ZAGADKA WRZEŚNIOWA /dla początkujących/ - Maria Respondek-Liberska. ZAGADKA WRZEŚNIOWA /dla zaawansowanych/ - Maria Respondek-Liberska

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1 ISSN X KARDIOLOGIA PRENATALNA ECHO PŁODU IC Journal Master List ICV 5.38; MNiSW 2 KWARTALNIK STOWARZYSZENIA NA RZECZ ROZWOJU KARDIOLOGII PRENATALNEJ NR 3 (14) wrzesień 2014 / 3 (14) September 2014 W numerze m.in.: Prevention of Preterm Delivery of Twins /Birgit Arabin/ DORV in fetuses: how to consult future parents at a prenatal cardiology center? /Małgorzata Soroka i wsp./ WAKACJE SZCZĘŚLIWYCH DZIECI Relacje z wakacyjnych inicjatyw dla dzieci i rodzin dotkniętych wadami serca PRENATALNE PROBLEMY KARDIOLOGICZNE Pod redakcją prof. Marii Respondek-Liberskiej i Zespołu U BLIŹNIĄT Łódź, szczegóły / rejestracja: P R E N A T A L C A R D I O L O G Y

2 KARDIO PRENATAL, 2014, 3 (14) Kwartalnik Kardiologia Prenatalna składa się (opcjonalnie) z 2 lub 3 części: naukowej, "prawo i medycyna" oraz części informacyjno-szkoleniowej. 1 SPIS TREŚCI Słowo od Redaktor Naczelnej / A Word From The Editor-In-Chief - Maria Respondek-Liberska PRACE NAUKOWE Prevention of Preterm Delivery of Twins" - Birgit Arabin DORV in fetuses: how to consult future parents at a prenatal cardiology center? Retrospective analysis of 39 cases" - Małgorzata Soroka, Maciej Słodki, Hanna Moczulska, Maria Respondek-Liberska First trimester diagnosis of Absent Pulmonary Valve (APV): a case report of prenatal treatment with a review of literature and data from The Polish National Registry of Fetal Cardiac Pathology" - Agnieszka Nawara, Beata Radzymińska-Chruściel, Maria Respondek-Liberska, Katarzyna Januszewska, Edward Malec An Unusual Complication of an Invasive Intrauterine Therapy: 6 year follow-up" - Aleksandra Świercz, Sylwia Lewandowska, Krzysztof Szaflik, Tadeusz Biegański, Anna Piaseczna-Piotrowska, Maria Respondek-Liberska 2 3 PRAWO I MEDYCYNA str. 3 str. 5 DOI /09141 str. 13 DOI /09142 str. 18 DOI /09143 str. 23 DOI /09144 PRAWO I MEDYCYNA: "Ku uwadze położników" - Maria Respondek-Liberska str. 27 ROZWIĄZANIE ZAGADKI Z CZERWCA - Maria Respondek-Liberska str. 28 ZAGADKA WRZEŚNIOWA /dla początkujących/ - Maria Respondek-Liberska str. 29 ZAGADKA WRZEŚNIOWA /dla zaawansowanych/ - Maria Respondek-Liberska str. 30 NOWOŚCI WYDAWNICZE: "Moje dziecko ma wadę serca" - prezentacja poradnika str. 31 WAKACJE SZCZĘŚLIWYCH DZIECI str. 34 AKTUALNOŚCI / WYDARZENIA Arłamów, Go Hearts 2014 str. 34 Nad morzem: Wzmocnijmy serca latem str. 35 Kolonie aktywne str. 37 Wydarzenia: INAUGURACJA ROKU AKADEMICKIEGO str. 38 SPRAWY ORGANIZACYJNE str. 39 PODZIĘKOWANIE str. 39 KARDIOLOGIA PRENATALNA - Echo Płodu - redakcja Kardiologia Prenatalna - Echo Płodu kwartalnik. Wydaje Stowarzyszenie na Rzecz Rozwoju Kardiologii Prenatalnej z siedzibą w Łodzi, przy współfinansowaniu przez Ministerstwo Nauki i Szkolnictwa Wyższego. Redaguje: prof. dr n. med. Maria Respondek-Liberska (Łódź) z zespołem (Poland, Germany, USA) Sekretarz Redakcji oraz osoba kontaktowa: red. Marek Lipiński (Warszawa) l_marek@wp.pl Redaktorzy tematyczni: Prof. Birgit Arabin (Germany): Fetal cardiac problems in multiple pregnancies Prof. Stuart Weiner (USA): Maternal diseases affecting fetal heart Dr hab. Maciej Słodki (Poland): Fetal congenital heart defects Dr n. med. Hanna Moczulska (Poland): Genetic and fetal heart problems Dennis Wood Jr., BA, RDMS, RDCS, RCPT (USA): Fetal heart functional abnormalities Korektor anglojęzyczny: lek. med. Joanna Płużańska, korektor polskojęzyczny: mgr Małgorzata Nesteruk Korektor statystyczny: dr Szymon Brużewicz MBA, Science Pro Adres Redakcji: ul. Rzgowska 281/289, Łódź; tel , echoplodu@fetalecho.pl Opracowanie graficzne i skład: Maciej Małachowski / pepperoni.pl Wydawnictwo: pepperoni publishing studio, Łódź, Piotrkowska 152/3, tel / office@pepperoni.pl Nakład: wersja drukowana 300 ezg. (wersja polskojęzyczna), wersja elektroniczna 960 odbiorców (wersja polskojęzyczna i angielskojęzyczna) Wersja elektroniczna: Maciej Gotlib, sonalutions.com Wersję elektroniczną KARDIO PRENATAL można otrzymywać mailem po zalogowaniu się na stronie 2

