,
  • F.I. Luks

      Affiliations

    • Program in Fetal Medicine, Alpert Medical School of Brown University, Providence, RI, USA

Accepted 24 February 2010. published online 22 March 2010.

Article Outline

Abstract 

Up to 21% of diamniotic-monochorionic twin pregnancies are complicated by severe birth weight discordance in the absence of twin-to-twin transfusion syndrome, a serious condition termed ‘selective’ birth weight discordance. While its pathogenesis remains incompletely understood, the development of selective intertwin growth discordance, related to fetal growth restriction of one twin, is generally attributed to aberrant placental characteristics. The aim of this study was to characterize the placental markers of selective birth weight discordance, with special emphasis on the choriovascular architecture. A prospective cohort of 319 consecutive diamniotic/monochorionic twin placentas was examined at Women and Infants Hospital between 2001 and 2009. After exclusion of placentas from pregnancies complicated by twin-to-twin transfusion syndrome (TTTS), monoamniotic, multiple and disrupted placentas, 216 placentas (36 birth weight (BW)-discordant and 180 BW-concordant) formed the subject of this study. Following dye injection, the anatomic characteristics and choriovascular anastomotic patterns of BW-discordant and BW-concordant placentas were compared. The BW-discordant placentas showed significantly higher frequencies of velamentous cord insertion (22% versus 8%, P < 0.001) and uneven placental sharing (56% versus 19%, P < 0.0001) compared with BW-concordant placentas. The frequencies of intertwin AA, VV and AV anastomoses, the net number of AV anastomoses, and the net cross-sectional area of AV anastomoses were similar in both groups. There was no correlation between the frequency of velamentous cord insertion and degree of placental sharing or patterns of choriovascular anastomoses in either group. In conclusion, velamentous cord insertion and uneven placental sharing are the two major placental determinants of selective birth weight discordance in diamniotic-monochorionic twins. The role of the intertwin anastomoses, even when unbalanced, is likely negligible. Elucidation of the mechanisms whereby velamentous cord insertion affects fetal growth may lead to more focused and effective therapeutic strategies for twin and singleton pregnancies complicated by dysregulated fetal growth.

Keywords: Monochorionic twin, Placenta, Vasculature, Anastomoses, Birth weight

 

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1. Introduction 

Monochorionic twin gestations are associated with a high risk of poor pregnancy and perinatal outcome compared with dichorionic gestations [1], [2]. A significant portion of the excess perinatal or neonatal morbidity and mortality in monochorionic pregnancies is attributable to severe chronic twin-to-twin transfusion syndrome (TTTS), a serious condition complicating approximately 9–15% of diamniotic-monochorionic twin pregnancies [2], [3], [4], [5]. TTTS is characterized by a gradual shift of blood from donor twin to recipient twin through placental vascular connections between the fetuses. We [6] and others [7], [8], [9], [10], [11], [12], [13] have previously described the placental anatomic markers of TTTS, which include velamentous cord insertion, uneven placental sharing, and characteristic choriovascular patterns.

TTTS is clinically defined by amniotic fluid discordance (polyhydramnios/oligohydramnios), often associated with body weight discordance between donor and recipient twins. Parenthetically, discrepancies in hematocrit and other causes of oligohydramnios and polyhydramnios might refine the assignment of TTTS in some cases. Importantly, growth discordance in monochorionic twins is not limited to TTTS. A significant proportion of diamniotic-monochorionic twin pregnancies is affected by ‘selective’ or isolated severe intertwin birth weight discordance, not occurring in the context of TTTS. Selective intrauterine growth restriction occurs in about 12.5–36% of all monochorionic pregnancies [3], [10], [14], [15] and is associated with increased perinatal mortality and morbidity rates [3], [16], [17], [18], [19].

The exact prevalence of birth weight discordance in diamniotic-monochorionic gestations is not clear, as most reported series contain a combination of TTTS and non-TTTS cases. In the largest prospective study of diamniotic-monochorionic twin pregnancies to date, Ortibus et al. [3] determined the frequency of selective severe birth weight discordance in non-TTTS twins to be as high as 21% (26/124). In cases of severe non-TTTS birth weight discordance diagnosed in the second trimester and managed expectantly, fetal mortality rates of up to 25% have been reported, most often affecting the smaller twin [17], [20], [21].

