Çoğul Gebeliklerde Perinatal Sonuçlar Prof.Dr. Mehmet Zeki TANER Gazi Üniversitesi Tıp Fakültesi Kadın Hastalıkları ve Doğum Anabilim Dalı Öğretim Üyesi

Zamansal Değişim İngilitere ve ABD de 1970 – 2003 ikiz gebelik %50 Üçüz gebelik %400 artmıştır. ONS; 2006. Natl Vital Stat Rep 1999;47:1-16. 1. Office for National Statistics. Births: maternities with multiple births: rates per 1,000 maternities, age of mother, 1938-2004, all maternities. London: ONS; 2006. 2. Martin JA, Park MM. Trends in twin and triplet births: 1980e97. Natl Vital Stat Rep 1999;47:1e16.

Figure 1. Rate of all multiple births in England and Wales per 1000 maternities since 1938.

Figure 3. Graph of changes in higher order birth rates globally Figure 3. Graph of changes in higher order birth rates globally. Data from Simmons et al.5 (England and Wales; includes higher order multiples), Russell et al. and Martin et al. 18(USA), and Perinatal Statistics in the Nordic Countries; Multiple births 1975e2006 (2009) (Finland). Triplet Birth Rates

U.S. Multiple Birth Rates 1995 - 2006 Year Twins Triplets Quadruplets Quintuplets or More Twin Birth Rate per 1,000 total births Triplet Birth Rate (per 100,000 total births) Quadruplet and Higher Birth Rate (per 100,000 total births) 2008 138,660 5,877 345 46 32.6 147.6 (triplet+) N/A 2007 138,961 5,967 369 91 32.2 138.2 10.7 2006 137,085 6,118 355 67 32.1 143.4 9.89 2005 133,122 6,208 418 68 150.0 11.7 2004 132,219 6,750 439 86 164.2 12.8 2003 128,665 7,100 468 85 31.5 173.8 13.5 2002 125,134 6,898 434 69 31.1 171.5 12.5 2001 121,246 6,885 501 30.1 171.0 14.6 2000 118,916 6,742 512 77 29.3 166.1 14.4 1999 114307 28.9 170.3 1998 110,670 6,919 627 79 28.1 175.5 17.9 1997 104,137 6,148 510 26.8 158.4 15.2 1996 100,750 5,298 560 81 25.9 136.1 16.5 1995 96,736 4,551 365 57 24.8 116.7 10.8

YÜT çoğul gebelik oranları üzerine etkisi YÜT çoğul gebeliklere katkısının %50-80 arasında olduğu bildirilmektedir (Nakhuda GS 2005). Ülkemizde yapılan en kapsamlı çalışma (15 merkezli-70091 doğum) (Yayla M 2008)

Number of embryos transferred and pregnancy rates in the UK and US Number of embryos transferred and pregnancy rates in the UK and US. A, Pregnancy rates in the UK in 1987. B, Live and multiple birth rates among women less than 35 in the US 1996. The multiple gestation epidemic: The role of the assisted reproductive technologies Allan Templeton, FRCOG* Department of Obstetrics and Gynecology, U American Journal of Obstetrics and Gynecology (2004) 190, 894e8

2005 2006 2007 Toplam Canlı doğan 1369 1505 2014 4888 bebek Çoğul bebek % 8.3 % 10.7 % 11.7 % 10.5 İkiz % 6.4 % 9.3 % 9.8 % 8.7 Üçüz ve ↑ % 1.9 % 1.4 % 1.7 % 1.7 İst.Tıp Fak. 2005-2007. Çoğul gebelik bebeklerinin YDYB yatış oranları

Çoğul Gebelik Komplikasyonları Maternal Fetal Anemi Polihidramnioz Preeklampsi Erken doğum Postpartum kanama Operatif doğum Gestastyonel Diabet Abortus Vanishing Twin Malpresentasyon Plasenta previa A. plasenta Erken membran rüptürü Kordon komplikasyonları İntrauterin Gelişme Geriliği Konjenital anomaliler Kromozomal anomaliler Düşük doğum ağırlığı Fetal ölüm Prematürite Özel komplikasyonlar: TRAP, TTTS, Yapışık ikizler, Uzun dönem etkiler: CP, v.b.

Abortus Abort materyalleri incelendiğinde term ikizlerin 3 katı ikiz gebelik saptandı. (Livingston and Poland, 1980; Uchida and co-workers, 1983). Monokorionik çoğul gebelikler de risk dikorionik gebeliklere göre 18 kat artmaktadır.