3 / September 2014 Witamy SŁOWO OD REDAKTOR NACZELNEJ Prof. dr hab. n. med. Maria Respondek-Liberska Przed nami pogodna, kolorowa jesień, nowy rok akademicki, kolejne spotkania. Wśród nich KARDIOPRENATAL i twinsy. Do poruszenia problemów kardiologicznych u bliźniąt sprowokowały mnie zarówno doniesienia na temat wad serca po IVF, jak i nasze "rodzime" doświadczenia. W wyniku postępu medycyny małżeństwo leczące się z powodu niepłodności uzyskało swoją upragnioną szansę, rozwijała się ciąża bliźniacza. Prenatalna diagnoza kardiologiczna ujawniła złożoną wadę serca u bliźniaka A oraz prawidłowe serce u bliźniaka Dopóki nowe pokolenie B. R o z w ó j położników nie nauczy się obydwu płodów dobrej interpretacji badanń był prawidłowy, kardiologicznych, to będziemy symetryczny, ale w 32 tygodniu ciąży mieć nadal takie ofiary zapis KTG jednego postępu medycyny... z płodów był nieprawidłowy i zapadła decyzja o cięciu cesarskim. Rodzą się wcześniaki, obydwa niewydolne oddechowo. Bliźniak A ma zabieg kardiochirurgiczny w okresie noworodkowym, potem w wieku 3 miesięcy. Umiera w wieku 6 miesięcy, po półrocznym pobycie na OIO-mie. Bliźniak B wychodzi do domu po 93 dniach pobytu w szpitalu, z powikłaniami neurologicznymi. Czy o taki sukces medycyny nam chodziło? A może trzeba było inaczej? Może już pora zapomnieć o starym KTG i monitorować problemy kardiologiczne u takich płodów za pomocą badania echokardiologicznego? Może KTG to już nie jest optymalna metoda do monitorowania chorych płodów z wadami serca? Zwłaszcza w ciąży bliźniaczej? Dopóki nowe pokolenie położników nie nauczy sie dobrej interpretacji badań kardiologicznych to będziemy mieć nadal takie "ofiary" postępu medycyny... Dlatego z zapartym tchem zapoznawałam się z doniesieniami naszych specjalnych gości: prof. B. Arabin jak i prof. I. Blicksteina - potwierdzających moje odczucia. Dla tych z Państwa, którzy zrozumieją ich przesłania, październikowe wykłady mogą się okazać punktem A WORD FROM THE EDITOR-IN-CHIEF Before us a cheerful, colorful autumn, a new academic year, further meetings. Among them CARDIO-PRENATAL and twins. The reason for raising the topic of cardiac problems in twins were both reports of heart defects following IVF as well as a personal experience. As the result of advancements in medicine a couple being treated for infertility received their long awaited chance, twin pregnancy was developing. Prenatal diagnosis revealed a complex heart defect in twin A and normal heart anatomy in twin B. The development of both fetuses was normal, symmetrical but at 32 weeks of gestation the recording on the fetal CTG (cardiotocography) monitor of one of the fetuses was invalid and the decision to deliver by cesarean section was made. They are born premature, with respiratory distress... Twin A undergoes heart surgery in the neonatal period, then again at the age of 3 months. He dies at the age of six months after a six-month stay in the ICU. Twin B goes home after 93 days with neurological complications. Is this the kind of medical success we hope to achieve? Maybe things could have been done differently? Perhaps it s time to forget Until the new generation of about the old obstetricians masters the proper CTG and monitor interpretation of cardiac cardiac problems studies we will continue to in such fetuses by echocardiography? have similar victims of Maybe CTG is medical advancements... no longer the optimal method for monitoring fetuses with heart defects? Especially in a twin pregnancy? Until the new generation of obstetricians masters the proper interpretation of cardiac examinations we will continue to have similar victims of medical advancements... Therefore, with bated breath I acquainted myself with the reports of our special guests: prof. B. Arabin and prof. I. Blickstein - confirming my feelings. For those of you who understand their message, the October lectures may prove to be a turning point in OKŁADKA: RADOŚĆ. Z dumą zawiadamiamy, że autor zdjęcia, dr hab. Maciej Słodki został nagrodzony wyróżnieniem podczas Międzynarodowego Salonu Fotografii Artystycznej Lekarzy PhotoArtMedica 2014! 3

4 KARDIO PRENATAL, 2014, 3 (14) zwrotnym w pracy. Także nasi polscy wykładowcy dowodzą, iż bez problemu nawiązujemy kontakt ze światową czołówką. Po pięknym lecie, kolorowej jesieni, po dobrej strawie duchowej wrócimy do codziennej pracy bogatsi o nowe wiadomości istotne dla naszych pacjentów. A ja Państwu życzę żebyście mogli się realizować podobnie jak ja. W wygodnych klimatyzowanych gabinetach, z dobrym sprzętem, z dobrym personelem, a wśród "prostych" pacjentów umieli znajdować perły i diamenty do szlifowania i cieszyli się z efektów swojej diagnozy nie tylko w 1 dobie po porodzie, ale także dużo, dużo później... Życzę dobrej lektury zarówno angielskojęzycznej części naukowej naszego kwartalnika (ta część w wersji polskiej na - jak i polskiej części informacyjnej. Z poważaniem Maria Respondek-Liberska, Redaktor Naczelna your work. Also, our Polish lecturers prove that we easily make contact with the best in the world. After a beautiful summer, colorful autumn, after good spiritual nourishment we will return to everyday work enriched with new information relevant to our patients. I wish everyone the luck to realize themselves like I am able to. In comfortable air-conditioned offices, with good equipment, with a good staff, and among "simple" patients where I wish you to find pearls and diamonds for grinding and enjoy the effects of your diagnosis not only on day 1 after delivery, but also much much later... I wish you good reading both the English research part of our quarterly (this part in Polish on - as well as the Polish part in the information section) Kindest regards Maria Respondek-Liberska, Editor in Chief KARDIOLOGIA PRENATALNA ECHO PŁODU Scientific Board Arabin Birgit (Berlin) obstetrician and fetal cardiologist Cuneo Bettina (Chicago) pediatric cardiologist and fetal cardiologist Gembruch Ulli (Bonn) obstetrician and fetal cardiologist Huhta James C. (Tampa) pediatric cardiologist and fetal cardiologist Katz Michael (New York) pediatrician Rizzo Giuseppe (Rome) obstetrician and fetal cardiologist Reuven Achiron (Izrael) obstetrician and fetal cardiologist Rychik Jack (Philadelphia) pediatric cardiologist and fetal cardiologist Shurland Gurleen (Londyn) pediatric cardiologist and fetal cardiologist Sklansky Mark (Los Angeles) pediatric cardiologist and fetal cardiologist Weiner Stuart (Philadelphia) obstetrician and fetal cardiologist Wood Dennis (Philadelphia) fetal cardiologist and Baka-Ostrowska Małgorzata (Warszawa) chirurg-urolog Banach Maciej (Łódź) kardiolog Dębski Romuald (Warszawa) położnik Gulczyńska Ewa (Łódź) neonatolog Helwich Ewa (Warszawa) neonatolog Jakubowski Wiesław (Warszawa) radiolog Jakubowski Lucjusz (Łódź) genetyk Kaliciński Piotr (Warszawa) chirurg Kornacka Maria (Warszawa) neonatolog Kałużewski Bogdan (Łódź) genetyk Krasomski Grzegorz (Łódź) położnik Limon Janusz (Gdańsk) genetyk Maroszyńska Iwona (Łódź) neonatolog Moll Jadwiga (Łódź) kardiolog dziecięcy Moll Jacek (Łódź) kardiochirurg Oszukowski Przemysław (Łódź) położnik Patkowski Dariusz (Wrocław) chirurg Piaseczna Piotrowska Anna (Łódź) chirurg dziecięcy Pietrzak Zbigniew (Łódź) położnik Preis Krzysztof (Gdańsk) położnik Rudziński Andrzej (Kraków) kardiolog dziecięcy Sikora Jerzy (Katowice) położnik Sieroszewski Piotr (Łódź) położnik Siwińska Aldona (Poznań) kardiolog dziecięcy Sąsiadek Maria (Wrocław) genetyk Sysa Andrzej (Łódź) kardiolog dziecięcy Szaflik Krzysztof (Łódź) położnik i chirurg płodowy Śmigiel Robert (Wrocław) genetyk Wilczyński Jan (Łódź) położnik

5 / September 2014 Review PREVENTION OF PRETERM DELIVERY OF TWINS Authors: prof. Birgit Arabin 1,2 1 Clara Angela Foundation, Witten and Berlin, Germany, 2 Center for Mother and Child University of Marburg, Germany KARDIO PRENATAL, 2014, 3 (14), 5-12 DOI /09141 Abstract The incidence of twin gestation has increased over the past decades and contributes to an increased rate of spontaneous preterm birth and increased mortality and morbidity up to adult age. Prevention of spontaneous preterm birth in twin pregnancies differs from interventions in singleton pregnancies. Up to now, many treatment modalities have been investigated such as bed rest, tocolytics, antibiotics, cerclage or progestagens, but have failed to prevent prematurity rates in twin gestations or were even combined with harmful effects. Cervical pessaries might be a non-invasive cost-effective option, but it is mandatory to evaluate vaginal progesterone and cervical pessaries in twin gestations with a short cervix in further randomized trials. Key words: twin pregnancy, prevention of sponatenous preterm birth, cervical assessment The high rate of perinatal mortality and morbidity associated with twin pregnancy is mainly due to prematurity. Multiple gestations account for 2 3% of all pregnancies but constitute at least 10% of cases of preterm delivery.many strategies have been suggested but up till present, failed to prevent spontaneous preterm birth (SPB) in a population-based approach. PATHOPHYSIOLOGY Precocious cervical ripening is characterized by collagenolytic activity, a decrease of total collagen content and an influx of inflammatory cells with increasing levels of cytokines and prostaglandins 1. Premature cervical ripening