While the pathogenesis of selective birth weight discordance in diamniotic-monochorionic twins remains poorly understood, various placental anatomic features have been implicated [2]. The higher frequency of peripheral cord insertion and uneven placental sharing in birth weight discordant placentas has been well documented [11], [12], [22], [23], [24], [25]; however, the role of the placental angioarchitecture remains to be further established.

In this study, we performed a detailed morphometric analysis of the placental anatomy in a large consecutive series of monochorionic twin gestations not complicated by TTTS. Our aim was to determine the characteristics of the choriovascular anatomy and, in particular, the potential role of arteriovenous imbalance in the pathogenesis of selective birth weight discordance. For optimal visualization and quantitation of the artery-to-vein anastomoses, our previously described vascular injection technique was used [26]. We determined not only the number and direction of the vessels, but also their caliber, thus allowing accurate estimation of the net artery-to-vein flow (im)balance between the two placental territories. Increased knowledge of the placental anatomy and choriovascular architecture in diamniotic-monochorionic twin gestations may contribute to a better understanding of the pathophysiology of growth discordance and, possibly, of TTTS.

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2. Materials and methods 

A consecutive series of monochorionic twin placentas were examined at the Department of Pathology at Women and Infants Hospital between 2001 and 2009. We studied the placental characteristics and angioarchitecture of diamniotic-monochorionic twin placentas not complicated by chronic twin-to-twin transfusion syndrome (TTTS). Chronic TTTS was defined by ultrasonographic evidence of severe polyhydramnios in one twin and concomitant oligohydramnios in the other, in some cases associated with collapse of the bladder in the donor twin, critically abnormal Doppler studies, hydrops and/or demise of one or both twins [27]. In addition to placentas from pregnancies with TTTS, triplet and quadruplet placentas, monoamniotic placentas, placentas of pregnancies complicated by twin reversed arterial perfusion (TRAP) sequence and placentas with remote (>48 h prior to delivery) demise of one twin were excluded. Cases in which cord avulsion or partial disruption of the chorionic plate vasculature precluded reliable vascular injection studies were excluded as well.

The accompanying charts were reviewed to determine the birth weights of both twins. Birth weight discordance was calculated as a percentage of the weight of the larger twin. Severe birth weight discordance was defined as a birth weight difference of ≥20%. The placental weight was compared with reported institutional reference values for age-matched twin placentas [28] and classified as small (<10th centile), large (>90th centile) or appropriate for gestational age. Gross examination of the placenta and injection of the placental vasculature were performed as previously described in detail [6], [26], [29].

The type of cord insertion (central/paracentral, marginal, or velamentous), the number of umbilical arteries, and the relative distribution of the vascular territories were noted. Velamentous cord insertion was defined as cord insertion into the fetal membranes rather than onto the placental disc. Marginal cord insertion was defined as cord insertion at the edge of the placental disc. In addition to these routine twin placental parameters, the vascular distribution patterns of each twin were recorded and categorized as disperse, magistral or mixed, as previously described [29]. The disperse pattern was defined as a superficial vascular arrangement characterized by regular, near-symmetric dichotomous branching, resulting in a progressive diminution of vascular caliber. For the purpose of this study, a pattern was categorized as disperse if ≥75% of the twin's vascular territory showed this pattern. A vascular pattern was categorized as magistral if ≥75% of the vascular territory showed relatively large-sized vessels, extending from the insertion of the cord to the periphery without a significant reduction of diameter. The mixed vascular distribution pattern was defined as the presence of combined disperse and magistral-type vessels, with each type involving less than 75% of the individual twin's territory.

