COMPLICAÇÕES EM GESTAÇÕES GEMELARES MONOCORIÔNICAS

Maurício Mendes Barbosa Doutor em Ciências pelo Departamento de Obstetrícia da UNIFESP EPM

Complicações Monocoriônicas • Síndrome de transfusão feto feto (STFF) • Sequência anemia policitemia (TAPS) • Restrição de crescimento fetal seletiva (RCFs) • Perfusão arterial reversa (TRAP) • Monocoriônica Monoamniótica (MA) • Gêmeos conjugados • Anomalias discordantes • Múltiplas monocoriônicas • Morte de um dos fetos

Introdução •  Taxa de gestações gemelares monozigóticas (MZ) é

constante em 3-5 por 1000 partos concebidos naturalmente

•  30% das gestações gemelares são MZ •  2/3 dos gemelares MZ são monocoriônicos (MC,

placenta única) • Portanto, 20% das gestações gemelares expontâneas

são MC

•  Chow JS. AIUM 2001

Introdução • Gêmeos MC dividem uma única placenta. • Eles são funcionalmente “conjugados”por anastomoses

vasculares na superfície e dentro da placenta - “chorioangiopagus” ( área de anastomoses vasculares na Placenta- Angioarquitetura placentária).

• Essa angioarquitetura explica a fisiopatologia das complicações das gestações MC, ajuda na racionalização do manuseio.

•  Também explica a proporcionalidade da doença que afeta as gestações MC – o que acontece com um afeta o outro.

Angioarquitetura placentária

Wee. Placenta 2005

Introdução •  As angioanastomoses são quase universais em

gestações MC • A maioria das gestações MC não tem complicações • O mecanismo que conduz a distribuição de sangue entre

os gêmeos de forma balanceada para uma forma não balanceada não é conhecido

• Doenças associadas com distribuição não balanceada de sangue entre os gêmeos são a síndrome de transfusão feto feto e a sequência anêmia policitemia

•  Denbow ML. AJOG 2000

Introdução • A divisão desigual na

placenta MC pode levar a restrição seletiva de crescimento fetal (RCFs).

•  Fluxo desigual entre os gêmeos e divisão da placenta também desigual podem coexistir.

Vascularização e divisão placentária anormais STFF TAPS RCFs

STFF e TAPS RCFs e STFF

TAPS e RCFs STFF e TAPS e RCFs Conexões vasculares

Equador da placenta

Introdução •  É imperativo que a corionicidade seja documentada o mais

cedo e definitivo possível •  “Gêmeos”não é diagnóstico •  DC ou MC •  “MC” deve ser tratado como uma gravidez de risco

•  O acompanhamento pré-natal deve ser diferente das gestações DC e únicas

•  Diagnóstico deve ser feito no primeiro trimestre •  98% acurácia no primeiro trimestre

•  Massa placentária única, sinal do “T” , mebrana mais fina, sexo igual •  90% acurácia no segundo trimestre

•  Carroll SG. BJOG 2002

Introdução

Introdução

Introdução

Introdução

Introdução

Introdução

Introdução • MC devem ser seguidas mais de perto do que as DC • Primeiro trimestre US para determinar corionicidade,

TN, DV • Cada duas semanas desde 16 semanas até o parto

•  Medida do LA nos dois sacos •  Avaliar a presença de bexiga em cada feto •  Doppler •  Aumentar a vigilância na presença de achados anormais

• Ultrassom morfológico entre 18-22 semanas • Ecocardiografia entre18-22 semanas • Pico sistólico da Artéria Cerebral Média

•  Thorson HL. Obstet Gynecol 2011

Introdução • Detecção precoce das complicações nas MC é associada com melhores resultados*

• Tempo para referir a paciente para um serviço de referência

• Tempo de compreensão para a paciente •  Fisiopatologia complicada • Opções de tratamento • Consequências de suas decisões

•  Huber A. Obstet Gynecol 2006*

SÍNDROME DE TRANSFUSÃO FETO FETO (STFF) • Mais comum e com maior potencial de gravidade das

complicações nas MC • Afeta 10-15% de todas MC • Responsável ~ metade das mortes nas MC* • Sem tratamento ~70-100% perdas, especialmente nas com

início precoce ** • Alta morbidade neurológica nos sobreviventes (10-30%)***

•  Lewi L. AJOG 2008* •  Berghella V. JRM 2001** •  van Hetern CF. Obsyet Gynecol 1998***

STFF fisiopatologia •  Fisiopatologia não está completamente elucidada •  “Doador” transferi volume para o “receptor” • Doador fica oligúrico (oligoâmnio) e com hipovolêmia

(ausência de bexiga, restriçao de crescimento, Doppler alterado da artéria umbilical)