with a loss of cervical integrity may be the result of a congenital disposition of the connective tissue, traumatic damage, uterine overdistension, vascular lesions in the placenta inducing membrane destabilization and local or ascending intrauterine infections 2. Cervical shortening and opening of the internal os may facilitate the ascension of microorganisms, injuries to the decidua-chorioamnion interface and of membrane activation and amnionitis. Sonographic findings of the cervix were compared with placental lesions and demonstrated a greater frequency of acute inflammatory lesions in patients in whom cervical shortening developed during the second trimester also in twin gestations 3. However, compared to singleton pregnancy microbial invasion of the amniotic cavity in twin gestations presenting with SPB is rare and only found in 11.9% of pregnancies with symptoms of SP B 4 suggesting that intra-amniotic infection is not responsible for the excessive rate of SPB in twin pregnancies. Uterine overdistension and pressure to the cervix may be leading pathogenetic factors in twin gestations. CERVICAL ASSESSMENT Early diagnosis of twin pregnancy and the membrane status by ultrasound is mandatory for appropriate planning of antenatal visits and for providing information to the parents. Digital examination was performed in twin gestations at weekly intervals in 86 twin gestations. Intervals to delivery decreased significantly with lower a short and/ or dilated cervix 5. Transvaginal sonography (TVS) can visualize more objectively the internal os and cervical shortening allowing the comparison of successive examinations by different examiners and during the course of pregnancy. The twodimensional transvaginal approach with probes of Mhz is regarded as the most feasible imaging modality for routine detection or exclusion of patients at risk for SPB. Corresponding author: Prof. Birgit Arabin, Centre for Mother and Child of the Philipps University Marburg, Baldingerstr Marburg - Germany Mail: bine.clara.angela@gmail.com, Tel. (portable): , Fax: Disclosure The author has a direct ownership interest in the company that designed, produces and now distributes the Arabin pessary. The company is privately held and the profit is used to support the Clara Angela Foundation. Data wpłynięcia artykułu: ; data zaakceprowania artykułu:

6 KARDIO PRENATAL, 2014, 3 (14) Before TVS, women are asked to empty their bladders. The closed endocervical canal should be visualized. The ratio of a curved/ straight cervix decreases with decreasing length, and, therefore, the disparity does not have essential implications. After serial measurements, the shortest result should be considered. Cervical length (CL), funneling width (Y, V or U-shaped) and length, the area of the internal opening, the position of the cervix and the thickness of the endocervical mucus all can be determined. Most examiners perform their examinations with the women in a supine position. In a pilot study of twin pregnancies we demonstrated that the closed cervix may shorten in the upright position due to an increasing opening of the internal os. 6 These changes significantly reflect a risk for SPB 7. The shorter the CL 8 in a recumbent position, the greater is the difference between recumbent and upright position. The findings clarify the risk of postural stress and may be useful for maternal lifestyle changes. In early pregnancy, the cervical glands can be identified by high resolution sonography 9. The endocervical canal is bordered by mucosa, which is of decreased but occasionally of increased echogenicity. Between 11 and 13 weeks, Greco et al. measured the linear distance of the glandular area of the endocervical canal and the isthmus separately but only in singleton pregnancies. 10 No investigations have been performed as early in twin gestations. There are still discrepant views how to measure the CL. Opposite to the group of Nicolaides most investigators use the standard technique described by Iams et al. 11 Vayssiere et al. used this technique in twin gestations 12, according to his opinion the inter-operator variance is less compared to the technique of the Fetal Medicine Foundation. Normal values measuring the CL from external to internal os demonstrate higher CL values compared to measurements obtained from the glandular area alone. We collected data of the CL and funneling width for normal singleton, twin and triplet pregnancies in the supine and upright positions using the standard technique. 