The presence, type, number and caliber of intertwin anastomoses (artery-to-artery (AA), vein-to-vein (VV) or artery-to-vein (AV)) were recorded by a single observer (MEDP) based on placental examination at the time of vascular injection, as previously described [6]. Superficial AA and VV anastomoses were identified as direct superficial communications between two homonymous umbilical vessels. Arteries were recognized by their general tendency to cross over corresponding veins. For AA and VV types, the caliber of the anastomosis was measured as the minimum external diameter along the course of the anastomosis. Deep AV anastomoses were identified where an unpaired artery from one twin was seen penetrating the chorionic plate close to (<1.0 cm) an unpaired vein from the other twin. The diameter of an AV anastomosis was defined as the diameter of the feeding artery at its narrowest point. The cross-sectional area (CSA) of each AV anastomosis was calculated (CSA = πr2 where r = radius of feeding artery). The sum of the cross-sectional surface areas of all AV anastomoses (total cross-sectional surface area) in one direction and that of all AV anastomoses in the opposite direction were calculated. Finally, we determined the net cross-sectional surface area (NCSA), defined as the total cross-sectional surface area of all AV anastomoses in one direction minus the total cross-sectional surface area of all AV anastomoses in the opposite direction, expressed as an absolute value. For this study, AV imbalance was arbitrarily graded as “moderate” or “severe” when the NCSA was greater than 1 mm2 or 5 mm2, respectively.

Finally, we determined the relative placental share of each twin, based on the distribution of respective chorionic vessels. All injected placentas were photographed. Each vascular territory was mapped by digital image analysis by manually tracing the margins demarcated by the presence of dye and expressed as a percentage of the overall surface area. Uneven placental sharing was defined as >25% difference in placental territory. Analysis of the placentas was performed by a single perinatal pathologist (MEDP) who had no knowledge of the clinical course or birth weight discordance. Chorionicity was confirmed by microscopic examination of the dividing membrane in all cases.

Data were compared by chi-square, Fisher exact, Mann–Whitney and Student t-tests, where applicable. A P value <0.05 was considered statistically significant. The study was approved by the Institutional Review Board.

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3. Results 

3.1. Patient population and clinical data 

A cohort of 319 consecutive monochorionic placentas was examined between 2001 and 2009. Placentas from pregnancies with TTTS (56, of which 30 laser-treated), triplet or quadruplet placentas (14), monochorionic-monoamniotic placentas (12), placentas of gestations complicated by twin reversed arterial perfusion (TRAP) sequence (2) and placentas with marked disruption of the chorionic plate (7) were excluded. In addition, cases with unknown birth weights (12) (usually from referrals) were excluded.

Of the remaining 216 diamniotic-monochorionic twin placentas, 36 (17%; 12% of all diamniotic-monochorionic twins) were associated with intertwin birth weight discordance of ≥20%. These placentas, designated as ‘BW-discordant’ and their 180 ‘BW-concordant’ counterparts are the subject of this study. The gestational age at delivery was slightly lower for BW-discordant twins than for BW-concordant twins (mean gestational age 33.4 weeks versus 34.9 weeks, P < 0.02) (Table 1). While the birth weights of the larger twins were similar, the birth weights of the smaller twins were significantly lower in the BW-discordant group. The birth weight discordance ranged between 20% and 47% in the BW-discordant group (median: 24%) and between 0 and 18% in the BW-concordant group (median: 8%). The frequency of associated intrauterine fetal demise was equally low in both groups.

Table 1. Patient data.
BW-discordant (36)BW-concordant (180)P
Gest. age (wks)33.4 ± 3.2 (25–38)34.9 ± 3.4 (23–40)<0.02
BW larger twin (g)2187 ± 692 (820–3845)2282 ± 693 (579–3730)NS
BW smaller twin (g)1641 ± 556 (495–3060)2094 ± 668 (520–3523)<0.001
Difference BW (%)25.0 ± 6.0 (20–47)8.2 ± 5.0 (0–18)<0.0001
Associated with IUFD1/36 (2.8%)1/180 (0.6%)NS

Values represent mean ± SD (range) or proportion (%) of (N) twins.

BW: birth weight; IUFD: intrauterine fetal demise.

3.2. General placental anatomy 

The placental weights were determined after removal of membranes and cords and compared with institutional reference values for twin placentas. The placental weights of BW-discordant twins were similar to those of BW-concordant twins (650 ± 213 g versus 719 ± 199 g, P = 0.06). The vast majority of placentas in both groups (>80%) were of appropriate weight for gestational age (Table 2).