Study group (n=46): singletons from a twin gestation Matched control group (n=92): singletons from a single gestation

Twin pregnancies with a ‘vanished’ embryo: a higher risk multiple gestation group? S.E. Barton , S.A. Missmer, and M.D. Hornstein, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA Human Reproduction, Vol.0, No.0 pp. 1–4, 2011 Methods: This is a retrospective cohort study of twins from a large academic IVF practice. Multivariate analysis was performed to examine the perinatal risks—including small for gestational age (SGA), low-birthweight (LBW), preterm delivery and early preterm delivery—in twins that resulted from an early vanished triplet compared with twins without a vanished embryo. Results: Of 829 IVF twin deliveries, 59 were a result of vanished triplet pregnancies (7.1%). There was no significant increase in SGA, LBW or delivery ,37 weeks in the vanished triplets compared with other twins; however, the risk of early preterm birth (,32 weeks) was significantly higher (OR 3.09, 95% CI 1.63–5.87) and the length of gestation of these pregnancies was on average 1.5 weeks shorter (P , 0.01). In addition, the unadjusted mean birthweight was lower by nearly 200 g in the vanished triplet pregnancies (P , 0.01). Conclusions: IVF twin pregnancies with a vanished triplet are at an increased risk for early preterm birth compared with other twin pregnancies. These pregnancies should be recognized at higher risk for early preterm birth and considered for increased obstetrical monitoring. A significant limitation of this study is that the cause for preterm birth was unknown.

Kongenital Anomaliler Çoğul gebeliklerde anomali oranı tekillere göre artmaktadır. YÜT gebelikleri ile spontan gebelikler arsında fark yoktur. (McDonald and associates, 2005). İkizlerde Major anomaliler %2 Minor anomaliler %4(. Cameron and colleagues, 1983; Kohl and Casey, 1975). Bu artışın hemen tamamı monozigotik ikizlerdeki yapısal anomalilerdir. -1-Bölünmeye bağlı mekanizma: akardiak fetus, NTD, holoprosencepahly, sirenomelia 2.Damar bağlantıları nedeni ile olan anomaliler: microcephaly, hydranencephaly, intestinal atresia, aplasia cutis, or limb amputation. 3.Dar alan nedeni ile olan anomaliler: talipes equinovarus (clubfoot) , kong. kalça çıkığı Schinzel and associates 1979