7 The CL decreases significantly from 15 weeks to term in both positions (p<0.001) and values between both positions are significantly different from 20 weeks onwards (p<0.001). In normal twin pregnancies, a width of the internal os of >5mm was observed in an upright position at >30 gestational weeks and funneling between the positions was significantly different from 25 weeks onwards (p = 0.005). These observations suggest a correlation with epidemiological data demonstrating that workload and physical activity have an adverse effect on the cervix. 13. Reference values should be integrated in daily practice. We recommend a reduction of physical stress and work load or even a pessary in multiple gestation when values are outside of the 50% -box, e.g. below the 25 th centile for CL (see below). Few others describe dynamic cervical changes with advancing twin gestation 14. The normal CL values of this study are comparable with our data where the mean values of CL decrease from 44 to 30 mm between 18 and 36 weeks. In the study of Bergelin and Valentin the values of CL decreased from 41mm to 31 mm between 24 and 32 gestational weeks 14. The same authors describe a higher shortening rate in women delivering preterm. In agreement with our results, three studies found that the cervix widened with advancing gestation 14, 15, a finding which had not yet been confirmed by other authors. Three-dimensional multiplanar sonography of the cervix has been proposed to improve our understanding of cervical morphology 16. PREDICTION OF SPB Variations exist with respect to gestational age at testing, definition of abnormality thresholds and of the outcome reference in twin pregnancies Published studies were stratified according to singleton or twin pregnancy, gestational age at testing, CL and funneling width thresholds or reference standards to produce summary estimates of likelihood ratios 34. The given thresholds to predict SPB vary, even if symptomatic and asymptomatic patients are analyzed separately, Both CL measurement and funneling, whether alone or in combination, appeared to be useful in predicting SPB in twin pregnancies, whereas CL appeared to be the predictor of choice at 27 weeks of gestation, at 22 weeks the diagnostic values of both parameters were comparable 12. In our longitudinal data set of twin pregnancies, we observed that CL < 25 mm and funneling width > 10mm between 20 and 28 weeks in both positions predict a risk of SPB. In a study of asymptomatic twin pregnancies, a CL of < 2.0 cm measured between 15 and 28 weeks gestation appeared to be a reasonable parameter at predicting SPB in twin gestations 26. The high specificities indicate that CL is better at predicting the absence than the presence of threatening SPB 26. Both a CL < 30 mm and cervical funneling in twin pregnancies under 26 weeks gestation are independently associated with a risk for SPB 26. Because a long cervix, of > 35 mm, is associated with very low risk (4%) for preterm birth, pregnant women can be reassured 25. After 30 weeks, CL was shown to be not predictive of SPB 29. A simple equation using the CL (in mm) divided by 3 can predict mid gestation scan-todelivery interval in twin gestation 33. The most recent systematic review and meta-analysis showed that among asymptomatic women with twin pregnancies, a CL < 20 mm at weeks of gestation had pooled positive and negative likelihood ratios of 10.1 and 0.64, and 9.0 and 0.64, respectively, to predict preterm birth at <32 and <34 weeks of gestation, respectively. 35 In symptomatic twin pregnancies TVS can identify impending SPB before advanced cervical dilatation and may therefore help to indicate maternal in-utero transfer. The high specificities underline that current use of CL and fetal fibronectin are of importance in situations where negative results can avoid unnecessary interventions 36. However, also in the most comprehensive systematic 6