• Receptor fica poliúrico (polidrâmnio) e com hipervolemia (distensão da bexiga, alteração do Doppler arterial e venoso)

• Passagem de substâncias vasoativas do doador para o receptor exacerbando a condição

Classificação STFF

Estágio Poli/Oli Ausência Bexiga

Doppler alterado

Hidropsia Morte fetal

I + II + + III + + + IV + + + + V + + + + +

Classificação de Quintero

Quintero RA. J Perinatol 1999

Conduta STFF • Parto • Conduta expectante • Septostomia amniótica • Amnioredução seriada •  Término da gestação •  Feticídio seletivo •  Fetoscopia para fotocoagulação a laser

•  Superior que a AR por um trial controlado randomizado •  Considerar como tratamento de escolha para a sobrevida dos dois

fetos •  Senat MV. NEJM 2004

STFF resultados/LASER • 85% de probalidade de 1 vivo* • 65% probalidade de os 2 vivos* • 54% probalidade de perda do doador no estágio IIID/DR**

• 8% probalidade de morbidade neurológica no sobrevivente (s)*

• Média de IG de nascimento com 33 semanas*

•  Senat MV. NEJM 2004* •  Chmait RH. AJOG 2011**

STFF resultados/Laser 31

36

54

48

39

49

36

35

60

58

50

66

66

67

67

73

77

76

65

71

81

81

79

88

76

73

84

81

88

85

92

91

87

94

91

0 20 40 60 80 100

Delia et al 1995 (26)

Ville et al 1995 (45)

Hecher et al 2000 (127)

Zikulnig L et al 1999 (121)

Quintero et al 2000 (89)

Martinez et al 2003 (110)

Senat et al 2004 (72)

Yamamoto et al 2005 (175)

Huber et al 2006 (200)

Middeldorp et al 2007 (100)

Muratore et al 2009 (163)

Habli et al 2009 (149)

Concotta et al 2009 (100)

Crisan et al 2010 (314)

Chmait et al2010 (682)

Johnson & Moise 2010 (232)*

CHOP 2010 (287)*

Texas Fetal Center 2013 (120)*

STFF Tratamento

STFF Tratamento

Articles

www.thelancet.com Published online March 7, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62419-8 5

the Solomon group and 135 in the standard group were included in the intention-to-treat analyses. The groups were similar with respect to maternal age, gestational age at treatment, placenta localisation, and Quintero stage (table 1).

In the intention-to-treat analysis, the primary outcome was identifi ed in 94 (34%) of 274 fetuses in the Solomon technique group compared with 133 (49%) of 270 fetuses in the standard treatment group (OR 0·54, 95% CI 0·35–0·82; table 2). Table 2 lists the individual parameters within the composite outcome. Survival did not diff er signifi cantly between the two groups. Eight women underwent selective feticide via cord occlusion of one of the twins; this occurred either during the initial treatment (Solomon group n=1, standard group n=1), as described earlier, or at a later stage due to severe cerebral injury (Solomon group n=3, standard group n=3).

We found no signifi cant diff erence between the groups with respect to gestational age at birth (32·4 weeks gestation [SD 3·3] in the Solomon group and 32·3 weeks gestation [3·3] in the standard group; p=0·89) or birth weight (1754 g [SD 594] in the Solomon group and 1762 g [611] in the standard group; p=0·82). 268 (98%) of 274 women underwent their assigned procedure. None of the women who were assigned to the standard treatment groups were treated with the Solomon technique. None of the aspects of the procedures were signifi cantly diff erent between the two treatment groups, except for total amount of laser energy (table 3). In the Solomon group, the operator reported a perceived complete separation of the placental parts in 118 (86%) of 137 women. None of the procedure-related complications diff ered between groups (table 4).

The placentas of 151 women (Solomon group n=74, standard group n=77) were viable for study using colour dye injection. An example of colour-dye-stained twin-to-twin transfusion syndrome placenta that was treated using the standard technique is shown in fi gure 2 and one treated using the Solomon technique is shown in fi gure 3. The remaining placentas were not injected because of maceration after intrauterine fetal death of one or both twins (n=41) or because they were lost (n=45), damaged (n=27), or placed in formalin (n=8). Placentas were mainly lost from women whose fetuses were delivered in referring hospitals. In these hospitals, placental injection studies were not a standard procedure and placentas were sometimes discarded or fi xed for routine pathology. In those placentas that were damaged, damage was due to manual removal with disintegration of morphology. Residual anastomoses were present in 14 (19%) of 74 and 23 (30%) of 77 of the placentas in the Solomon and standard treatment groups, respectively (p=0·12).

