Twin Anemia Polycythemia Sequence in a Dichorionic Twin Pregnancy Leading to Severe Cerebral Injury in the Recipient

• Monochorionic twins share 1 placenta and have placental anastomoses connecting the 2 fetal circulations, whereas dichorionic twins have separate placentas without anastomoses.

• Twin anemia polycythemia sequence can occur in monochorionic twins as the result of chronic unbalanced feto-fetal transfusion through minuscule placental anastomoses.

• In rare situations, dichorionic twins may also have small placental anastomoses which can lead to twin anemia polycythemia sequence.

• In dichorionic twins with large intertwin hemoglobin difference, measurement of reticulocyte count and placental injection is required to assess or rule out the presence and nature of feto-fetal transfusion pathology.

A 22-year-old woman (G3P0) was pregnant with a dichorionic twin pregnancy. Dichorionicity was confirmed based on the lambda sign during the first-trimester ultrasound scan at her local hospital. Aside from gestational diabetes, the course of pregnancy was uneventful. Monthly ultrasound examination revealed normal amniotic fluids and adequate linear growth for both fetuses. Middle cerebral artery peak systolic velocity ultrasound Doppler measurements were not performed. At 32⁺⁶ weeks of gestation, the patient had premature uterine contractions for which corticosteroid therapy was administered. At 33⁺² weeks’ gestation, a cesarean section was performed for fetal distress on CTG registration. Two boys were born. Twin 1 had Apgar scores of 3/6/9, weighed 1,962, g and was plethoric (Fig. 1a). Twin 2 had an Apgar score of 5/8/8, weighted 1,994, g and was pale (Fig. 1b). A full blood count revealed a hemoglobin value of 22.4 and 9.8 g/dL (normal range (p5–p95): 13–20 g/dL) for twin 1 (plethoric) and twin 2 (pale), respectively. Reticulocytes count was 72‰ in twin 2 (normal range 40–60‰). The reticulocyte count in twin 1 was not measured. In twin 2, also a low leukocyte count (6.2 × 10⁹/L) and platelet count (30 × 10⁹/L) were detected. The inter-twin hemoglobin difference was 12.6 g/dL, raising the suspicion of an unbalanced feto-fetal transfusion. To reevaluate the chorionicity and examine the presence of placental anastomoses, the placenta was shipped to our hospital, which is the national referral center for fetal therapy and complicated twin pregnancies. The twins were transferred to an academic hospital nearby for respiratory support at the neonatal intensive care unit.

At macroscopic placental examination, a thick opaque intertwin placental membrane was observed, supporting the likelihood of a true dichorionic twin pregnancy (Fig. 2a), without evidence of placental anastomoses at first sight. To further examine the angioarchitecture of the placenta, color-dye injection of the placental vessels was performed. Dark blue color dye was used for the arteries, and pink color dye was used for the veins in twin 1. After injection of 40 mL of pink color dye into the vein of twin 1, a subtle hint of pink color dye was observed in one of the distant small veins in the placental share of twin 2 (Fig. 2b), suggesting the presence of a deep-hidden small veno-venous (VV) anastomosis. To confirm the suspicion, more pink color dye was pumped into the venous circulation of twin 1 (Fig. 2c), hereby slowly achieving full injection of the venous placental circulation of twin 2. The arteries of twin 2 were injected with green color dye. No visible anastomoses were observed after the injection of both circulations was finished. The maternal side of the placenta showed a color difference, with a plethoric placental share for twin 1 and a pale placental share for twin 2, similar to their skin color (Fig. 3b). The color difference ratio between the 2 shares was 1.3, measured using ImageJ version 1.53 (U.S. National Institutes of Health, Bethesda, MD, USA). To unveil the type and number of deep anastomoses, the placenta was injected with iobitridol contrast fluid and photographed under X-ray. Unfortunately, this gained inconclusive results due to excessive leakage of fluid from the vessels into the adjacent placental tissue. Histologic examination of the intertwin membrane demonstrated the presence of 2 amniotic and 2 chorionic membranes, confirming the dichorionic nature of the twin pregnancy.

Based on the large hemoglobin difference (>8 g/dL), the increased reticulocyte measure in the anemic infant, and the placental characteristics (small anastomosis and placental color difference), this dichorionic twin was diagnosed with twin anemia polycythemia sequence (TAPS), with twin 1 being the TAPS recipient and twin 2 being the TAPS donor twin. Further management was carried out according to our protocol for TAPS twins, including a cerebral ultrasound, neonatal hearing screening, and long-term follow-up appointments.

The TAPS donor was diagnosed with respiratory distress syndrome grade 3–4 for which a total of 3 doses of exogenous surfactant was required. On day 2, its hemoglobin and platelet levels had dropped to 7.1 g/dL and 18 × 10⁹/L, respectively, for which an erythrocyte and platelet transfusion was performed. Cerebral ultrasound (performed on days 1 and 4) showed no abnormalities. After 5 days at the neonatal intensive care unit, the donor twin was transferred to a step-down unit. After 4 weeks in the hospital, the boy was discharged to home. The TAPS recipient initially showed clinical signs of respiratory distress syndrome, but these resolved within the first 24 h after birth. Polycythemia was adequately treated with hyperhydration therapy. Cerebral ultrasound on day 1 revealed a unilateral intraventricular hemorrhage grade 2 [1], with mild posthemorrhagic ventricular dilatation and the presence of blood in third and fourth ventricle. This progressed toward a severe posthemorrhagic ventricular dilatation (>97th centile [2]) with periventricular echogenicities, for which treatment with a Rickham reservoir and a subsequent ventriculoperitoneal shunt was required. After 8 weeks of hospital admission, the TAPS recipient was discharged home.