7 / September 2014 review of TVS in twin gestations, the predictive accuracy of CL for SPB was low in symptomatic women 35. As reported by the first study of the National Institute of Child Health and Human Development -Maternal-Fetal Medicine Network Preterm Prediction Study dealing with twin pregnancies, most widely known risk factors for SPB were not significantly associated with SPB of twins. At 24 weeks, a CL < 25 mm was the best predictor of SPB. Of all other risk factors evaluated at 28 weeks, fetal fibronectin was the only statistically significant predictor of SPB 17. Interventions and expectant management Although studies have demonstrated that TVS of CL is predictive of SPB in women with twin pregnancies, it is unclear if antenatal management can prevent preterm birth. 125 women with twin pregnancies were randomly assigned to undergo a TVS measurement of the CL and a cervical digital examination every 4 weeks from t weeks until 28 weeks or to a digital cervical examination alone at the same intervals. Women who underwent TVS were treated with a predetermined algorithm for cerclage and bed rest. Treatment decisions in the control group were not based upon a predetermined algorithm. There was no significant difference between groups in mean length of gestation, but life table analysis revealed that SPB < 35 weeks in the TVS group was significantly reduced (P<.02). 37 Otherwise, neither bed rest, oral betamimetics, cervical cerclage nor progesterone have been successful to reduce SPB in twin gestations. Most of these procedures lack any evidence at all whether they contribute to improved outcome but may even add unnecessary costs and risks for both mother and fetus. The lack of well-designed randomized controlled trials (RCT s) for twin pregnancies has led to a policy where management decisions are based on indirect conclusions from RCT s from singleton pregnancies, although results could be different. Cervical assessment and the described thresholds is therefore an essential tool to exclude patients from unnecessary and possibly even harmful therapies. A recent review summarizes all treatment modalities to prevent SPT in twin gestations. 38 Routine hospitalization and bed rest Hospitalization was a stressful experience for twin mothers and their families, as well as costly for the health care system 39. No observational study describes cervical changes during hospitalization. The results from RCT s suggest that bed rest may even increase the rate of SPB in uncomplicated twin pregnancies and that hospitalization did not reduce the rate of SPB nor any outcome parameter in twin pregnancies with cervical effacement and dilatation 39. Nevertheless, based on studies of Papiernik 13, a reduction of physical stress for women with multiple pregnancies in an outpatient setting is recommendable. Tocolytic treatment Tocolytics have not been shown to improve perinatal and neonatal outcomes. Moreover, they cause adverse effects on women in preterm labor 40. Premature labor occurs frequently in twin gestations, but no RCT s have been designed for twin pregnancies. Intravenous magnesium sulfate and ß-mimetics have been commonly prescribed and have been compared in twin versus singleton pregnancies. For magnesium sulphate, frequencies of side effects, durations of therapy, the number of days until delivery and delays in delivery during the first 72 hours were the same, and the therapy was deemed equally safe in both groups 39. However, when ß-mimetics were used, multiple pregnancies were associated with a marked increase in the duration of therapy, incidence of delivery before 37 weeks, and of the incidence of maternal cardiovascular complications. There was no effect on the neonatal outcome 41. A further study confirmed that pulmonary capillary pressure, cardiac index and the ratio of preejection period to left ventricular ejection time significantly increased during the infusion period with ß-mimetics in twin gestations 42. Oxytocin antagonists and calcium channel blockers have been used, but no data in twin gestations are available. Corticosteroids Antenatal treatment with corticosteroids is indicated for pregnant women at risk for SPB delivering more than 24 hours and less than 7 days after start of treatment, as it results in a substantial decrease of neonatal mortality and morbidity, as well as in savings of health care costs 43. The use of repeated doses in women whose risk of SPB persists for more than a week may reduce the incidence of respiratory distress syndrome but may cause harmful effects on mother and fetus 43. Antenatal corticosteroid therapy appears to be less beneficial in multiple compared to singleton pregnancies possibly due to the shorter halflife of betamethasone in mothers with twin pregnancies 44. A study with the largest series of retrospectively evaluated nonrandomized antenatal glucocorticoid responses in twins concluded that corticosteroids have no beneficial effect on the risk of respiratory distress syndrome in preterm twin babies, but exposed a large number of infants to unnecessary treatment that might adversely affects growth 45. The Cochrane database states that studies show no benefit of antenatal standard doses of glucocorticoids in twin pregnancies 43, possibly because the causes of SPB in singletons differ from twins. As the risks and benefits of repetitive application are still controversial in singleton pregnancies, multiple doses should not be encouraged in twin pregnancies in the absence of well-designed RCT s. 7