Table 2. Placental and choriovascular anatomy.
BW-discordant (36)BW-concordant (180)P
General anatomy
Placental weight (g)650 ± 213719 ± 1990.06
Placenta AGA29/36 (81%)157/180 (87%)NS
Placenta LGA2/36 (6%)9/180 (5%)NS
Placenta SGA5/36 (13%)14/180 (8%)NS
Velamentous cord insertiona16/72 (22%)29/360 (8%)<0.001
Marginal cord insertiona15/72 (21%)84/360 (23%)NS
Magistral/mixed vascular distribution24/36 (67%)101/180 (56%)NS
>25% difference placental share20/36 (56%)34/180 (19%)<0.0001
Single umbilical artery1/72 (1.4%)9/360 (2.5%)NS

Choriovascular anatomy
Anastomoses present34/36 (94%)176/180 (98%)NS
Total # anastomoses6.5 (0–17)7 (0–23)NS
AA anastomoses present31/36 (86%)161/180 (90%)NS
VV anastomoses present6/36 (17%)25/180 (14%)NS
AV anastomoses present33/36 (92%)173/180 (96%)NS
Total # deep AV anastomoses5 (0–16)6 (0–22)NS
Net # deep AV anastomoses1 (0–7)2 (0–15)NS
NCSA (mm2)2.02 ± 3.41
0.79 (0–19.63)		2.59 ± 4.94
0.79 (0–42.78)		NS
Fraction with NCSA > 1mm2 (%)14/36 (39%)82/180 (46%)NS
Fraction with NCSA > 5mm2 (%)2/36 (6%)24/180 (13%)NS

Values represent mean ± SD and median (range) or proportion (%) of (N) twins or placentas.

AGA: appropriate for gestational age; LGA: large for gestational age; SGA: small for gestational age. NCSA: net cross-sectional area of AV anastomoses. BW: birth weight.

aType of cord insertion per individual fetus.

Velamentous cord insertion was almost three times as frequent in BW-discordant placentas as in BW-concordant placentas (22% versus 8%, P < 0.001). The frequency of marginal cord insertion was similar in both groups, as were the vascular distribution patterns. Markedly uneven placental sharing, defined as >25% difference in placental territory, occurred three times more frequently in BW-discordant placentas (P < 0.0001). The smaller side corresponded to the side of the smaller twin in all cases with uneven placental share in which the twins were marked (88% of cases). A single umbilical artery was seen infrequently in either group.

3.3. Choriovascular anatomy: superficial anastomoses (AA and VV) 

The intertwin vascular anastomoses were categorized (AA, VV or AV) and quantified following color-coded dye injection of the placental vessels. The total number of intertwin anastomoses ranged between 0 and 17 in BW-discordant placentas and between 0 and 23 in BW-concordant placentas (Table 2). Superficial AA anastomoses were equally frequent in both groups. Multiple AA anastomoses were rare in both groups. Among the BW-discordant placentas, 1/36 (2.7%) had two AA anastomoses, while among BW-concordant placentas 4/180 (2.2%) had more than one AA anastomosis; three placentas had 2 and one had 3 AA anastomoses. The diameter of AA anastomoses ranged from 0.05 to 0.5 cm in BW-discordant placentas (mean: 0.179 ± 0.108 cm) and from 0.05 to 0.6 cm in BW-concordant placentas (mean: 0.173 ± 0.100 cm).

The frequency of superficial VV anastomoses was similar in both groups (17% versus 14%). One BW-discordant and 5 BW-concordant placentas had 2 VV anastomoses. The maximal diameter of VV anastomoses was 0.2 cm in BW-discordant placentas (mean: 0.143 ± 0.079 cm) and 0.4 cm in BW-concordant placentas (mean: 0.224 ± 0.105 cm; difference not significant).

3.4. Choriovascular anatomy: deep AV anastomoses 

Deep AV anastomoses were seen in virtually all BW-discordant and BW-concordant placentas (Table 2). The total number of deep AV anastomoses (both directions combined) was comparable in both groups. The net number of AV anastomoses, defined as the absolute value of the number of AV anastomoses in one direction subtracted from the number of anastomoses in the other direction was similar in both groups. The largest net number of AV anastomoses (15) was seen in BW-concordant placentas (Table 2).