Outside of the common and well-known complications of twin-to-twin transfusion syndrome and its treatment, no serious adverse events occurred.

DiscussionIn this randomised controlled trial, we found that fetoscopic laser coagulation of the entire vascular equator (Solomon technique) signifi cantly reduced the incidence of twin anaemia polycythaemia sequence and recurrent twin-to-twin transfusion syndrome in monochorionic pregnancies complicated by twin-to-twin transfusion syndrome. The Solomon technique did not seem to be associated with an increase in any identifi able adverse outcome or complication. However, this study

Solomon group (n=137 women, 274 fetuses)

Standard group (n=135 women, 270 fetuses)

OR (95% CI)

Iatrogenic monoamnioticity 17 (12%) 14 (10%) 1·22 (0·58–2·60)

Amniondehiscence (membrane separation) 7 (5%) 13 (10%) 0·51 (0·20–1·31)

Bleeding at the introduction side 9 (7%) 7 (5%) 1·29 (0·47–3·56)

Bleeding at the placental surface 8 (6%) 3 (2%) 2·73 (0·71–10·51)

Intrauterine infection* 1 (1%) 0 (0%) 0·34 (0·002–6·35)

Rupture of membranes <24 h 4 (3%) 6 (4%) 0·65 (0·18–2·35)

Premature rupture of membranes 57 (42%) 46 (34%) 1·38 (0·84–2·26)

Intrauterine death of the fetus† 45/274 (16%) 48/270 (18%) 0·90 (0·56–1·49)

Death of fetus before 24 weeks of gestation† 15/274 (6%) 11/270 (4%) 1·34 (0·63–2·87)

Neonatal death within 28 days of birth†‡ 11/214 (5%) 13/211 (6%) 0·79 (0·30–2·07)

Data are number (%) or n/N (%) unless otherwise specifi ed. OR=odds ratio. *Measured using the methods of Firth.22 †Measured per fetus using the generalised estimated equation module. ‡Denominator is the number of liveborn neonates.

Table 4: Procedure-related complications

Figure 2: Colour-dye-stained twin-to-twin transfusion syndrome placenta that was treated using the standard techniqueBlue and green dye was used to stain the arteries, and pink and yellow dye was used to stain the veins. The arrows point to the individual laser spots.

Articles

6 www.thelancet.com Published online March 7, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62419-8

was not powered to detect diff erences in all possible outcome measures or complications.

Ultimate safety and effi cacy parameters in our trial were perinatal morbidity and mortality. We included these two variables in the primary outcome to provide evidence that the Solomon technique is not less safe than the standard procedure. The overall primary outcome and individual comparison of these parameters showed no increased risks related to the Solomon technique. We therefore conclude that the new procedure is at least as safe as the standard procedure. Effi cacy was assessed by measuring the recurrence of twin-to-twin transfusion syndrome and twin anaemia polycythaemia sequence, both part of our primary outcome. There was a signifi cant reduction of recurrent twin-to-twin transfusion syndrome and twin anaemia polycythaemia sequence. Future trials by other investigators will hopefully confi rm the robustness of these fi ndings.

In the Solomon group, survival of both twins occurred in 64% of cases, with survival of at least one twin in 85% of cases. These values are on par with recent reports by other centres8,9,23 and are substantially higher than in the early study on fetoscopic laser surgery.4 Nevertheless, the overall survival rate in twin-to-twin transfusion syndrome is still far from optimum, and improved methods for both diagnosis and intervention are urgently needed.

In two recent retrospective studies, the Solomon technique was compared with the standard technique

(panel). Ruano and colleagues24 compared 26 preg-nancies treated with the Solomon technique with 76 pregnancies treated with the standard technique and found a substantially higher double survival rate in the Solomon group (84·6% vs 46·1%; p<0·01). Moreover, the Solomon-treated pregnancies had no twin anaemia polycythaemia sequence or recurrent twin-to-twin transfusion syndrome, compared with 7·9% (p=0·33) and 5·3% (p=0·57), respectively, in the standard technique group. Baschat and colleagues25 compared the outcome of 71 women treated with the Solomon technique with 76 standard-treated women and found a reduction in the incidence of twin anaemia poly-cythaemia sequence (2·6% vs 4·2%) and recurrent twin-to-twin transfusion syndrome (3·9% vs 8·5%), with a higher double-survival rate in the Solomon group (68·4% vs 50·7%; p<0·05).