8 KARDIO PRENATAL, 2014, 3 (14) ANTIBIOTICS Antibiotics are recommended during pregnancy for the prevention of SPB in patients with recurrent symptomatic bacterial vaginosis and a history of SPB 46, as they reduce the incidence of pyelonephritis during pregnancy and possibly of SPB 47. There is no proven evidence that antibiotics improve the outcome in pregnancies with intact membranes and threatening SPB, but there is concern about increased neonatal morbidity 48. Although no specific studies exist for twin pregnancies, it seems probable that the results from singleton pregnancies also hold true for twins. Antibiotic administration following PROM is associated with a delay of preterm birth and with an improvement of the major indicators of neonatal outcome 49. In a study considering twin pregnancies after PROM it was shown that the latency period was significantly shorter in twins, and more twins were born within 48 hours compared to singletons 50. The role of cervical assessment in pregnancies with PROM has only been evaluated in singleton pregnancies 51. The results of the ORACLE trial stress the importance of carrying out long-term follow up of infants after interventions aimed at prolonging gestational age at delivery and reducing short-term risks of infection. Pathological processes associated with increased risk of preterm delivery, such as infection, may affect infant outcome, and may potentially even increase risk of neonatal complications in relation to pregnancy prolonging treatments 52. CERCLAGE Soon after the introduction of a cervical cerclage by Mc Donald and Shirodkar, or anatomic cervical incompetence, prophylactic cerclages in twin pregnancies were embraced with enthusiasm but questionable indications. In a prospectively conducted randomized trial of the Royal College of Obstetricians and Gynaecologists, no significant differences in perinatal or neonatal mortality were found in spite of a reduced rate of SPB <33 weeks in the study compared to the control group 53. Moreover, the risk of long hospital stay, further interventions and maternal complications was increased in the study group. After the introduction of TVS it could be visualized that the internal os can weaken and the membranes descend to the level of the suture. These findings were associated with earlier preterm delivery in the study group of 44 singleton, 6 twin and 3 triplet gestations who had undergone cervical cerclage, and all births occurred before 28 weeks 54. Currently, results from studies in women with twin gestations who may benefit from a cerclage based on TVS results are rare. In one observational study, cases with multiple pregnancy and prophylactic cerclage were compared to cases with a cerclage based on TVS findings 55, the duration of pregnancy did not differ between both groups. In patients without prophylactic cerclage, the frequency of preterm contractions was lower. However, the frequency of PROM was higher, and it was concluded that prophylactic cerclage did not improve the outcome of twin pregnancies. In a more recent prospective (nonrandomized) cohort study of 147 twin pregnancies who underwent TVS measurement between 18 and 26 weeks gestation, cerclage was offered to 21 women with a CL < or = 25 mm. The results were compared to the data of 13 twin pregnancies with the same TVS results who received no cerclage 56. Decreasing CL was significantly associated with a shorter length of gestation, delivery at < 34 weeks and PROM, however, none of these outcomes was altered by cerclage placement. Only one pilot study using historic controls compared cervical cerclage in patients with twin-to-twin perfusion syndrome when CL was < 15 mm and found that cerclage might reduce SPB. 57 In a meta-analysis of four RCTs Berghella et al. found a significant increase in SPB at less than 35 weeks in twin gestations (RR 2.15, 95% CI ). 