In addition to the total and net number of deep AV anastomoses, we determined their net cross-sectional area (NCSA). The NCSA takes into account not only the number and direction, but also the caliber of AV anastomoses, and thus may serve as closer anatomic proxy for net blood flow through deep AV anastomoses. Surprisingly, the median NCSA was exactly identical (0.79 mm2) in BW-discordant and BW-concordant placentas. The fraction of cases with moderate or marked AV imbalance (arbitrarily defined as NCSA >1 mm2 or 5 mm2, respectively) tended to be higher in BW-concordant placentas, although that difference was not statistically significant. There was no morphometric evidence of any AV imbalance at all (NCSA = 0) in 3/36 (8.3%) BW-discordant and 20/180 (11.1%) BW-concordant placentas.

3.5. Correlation between velamentous cord insertion and placental sharing/choriovascular anatomy 

Our results demonstrated that the risk of BW discordance was three-fold higher in placentas with velamentous cord insertion compared with non-velamentous cord insertion. In order to gain a deeper understanding of the mechanisms whereby velamentous cord insertion might contribute to BW discordance, we examined the interrelationships between cord insertion and other placental variables of potential functional significance. First, we examined the association between cord insertion and placental sharing as we speculated that velamentous cord insertion might be associated with a higher risk of uneven placental sharing. Fig. 1 illustrates the frequency of uneven sharing in placentas with or without velamentous cord. Our calculations confirmed the significantly higher frequency of uneven placental sharing in BW-discordant versus BW-concordant placentas. Surprisingly, however, within each group the frequency of uneven sharing was similar whether cord insertion was velamentous or not. These results suggest there is no correlation between velamentous cord insertion and frequency of uneven placental sharing.

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  • Fig. 1 

    Correlation between velamentous versus non-velamentous cord insertion and placental sharing. BW conc: birth weight concordant; BW disc: birth weight discordant. *: P < 0.0005; **: P < 0.05 versus corresponding BW-concordant placentas.

We then studied the relationship between the presence or absence of velamentous cord and the frequency of the various types of intertwin anastomoses. The presence or absence of velamentous cord insertion did not impact on the prevalence of AA, VV or AV anastomoses in BW-discordant or BW-concordant placentas. Similarly, the degree of AV imbalance, estimated by the NCSA, was comparable in placentas with velamentous or non-velamentous cord insertion (NCSA was 1.93 ± 2.06 mm2 in placentas with velamentous cord (N = 43) versus 2.63 ± 5.17 mm2 in placentas with non-velamentous cord insertion (N = 173)). These findings suggest that any functional contributions of velamentous cord insertion to BW discordance are mediated by mechanisms unrelated to effects on placental sharing, choriovascular architecture or AV imbalance.

3.6. Correlation between placental sharing and choriovascular anatomy 

Our study identified uneven placental sharing as a significant risk factor for BW discordance. Others [12], [30] previously reported that unevenly shared placentas display altered choriovascular patterns that may play a role in the associated BW discordance. We therefore determined the association between even or uneven placental sharing and the various types of intertwin anastomoses in our cohort. The frequency of AA anastomoses was similar in unevenly or evenly shared placentas (85% versus 90%, respectively). Similarly, VV anastomoses were equally prevalent in placentas with uneven or even sharing (20% versus 12%). These associations were not affected by growth discordance or concordance. The total and net number of AV anastomoses was similar in placentas with uneven versus even sharing. The NCSA, however, which also considers the diameter of the AV anastomoses, was significantly larger in placentas with uneven sharing compared with even sharing (3.75 ± 7.67 mm2 (N = 54) versus 2.08 ± 3.11 mm2 (N = 162; P < 0.05). This difference was significant in BW-concordant cases (4.43 ± 9.12 mm2 in unevenly shared placentas (N = 34) versus 2.21 ± 3.19 mm2 in evenly shared placentas (N = 146); P < 0.02). A similar, but not statistically significant, tendency was noted in the smaller group of BW-discordant placentas (2.63 ± 4.36 mm2 in unevenly shared placentas (N = 20) versus 1.26 ± 1.42 mm2 in evenly shared placentas (N = 16)).