Kongenital Anomaliler 8 çalışma 17 milyon tekil 380 000 ikiz Risk 1.3 IVF, ICSI ve spontan gebeliklerde risk aynı bulunmuş. Monozigotiklerde risk 3-5 kat fazla Baldwin VJ. Pathology of multiple pregnancy. New York: Springer-Verlag; 1994. Sebire NJ. Anomalous development in twins (including monozygotic duplication). In: Kilby M, Baker P, Critchley H, Field D, editors. Multiple pregnancy. London: RCOG Press; 2006. p. 59-88. Pinborg A, Loft A, Rasmussen S, et al. Neonatal outcome in a Danish national cohort of 3438 IVF/ICSI and 10,362 non-IVF/ICSI twins born between 1995 and 2000. Hum Reprod 2004;19:435-41. Genetics and developmental pathology of twinning. Martin A. Weber , Neil J. Sebire Seminars in Fetal & Neonatal Medicine 15 (2010) 313-318 11. Summary of congenital anomalies in twins Despite the limitations of the available data, best estimates suggest that the overall rate of congenital anomalies in twin infants is about 1.3 times higher than in singletons. 29 Data suggest that, once prematurity-related complications are excluded, the congenital anomaly rate in dizygotic twins is not significantly greater than for singletons, but that the rate in monozygotic twins infants is around 3-5-fold greater. The majority of anomalies seen with increased frequency in twin infants are associated with defects in laterality or secondary to vascular disruptions, with both mechanisms preferentially affecting monozygotic, monochorionic twins 29. Sebire NJ. Anomalous development in twins (including monozygotic duplication). In: Kilby M, Baker P, Critchley H, Field D, editors. Multiple pregnancy. London: RCOG Press; 2006. p. 59e88. Genetics and developmental pathology of twinning Martin A. Weber a , Neil J. Sebire a, b, *Seminars in Fetal & Neonatal Medicine 15 (2010) 313e318 9. Specific malformations in twins Since many individual anomalies are rare, data are only available from large population-based registry studies or autopsy series. 40 Anomalies may affect all organ systems, but the commonest involve cardiovascular and central nervous systems, followed by ophthalmic and gastrointestinal abnormalities. Types of anomaly include those: (i) presumed primary malformations which may be related to midline formation and/or dependent on laterality, such as neural tube defects and some cardiac defects; (ii) anomalies that have a disruptive aetiology, usually haemodynamic, such as destructive brain lesions, limb reduction defects, some cardiac defects, renal agenesis, aplasia cutis and intestinal atresias; (iii) anomalies associated with prematurity, including patent ductus arteriosus and retinopathy of prematurity; and (iv) those anomalies not fitting any of the above categories. . Concordance rates for fetal malformations in twins Whereas monozygotic twins are usually concordant for chromosomal or genetic defects, most twin pregnancies are discordant for fetal malformations regardless of type of anomaly; data derived from the largest available series report an 81% discordance for all anomaly types, consistent with similar rates reported in smaller studies. 40,41 The concordance rate of major congenital malformations is around 20% for monozygotic twins, with most dizygotic twin pairs being discordant. 38 This is consistent with the hypothesis that malformations in dizygotic twins occur at a similar rate to that in singletons, making the probability of two affected dizygotic co-twins very small, whereas most anomalies in monozygotic twins are either the result of the twinning process or the effect of interfetal haemodynamic complications, both of which may affect the two fetuses unequally 7. Malformation rates in monozygotic versus dizygotic twins To examine the possible relationship between zygosity or chorionicity and anomaly rates, data are required detailing twin congenital anomaly rates by gender, chorionicity and/or genetic zygosity testing. Only one study provides direct data on congenital anomaly rates in singleton and twin infants from the same population in whom zygosity determination had been performed. In this study of 73,264 deliveries in Taipei, including 1688 twin infants, the overall frequency of malformations in twin infants was greater than singletons; subgroup analysis revealed that the prevalence of malformations was not significantly different between singletons and dizygotic twins, whereas the rate for monozygotic twins was five-fold greater than for singletons. Several small studies, although not providing such quantitative estimates, suggest further supportive evidence that the prevalence of malformations in twins appears greater in like-sex twins only, with little or no increased frequency of malformations amongst unlikesex (i.e. dizygotic, dichorionic) twin pairs. In particular, malformations of the central nervous system, cardiovascular system and genitourinary system appear to be significantly more frequent in like-sex twins

İkizlerde kromozomal anomaliler İkiz ve tekil gebeliklerde kromozomal anomali sıklığı bir çok çalışmada aynı bulunmuştur. Çoğul gebeliklerde ileri maternal yaş nedeni ile daha sık trisomy saptanır. Her fetusun tekil gebelik kadar riskli olduğu için ikiz gebelikte gebelik başına risk tekil gebeliğin 2 katıdır. Bir çok kromozomal anomali için DZ ikizler Diskordan MZ ikizler Konkordandır. Jamar M, Lemarchal C, et al. Genet Couns 2003 Jamar M, Lemarchal C, Lemaire V, Koulischer L, Bours V. A low rate of trisomy 21 in twin-pregnancies: a cytogenetics retrospective study of 278 cases. Genet Couns 2003;14:395-400.

Doğum Ağırlığı Çoğul gebeliklerde IUGR ve preterm doğuma bağlı doğum ağırlığı düşük olur. Bu fark 28-30 haftadan sonra belirginleşir. (Buekens and Wilcox, 1993). Fetus sayısı arttıkça doğum ağırlığı azalır. Diagramlar tekil gebeliğe göredir. Çoğul gebelik diagramı kullanılmalıdır. Canada, 1986–1988. (Modified from Arbuckle TE, Wilkins R, and Sherman GJ: Birth weight percentiles by gestational age in Canada, Obstetrics & Gynecology, 1993, vol. 81, no. 1, pp. 39–48, with permission Erkek fetuslar için tekil ve ikiz doğum ağırlığı Canada, 1986–1988. (Arbuckle TE, Wilkins R, and Sherman GJ 1993

IUGR İkizlerde düşük doğum ağırlığı oranı % 60-70 (Moise J 1998). Güney ve ark (2006) %51-65 oranında 2500 gr altında ve %10-15 oranında 1500 gr altında doğduğunu bildirmişlerdir. Yıldırım ve ark 2007 DZ ve MZ leri 2037-2053 gr Güney ve ark (2006) IVF-Spontan/ 2090-2210 gr