At 4 months of age, both boys are doing well. Neonatal hearing screening showed no abnormalities for both boys. The TAPS recipient will be seen regularly by the pediatric neurologist to evaluate neurologic development.

We report an unusual case of TAPS in a dichorionic twin pair, leading to severe cerebral injury in the recipient twin. TAPS is known to result from chronic blood flow through minuscule placental anastomoses and has been reported to occur only in monochorionic twins [3]. However, this report shows that in rare cases, placental anastomoses can be present in dichorionic twins as well, potentially leading to TAPS and its associated severe consequences.

Although very uncommon, anastomoses in dichorionic twins have been described previously in 6 different case reports [4-9]. The majority of these cases (5/6) were identified because of the development of twin-twin transfusion syndrome (TTTS), and in all cases, superficial anastomoses could be detected at the placental surface. Recently, Zilliox et al. [10] probably described the first case of severe TAPS in a dichorionic twin. However, the definitive diagnosis was not confirmed with reticulocyte count measurements, and placental injection failed to show minuscule placental anastomoses, which are characteristic for TAPS. Whether the large placental vessels shown in the figure of the reported case by Zilliox et al. [10] truly represent vascular anastomoses is a matter of controversy (we suspect that this was not the case). We, therefore, present the first case of TAPS in a dichorionic twin, confirmed by the presence of a small deep-hidden VV anastomosis after placental injection. These case reports show that the distinction between monochorionic and dichorionic twins is not as strict as thought previously, and that in rare cases, anastomoses can also be present in dichorionic twins, potentially leading to feto-fetal transfusion pathology with severe consequences. Therefore, when a pale and plethoric twin pair is born, we recommend to perform a full diagnostic work-up to investigate the presence of a feto-fetal transfusion problem, regardless of the type of chorionicity of the twin pregnancy.

In case of a large intertwin hemoglobin difference, a distinction needs to be made between TAPS and acute peripartum TTTS. The diagnosis of TAPS is confirmed when at least 1 of the following criteria is met: a reticulocyte count ratio >1.7 (reticulocyte count donor/reticulocyte count recipient) representing reticulocytosis in the donor twin, or the presence of only small vascular anastomoses (diameter <1 mm) [3, 11]. In acute peripartum TTTS, there is an abrupt transfusion through large bidirectional anastomoses (diameter >1 mm), without reticulocytosis in the donor twin (resulting in a reticulocyte ratio <1.7) [12]. It should be noted that in our case there was not enough information available to provide conclusive answers to these 2 criteria, but the data that we have indicate that TAPS is more likely than acute peripartum TTTS. First, although the reticulocyte count in the recipient twin was not measured, we found an increased reticulocyte count in the donor twin [13], corroborating the potential chronic nature of the transfusion. Moreover, this donor twin also demonstrated low platelet and leukocyte counts. Thrombocytopenia and leukopenia in TAPS donors have previously been described to occur and likely result from the suppression of WBCs and platelets production due to chronic anemia and increased erythropoiesis [14]. With placental injection, we were also able to confirm the presence of a deep-hidden VV anastomosis. Although suboptimal contrast-angiography prevented adequate examination of the size of this anastomosis, it is very likely that the diameter was small, as it took a long time and a lot of pressure to achieve full injection of the co-twin’s venous circulation. Whether this anastomosis was the only one that caused the unbalanced transfusion or that other arteriovenous anastomoses contributed to the development of TAPS as well, will remain unknown. Previous literature has reported that in rare cases of TAPS only one VV anastomosis was present [15]. It is possible that a VV anastomosis might act like an AV anastomosis under certain circumstances. Last, the maternal side of the placenta of this case showed a color difference, concordant with anemia, and polycythemia in the infants. This color difference is only seen in TAPS placentas and not in placenta from twins with acute peripartum TTTS [16].

This case illustrates that the consequences of TAPS should not be underestimated. Although donor twins are at increased risk for perinatal mortality [15], TAPS recipients might also experience severe consequences of polycythemia, including limb ischemia and severe cerebral damage [17]. A case of extensive brain injury leading to fatal outcome in a TAPS recipient was previously reported by our study group in 2014 [18]. Moreover, the rate of long-term neurodevelopmental impairment in TAPS is high, with TAPS donors having a 15% chance of hearing loss and a 34% of mild-to-severe cognitive impairment [19]. To timely detect and treat both short- and long-term morbidities of TAPS, we strongly recommend to perform cerebral ultrasound and neonatal hearing screening in the first days after birth and plan long-term follow-up appointments for both infants to monitor cognitive and motor development. In conclusion, this case report adds to the small body of knowledge of rare cases of feto-fetal transfusion in dichorionic twins and shows us that the clinical picture, rather than the established type of chorionicity, should be leading in medical decision-making regarding the required postnatal diagnostics and treatment.

Written informed consent was obtained of both parents for the publication of this case report and accompanying images. The research complies with the guidelines for human studies and was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.

The authors have no conflicts of interest to declare.

There was no sponsorship or funding arranged for this case report.

L.S.A. Tollenaar, S.A. Prins, S. Beuger, F. Slaghekke, D. Oepkes, and E. Lopriore have all contributed to the concept, writing, and revision of this manuscript.