The above findings raised the possibility that AV imbalance might play a functional role in uneven placental sharing and, possibly, in the birth weight discordance associated with unevenly shared placentas. To assess this possibility, we compared the direction of the AV imbalance with respect to the larger/smaller placental share in unevenly shared placentas. In 5/54 (9%) of unevenly shared placentas, there was no morphometric evidence of any AV imbalance (NCSA = 0 mm2). In the remaining 49 unevenly shared and AV-unbalanced placentas, the direction of the AV imbalance, as estimated by the sense of the NCSA, was from smaller to larger share in 34 cases (69%). In the remaining 31% of cases, the AV imbalance was directed from larger to smaller placental share. These associations were also maintained when only placentas with more significant AV imbalance, defined as NCSA > 1 mm2, were considered. In these more AV-unbalanced cases, AV imbalance was also directed from small to large placental share in most cases (16/23, 70%).

We then studied whether the relationship between the direction of AV flow and placental sharing was different in BW-discordant versus BW-concordant placentas. Uneven placental sharing combined with AV imbalance (NCSA > 0 mm2) was observed in 19 BW-discordant placentas. The AV imbalance was directed from small to large placental share in 11/19 (58%) of these BW-discordant placentas. In unevenly shared BW-concordant placentas, the AV imbalance was directed from small to large placental share in 23/30 (77%) cases (difference with BW-discordant placentas not significant). These findings suggest that the direction of the AV flow imbalance is not a critical determinant of placental sharing and/or birth weight discordance in diamniotic-monochorionic twins.

3.7. Correlation between uneven placental sharing and birth weight discordance: effect of superficial and deep anastomoses 

A recent study by Hack et al. [23] has suggested that the relationship between uneven placental sharing and birth weight discordance may be influenced by the presence or absence of AA anastomoses. To test the validity of this concept, we determined the frequency of BW discordance in evenly or unevenly shared placentas in the presence or absence of AA anastomoses. In the presence of AA anastomoses, uneven placental sharing was associated with a four-fold higher frequency of severe BW discordance (P < 0.0001) (Fig. 2). In the absence of AA anastomoses, the frequency of BW discordance was similar in placentas with even or uneven sharing. These results appear to support the notion that uneven sharing only correlates with BW discordance when AA anastomoses are present. However, two points of caution need to be emphasized. First, the number of BW-discordant cases in the ‘AA absent’ groups is small (only 3 evenly shared and 2 unevenly shared cases). Second, Fig. 2 illustrates that, in the absence of AA anastomoses, the frequency of BW discordance is relatively high even in evenly shared placentas, possibly masking any effect of uneven sharing on BW discordance in these small samples.

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  • Fig. 2 

    Correlation between placental sharing and frequency of birth weight discordance in association with superficial AA and VV anastomoses. *: P < 0.0001; **: P < 0.02; ***: P < 0.005 versus even sharing.

We then determined whether the presence or absence of VV anastomoses might affect the association between placental sharing and BW discordance (Fig. 2). In evenly shared placentas, the frequency of BW discordance was low, whether VV anastomoses were present or not (5% versus 11%, respectively). Similarly, the frequency of BW discordance was equally high in unevenly shared placentas with or without VV anastomoses (45% versus 35%), indicating VV anastomoses do not affect the correlation between placental sharing and BW discordance.

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4. Discussion 

We determined the placental characteristics of selective birth weight discordance in a large cohort of diamniotic-monochorionic twin placentas examined over a 9-year period in a single institution. In addition to recording standard gross anatomic placental features, we performed a detailed injection-based morphometric analysis of the choriovascular architecture. Our study demonstrated that placentas of diamniotic-monochorionic twin pregnancies without TTTS, but complicated by severe birth weight discordance (“BW-discordant placentas”) showed significantly increased frequencies of velamentous cord insertion and uneven placental sharing compared with BW-concordant placentas. In contrast, the choriovascular patterns, including frequencies of superficial AA and VV anastomoses as well as deep AV anastomoses, were comparable between both groups.

Previous studies have reported a higher frequency of velamentous cord insertion in BW-discordant placentas [11], [22], [23]. In agreement with Hanley et al. [22], we found that only velamentous, but not marginal, cord insertion was associated with increased frequency of birth weight discordance. A similar dissociation of the effects of velamentous versus marginal cord insertion was previously demonstrated in diamniotic-monochorionic twin placentas with TTTS [6]. In current pathology practice, marginal and velamentous cord insertion are often considered part of a spectrum of aberrant cord insertions with equivalent adverse effects on pregnancy outcome. Our findings indicate that the pathophysiology of these peripheral types of cord insertion may be different and that the consequences of velamentous cord insertion may be more severe than those of marginal insertion.