Gebelik Süresi-Preterm Eylem/Doğum Fetus sayısı arttıkça gebelik süresi kısalmaktadır. İkizlerin %60’ı üçüzlerin %98’i preterm doğmaktadır. Martin2009. Preterm Doğum: Neonatal morbidite ve mortalitenin en büyük nedenidir. FIGURE 39-11 Cumulative percent of singleton, twin, and triplet or higherorder multifetal births according to gestational age at delivery in the United States during 1990. (Redrawn from Luke B: The changing pattern of multiple births in the United States: Maternal and infant characteristics, 1973 and 1990, Obstetrics & Gynecology, 1994, vol. 84, no. 1, pp. 101–106, with permission.) Luke B, 1994

Preterm Eylem-Doğum

90 IVF 190 spontan tekil gebelik karşılaştırılmış Are Singleton Assisted Reproductive Technology Pregnancies at Risk of Prematurity? T. PERRI, 1 R. CHEN, and I. BAR-HAVA 1,3 1 R. YOELI, 1 P. MERLOB, 2 R. ORVIETO, 1 Y. SHALEV, Z. BEN-RAFAEL, Journal of Assisted Reproduction and Genetics, Vol. 18, No. 5, 2001 1 90 IVF 190 spontan tekil gebelik karşılaştırılmış Preterm doğum riski IVF gebeliklerinde % 20 Spontan gebeliklerinde % 4 Açıklama : uterin malformasyon, geçirilmiş cerrahi, pelvik enfeksiyon The rate of preterm birth among multifetal gestations has increased over the past two decades. In an analysis of nearly 350,000 twin births, Kogan and colleagues (2002) showed that during the 16-year period ending in 1997, the rate of term birth among twins declined by 22 percent. Joseph and colleagues (2001) attributed this decline to an increased rate of indicated preterm deliveries. This trend is not necessarily negative, as it was associated with decreased perinatal morbidity and mortality rates among twins that reached 34 weeks. Similarly, twin gestations in women receiving more than the recommended number of prenatal visits showed higher rates of preterm birth but lower neonatal mortality rates (Kogan and colleagues, 2000). Although the causes of preterm delivery in twins and singletons may be different, once delivered, neonatal outcome is generally the same at similar gestational ages (Gardner and co-workers, 1995; Kilpatrick and colleagues, 1996; Ray and Platt, 2009). The previous statements apply to twins who are essentially concordant. As perhaps expected, outcomes for preterm twins who are markedly discordant may not be comparable with that of singletons because whatever caused the discordance may have long-lasting effects

Fetuslardan birinin ölümü Aynı cinsyetteki fetuslarda %2.6 karşı cinsyetteki fetuslarda %1.1 fetal ölüm görülmektedir. Rydhström 1994 Bir fetusun ölümü durumunda diğer fetusun ölüm riski aynı cinsyette iseler 6 kat daha fazladır. Kalan fetusun prognozu Gebelik haftası, korionisite, fetal ölüm-doğum arası süreye bağlıdır. “vanishing twin” olumsuz etki yapmaz?. Bir fetusun ölümünde nörolojik anormallik MK ikizlerde %18 DK ikizlerde %1. Ong 2006 Koagulopati teorik olaak beklenir ancak nadir görülür veya geçici olarak tüketim görülebilir. Muhtemelen fetusun ölümü- doğum süresinin kısa olmasından kaynaklanmaktadır.

Koryonisite- Komplikasyonlar DK MK Abortus % 2 % 10 Perinatal mortalite % 2 % 5 < 32 hafta doğum % 5 % 10 IUGR % 20 % 30 Anomali % 3 % 6 İkizlerde intrauterin ölümlerin ¾’ünden monokoryonik plasentasyon sorumludur