Strengths of our study are the large number of women and fetuses included, the randomised design with intention-to-treat analysis, and the international, multi-centre collaboration, which enhances its generalisability. This design might in part explain the diff erences with respect to survival rates compared with two recent retrospective cohort studies.24,25 Survival rates in our two groups were similar, whereas the other studies reported a substantial improvement in survival with the Solomon technique compared with the standard technique. We assume that part of the improvement Ruano and colleagues24 and Baschat and colleagues25 noted could be because of increased experience with fetoscopic laser in general and not by the use of the Solomon technique. This type of bias was excluded in our trial by the randomised design.17

In this study, in 86% of women in the Solomon technique group, complete coagulation of the entire vascular equator was, according to the operators’ judgment, done as planned. Nevertheless, a small percentage of residual anastomoses as well as twin anaemia polycythaemia sequence and recurrent twin-to-twin transfusion syndrome were still reported. This information should raise awareness by both clinicians and women that close monitoring (including serial MCA-PSV measurements) remains necessary until delivery.

We were unable to show a clear improvement in neonatal morbidity and survival. However, women whose pregnancies are complicated with recurrent twin-to-twin transfusion syndrome and twin anaemia polycythaemia sequence will need frequent visits or admission to the hospital and might need another potentially hazardous fetal intervention, which cause increased amounts of stress and anxiety for both women and doctors. Two factors probably play a part in the absence of statistically signifi cant diff erences in neonatal morbidity and mortality in this study. First, these women were treated in highly specialised fetal therapy centres where these complications were optimally managed resulting in a low rate of adverse outcomes. Second, some adverse

Figure 3: Colour-dye-stained twin-to-twin transfusion syndrome placenta that was treated using the Solomon techniqueBlue and green dye was used to stain the arteries, and pink and yellow dye was used to stain the veins. After identifi cation and coagulation of each individual anastomosis, the complete vascular equator was coagulated from one placental margin to the other.

EPM / HMSJ 25

Leiden 137

Idade gestacional do laser 20,8 19,4

Tempo total de cirurgia (minutos) 51,7 35

Tempo de fetoscopia (minutos) 36,0 23

Idade gestacional ao nascimento (semanas) 30,5 33

Separação das Membranas 16% 5%

Rotura das membranas < 24 horas 0% 3%

Rotura prematura das membranas 29% 42%

Infecção intrauterina 0% 1%

STFF resultados/Laser

EPM / HMSJ 25

Leiden 137

Sangramento na introdução do Trocater 4% 7%

Sangramento da placenta 16% 6%

Pelo menos 1 feto vivo 88% 85%

Dois fetos vivos 52% 64%

Recorrência STFF 16% 1% (21%)

Taps pós laser 4% 3%(7%)

STFF resultados/Laser

TAPS • Distribuição não balanceada de sangue entre os fetos com

ou sem discordância entre quantidade de líquido amniótico.

• Através de vasos muito pequenos (<1mm) • Unidirecional, AV anastomoses próximo da periferia da

placenta • Mais comum depois do laser (13%) do que espontâneo

(3-5%) • Diagnóstico típico após 26 semanas

•  Lopriore E. Placenta 2007

TAPS classificação

Estágio Descrição I VPSACM >1.5 MoM e < 1.0 MoM, sem comprometimento II VPSACM >1.7 MoM e <0.8 MoM, sem comprometimento III Estágio I ou II e comprometimento cardíaco (Doppler anormal) IV Hidropsia do doador V Morte de um ou ambos fetos após TAPS

Slaghekke F. Fet Diag Ther 2010

TAPS

HB 21 HB 12

TAPS

TAPS

RCFs • Desproporção na divisão placentária • Variação nos critérios diagnósticos

•  Peso fetal estimado < percentil 10 de um feto •  Diferença de PFE >25% entre os fetos

• Associação entre morte fetal e morbidade neurológica •  20% risco de morte fetal, usualmente o menor •  36% risco neurológico, usualmente o grande independe da perda

ou sobrevivência do menor

•  Gratacos E. UOG 2004

RCFs classificação

Tipos Doppler Artéria Umbilical I Fluxo normal II Diástole zero ou reversa da artéria umbilical persistente III Diástole zero ou reversa da artéria umbilical intermitente

Gratacos E. UOG 2007

RCFs conduta • Melhor conduta ainda não foi estabelecida • Conduta expectante • Parto •  Feticidio seletivo por oclusão do cordão •  Fetoscopia com fotocoagulação com laser

Resumo • Determinar a corionicidade precoce e definitiva • Estudo e atendimento da angioarquitetura placentária •  Inicio da vigilância a cada 2 semanas a partir de 16

semanas • Ultrassom morfológico entre18-22 semanas • Ecocardiografia fetal entre18-22 semanas • Biometria fetal a cada 4 semanas • Parto das MC gemelares ñ complicadas com 360-376

semanas • Vigilância individual de cada gêmeo • Referir para um centro de referência de maneira precoce

na presença de qualquer alteração

Obrigado !!!