Unexpectedly, we found no correlation between the frequencies of velamentous cord insertion and uneven placental sharing. Equally surprisingly was the lack of correlation between velamentous cord insertion and choriovascular anatomy. Specifically, the frequencies of AA, VV and AV anastomoses, and the value of NCSA were similar in diamniotic-monochorionic twins with or without velamentous cord insertion. While the relationship between velamentous cord insertion and impaired fetal growth is indisputable, both in twin and singleton pregnancies [19], [22], [31], [32], [33], the mechanisms by which velamentous cord insertion contributes to birth weight discordance remain incompletely understood. Hormonal factors, as well as hemodynamic factors related to blood flow reduction due to cord compression [9], may contribute to fetal growth disruption in the setting of velamentous cord insertion.

In agreement with other studies [12], [23], [24], [25], we identified uneven placental sharing as a key determinant of birth weight discordance. Previous studies have described a strong linear correlation between placental territory discordance and birth weight discordance [12], [30]. In our study, uneven placental sharing was not associated with altered frequencies of AA, VV or AV anastomoses. In contrast, recent studies by Lewi et al. [25], [30] demonstrated a more elaborate intertwin vascular network in unequally shared placentas of diamniotic-monochorionic twins not affected by TTTS, especially in those complicated by early-onset discordant growth. The reasons for the discrepancies between the study by Lewi et al. and ours remain undetermined. Several methodological differences exist between the study of Lewi et al. and the current study. For instance, Lewi et al. studied stored and refrigerated, not freshly delivered placentas; they measured the vascular diameter using digital images, not by direct visualization of the placenta at the time of injection; they assessed AA and VV anastomoses based on diameter, not number; and they evaluated AV imbalance based on the diameters of the veins participating in the AV anastomoses, not based on the cross-sectional surface area of the arteries. However, it is unlikely that these different methodological approaches can account for the discrepancies between the two studies.

While we were not able to confirm the reported increased AA and VV connections, our study corroborated the increased net arteriovenous transfusion described by Lewi et al. [30] in unevenly shared placentas. In our study, uneven placental sharing was associated with a larger mean NCSA, suggesting a twin–twin flow imbalance. While this may lead to the suggestion that uneven placental sharing and, possibly, birth weight discordance, are attributable, at least in part, to imbalanced flow, it must be stressed that this association is tenuous at best. Indeed, there was no morphometric evidence of any AV imbalance (NCSA = 0) in 5/54 (9%) unevenly shared placentas. Furthermore, the AV imbalance was directed from smaller to larger placental share in two thirds of cases of uneven placental sharing, which is to be expected if AV imbalance is believed to be functionally involved in uneven growth. More difficult to explain was the fact that the AV imbalance was directed in the opposite direction in the remaining third. In concordance with our results, Denbow et al. [12] reported a higher rate of birth weight discordance when the net number of AV anastomoses was directed towards the larger placental share, rather than towards the smaller share.

Others have suggested that in unevenly shared placentas AV flow directed from larger to smaller share may counteract the effects of uneven sharing by ‘rescue transfusion’ [2], [12]. However, in our study, the frequency of larger to small placental share directed AV imbalance tended to be smaller in BW-concordant placentas compared with BW-discordant placentas (23% versus 42%), raising doubt about a protective role for AV anastomoses in the context of uneven placental sharing.

A recent study has suggested that the relationship between uneven placental sharing and birth weight discordance may be influenced by the presence or absence of AA anastomoses [23]. In concordance with Hack et al. [23], we found that uneven placental sharing is only associated with significantly higher frequency of birth weight discordance when AA anastomoses are present. While this may suggest that AA anastomoses have a functional – and adverse – role in unevenly balanced placentas, these data need to be interpreted with caution. First, the number of cases with absent AA anastomoses was very low, rendering reliable statistical analysis difficult. Second, in our study, absence of AA anastomoses was associated with a tendency to increased birth weight discordance even in placentas with even sharing, possibly masking any effects in these small groups. Third, as in the context of TTTS [6], it is not clear whether AA anastomoses play an active functional role as regulators of intertwin hemodynamics, or should be considered as innocent bystanders and mere markers of general choriovascular angiogenesis.