Serebral Palsi (CP) CP çoğul gebeliklerde tekil gebeliklerden daha sık görülür. Tekillerde 2.3/ 1000 yaşayan bebek İkizlerde 13/ 1000 yaşayan bebek Üçüzlerde 45 / 1000 yaşayan bebek Pharoah PO., and Cooke T. (1996). Cerebral palsy and multiple births [abstract]. Archives of Disease in Childhood-Fetal and Neonatal Edition, 75, 174-177. Petterson et al. [11] examined the rates of cerebral palsy (excluding post neonatal cases) in twins and triplets born from 1980—1989 in western Australia. Cases were taken from the Western Australian Cerebral Palsy Register. Triplets were found to have a higher risk than twins, who similarly had a higher risk than singletons (28 per 1000 95% CI 11 to 63, 7.3 per 1000 95% CI 5.2 to 10, 1.6 per 1000 95% CI 1.4 to 1.8). Risk was increased further for a surviving twin from a fetal death (96 per 1000 95% CI 36 to 218) compared to twin pregnancies where both survived (12 per 1000 95% CI 8.2 to 17). This trend was found to be similar, but not statistically significant, in triplets where one fetus died. Singletons and twins had a similar risk of cerebral palsy in low birth weight categories, but the risk was increased in twins when birth weight was N2500 g (4.2 per 1000 95% CI 2.2 to 7.0 compared to 1.1 per 1000 95% CI 1.0 to 1.3). Information on zygosity was based on same-sex orfferent-sex twin registers. Midwives’ notifications did not always record a fetal death; in some cases, live born children were recorded as twins when they were originally from a triplet pregnancy. However, problems were found in all these studieParticipants were often recruited from registers of cerebral palsy sufferers; how comprehensive these registers werenot known. Comprehensive neonatal and delivery data was not always included. With the exception of Petterson et al. [11], those cases of cerebral palsy due to post neonatal causes could act as a confounding factor. It has been suggested that the increased rate of caesarean section could be another confounding factor rather than being a twin in itself [12].

Cerebral Palsy-Etiyoloji Nedenler Sıklık Prematürite, düşük doğum ağırlığı % 40-50 Asfiksi, doğum travması % 25-30 Neonatal inme % 5-10 İntrauterin infeksiyonlar Kromozomal anomaliler Kalıtsal metabolizma bozuklukları Diğer nedenler(neonatal sepsis/menenjit kernikterus, Hipoglisemi, çevresel toksinler, drog ve alkol, postnatal inf. ve travma vs.) İdiyopatik % 5-10 Hermansen MC. Clin Perinatol 2006

Twin Twin Transfusion Syndrome

Best practice guidelines Long-term neurodevelopmental outcome in monochorionic twins after fetal therapy. Jeanine M.M. van Klink, Hendrik M. Koopman,, Dick OepkesEarly Human Development 87 (2011) 601–606

Best practice guidelines Long-term neurodevelopmental outcome in monochorionic twins after fetal therapy. Jeanine M.M. van Klink, Hendrik M. Koopman,, Dick OepkesEarly Human Development 87 (2011) 601–606

Best practice guidelines Long-term neurodevelopmental outcome in monochorionic twins after fetal therapy. Jeanine M.M. van Klink, Hendrik M. Koopman,, Dick OepkesEarly Human Development 87 (2011) 601–606

TTTS Sonuç Uzun dönem nörogelişim açısından amnioredüksiyon laserden daha kötüdür. RKÇ ile laserin amnioredüksiyona üstünlüğü gösterilmemiştir. • Yüksek Quintero Evresi sadece perinatal mortalite artışı değil aynı zamanda uzun dönem NDI göstergesidir. • Erken gebelik haftası kötü prognoz için en büyük risk faktörüdür. Selektif fetosidin uzun dönem ND sonuçları bilinmemektedir.

Tekil doğanlarda Risk 1.4 : En sık sekel CP Neurological sequelae in children born after in-vitro fertilisation: a population-based study Dr B Strömberg MDa , Prof G Dahlquist et al. The Lancet, 2002 Volume 359((9305):461 – 465, Retrospektif 5660 IVF 11360 kontrol grubunda nörolojik problemler karşılaştırıldır. IVF gebeliği sonucu doğan çocuklarda rehabilitasyon gereksinimi daha fazla Tekil doğanlarda Risk 1.4 : En sık sekel CP Şüpheli gelişim defekti riski IVF çocuklarında 4 kat İkizlerde nörolojik sekel riski IVF ve Spontan gebeliklerde farklı değildi. DDA ve prematur bebeklerde rehabilitasyon gereksinimi daha fazla bulundu.

ÖZET YÜT gebeliklerinde riskleri azaltmada çoğul gebeliklerin Çoğul gebelikler tekil gebeliklere göre maternal ve fetal risk oluştrumaktadır. YÜT gebelikleri spontan gebeliklere göre daha risklidir Sonucu belirleyen en önemli faktörler: IUGR, prematurite ve zigositedir. Prematurite en önemli risk faktörüdür. Prematurite olmadığında sonuçlar spontan gebelikler ile benzerdir MK gebelikler özel ilgi gerektiren yüksek risk grubudur. YÜT gebeliklerinde riskleri azaltmada çoğul gebeliklerin önlenmesi temel hedef olmalıdır.

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