We previously reported the placental markers of TTTS using similar analytical methods [6]. Several similarities can be observed between TTTS and non-TTTS BW-discordant placentas. In particular, both types of placentas displayed an increased frequency of velamentous cord insertion and uneven placental sharing. A striking distinction between TTTS and BW-discordant non-TTTS placentas was the lack of choriovascular anatomic aberrations in the latter. Indeed, TTTS placentas exhibited a significantly lower frequency of AA and higher frequency of VV anastomoses compared with non-TTTS placentas [6]. In contrast, the choriovascular anatomy of non-TTTS BW-discordant placentas was remarkably similar to that of BW-concordant placentas. This supports the notion that the mechanisms of TTTS, which distinguish TTTS from non-TTTS BW discordance, may be related to the peculiar choriovascular characteristics of that disorder.

A major strength of this study, in addition to its large size, was the detailed morphometric analysis of AA, VV and AV anastomoses, performed by a single observer in a single institution. Using vascular injection techniques described elsewhere [26], we demonstrated that the numbers of AA, VV and AV anastomoses, as well as the value of the AV NCSA, were equivalent in BW-discordant and BW-concordant placentas. The striking similarity of choriovascular architecture in both groups suggests that the functional contribution of vascular intertwin anastomoses to discordant growth is probably modest, at least in the absence of TTTS. This may explain, in part, why coagulation of communicating vessels failed to improve the perinatal outcome of diamniotic-monochorionic twins with selective birth weight discordance [17].

Limitations of this study deserve mention. First, we only reported the macroscopic placental findings. We suspect that microscopic, and especially histomorphometric comparison of BW-discordant and BW-concordant placentas, with emphasis on villous growth patterns, may provide deeper understanding of the pathophysiology of growth discordance in diamniotic-monochorionic twins. Redline et al. [34] previously reported a higher frequency of avascular villi in dichorionic and monochorionic twin gestations complicated by growth discordance. Second, intertwin AV flow imbalance was estimated by absolute net cross-sectional area (NCSA). While NCSA serves as an anatomic, postpartum proxy of AV flow balance between the twin circulations, it does not take into account flow volume or velocity of flow. The cross-sectional area of a blood vessel only correlates with blood flow if it can be assumed that pressure differential, blood vessel diameter and even viscosity are constant, which is likely not the case in vivo. Third, this study did not make a distinction between early- and late-onset discordant growths. A recent study suggested that the placental characteristics and pathophysiology of birth weight discordance may differ depending on the timing of onset of growth discordance [25]. Finally, similar to virtually all studies of monochorionic placentation so far, this study does not take into account the role of genetics or epigenetics in birth weight discordance in monochorionic twins. Although by definition monozygotic, monochorionic twins are rarely completely identical [35]. An expanding range of genetic/epigenetic and prenatal environmental postzygotic events, including heterokaryotypia, parental imprinting effects, skewed X-chromosome inactivation, and DNA methylation have been reported that may contribute to often striking phenotypic discordance between the twins [35], [36]. Future studies of the genetics and epigenetics of birth weight discordance – and TTTS – may provide a deeper understanding of the pathogenesis of these disorders.

In conclusion, placentas of non-TTTS diamniotic-monochorionic pregnancies complicated by birth weight discordance showed a significantly higher frequency of velamentous cord insertion and uneven placental sharing. As in all diamniotic-monochorionic twin placentas, intertwin anastomoses were present in virtually all BW-discordant placentas. However, the patterns of these anastomoses, including superficial as well as deep AV anastomoses, and the degree of AV imbalance were strikingly similar between BW-discordant and -concordant placentas. These findings suggest that the pathogenesis of growth discordance in non-TTTS diamniotic-monochorionic twins is linked to the type of cord insertion and degree of placental sharing, rather than to aberrations of choriovascular architecture. Elucidating the mechanisms whereby velamentous cord insertion exerts its adverse effects on pregnancy outcome may lead to a better understanding of growth dysregulation in twin gestations, singletons and TTTS, and eventually lead to further refinement of therapeutic strategies for these conditions.

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PII: S0143-4004(10)00097-4

doi:10.1016/j.placenta.2010.02.018

Placenta
Volume 31, Issue 5 , Pages 380-386, May 2010

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