58 This is why it is nowadays not any longer recommended to perform a cerclage in twin gestations. In exceptional patients with a history of trachelctomy abdominal cerclage might be an option even in twin pregnancies to prevent pregnancy loss or early SPB 59. Cervical (Arabin) pessary Vaginal pessaries have been used in pregnant women to direct the cervix posteriorly. It is postulated that they might prevent further opening of the internal os or even premature rupture of membranes. Compared with operative cerclage, pessaries have the advantage of being cost-effective and operator-independent. In 2003 we published a matched control analysis of 46 pairs with twin pregnancies. 60. All had a short cervix of < the 10 th centile before 28 weeks; 23 pregnant women were treated with vaginal pessaries, and 23 had expectant management. The interval from treatment to delivery was 85 (43-129) days in the treatment and 67 (21-100) days in the control group (p=0.001), gestational age at delivery was 35+6 and 33+2 respectively (p=0.02). Within the pessary group, there were 8/23 cases with SPB <36 weeks but none with SPB <32 weeks, compared to 12/23 cases with SPB <36 weeks and 7/23 with SPB <32 weeks in the control group (p<0.001). Another pilot study in monochorionic twin pregnancies with twin-totwin transfusion syndrome and laser coagulation where patients with a pessary were compared to historic controls without pessary both with a CL< 25 mm found a significant reduction of SPB by 4 weeks in the treatment group. 61 The so-called Pro-Twin trial was a multicentre, openlabel randomised controlled trial in 40 hospitals in the Netherlands, whereby women with a multiple pregnancy between 12 and 20 weeks gestation were randomly assigned (1:1) to pessary or control groups using a webbased application with random block sizes stratified by hospital. 813 women underwent randomisation, of whom 808 were analysed (401 in the pessary group; 407 in the control group). At least one child of 53 women (13%) in the pessary group had poor perinatal outcome, compared 8

9 / September 2014 with 55 (14%) in the control group (relative risk 0 98, 95% CI ). However, in the prespecified subgroup of women with a CL<25th percentile (38 mm), the pessary group (n=78) had a lower adverse neonatal outcome rate as compared the non-intervention group (n=65) (10% vs 25%, RR 0.41; ). This was accompanied by a significantly reduced preterm delivery rate <32 weeks (12% vs 28%,RR 0.43; ), but not <37 weeks (61% vs 75%, RR 0.80; ). 62 Figure 1. Transvaginal sonography in a twin pregnancy demonstrating with a short cervix and funneling at 22 weeks The most recent RCT from Spain compared twin gestations whereby women were randomized with a CL < 25mm to either pessary or expectant management. Patents in the pessary group showed a significant reduction of SPB before 34 weeks (Carreras, personal communication and contribution of the FMF World Congress, Nizza, 2014). Several randomised trials in multiple pregnancies are registered with and will be conducted in France, the Netherlands, the US and England. The history and state of the art related to the treatment with pessaries to prevent SPB was recently summarized 63 and the cervical changes reflected by a MRI study 64. In this study it could be suggested that the angle between cervix and lower uterine segment is changed by the pessary and in some patients funnelling during the course of treatment even disappears. Similarly, we could demonstrate that in some twin pregnancies, funnelling as shown by TVS disappeares during the course of pessary treatment (Figure 1 a and b). Progesterone Figure 2. Transvaginal sonography in a twin pregnancy demonstrating elongation of the cervial length without funneling during the course of pessary treatment ( shadow evoked by the pessary) at 28 gestational weeks Progesterone plays an important role in the prevention of SPB in singleton pregnancies. Natural progesterone is administered vaginally as gel or tablets containing micronised progesterone. The synthetic compound 17-alpha-hydroxyprogesterone caproate (17-OHPC) is administered intramuscularly, has a longer half life and has been shown to be effective in patients with previous SPB. Romero et al. published an individual patient data meta-analysis of cases with vaginal progesterone. 65 This study yielded a nonsignificant relative risk of 0.7 (95% CI 0.3 to 1.4) for SPB before 33 weeks. When evaluating composite neonatal morbidity and mortality, the effect of progesterone was statistically significant (RR 0.5, 95% CI 0.3 to 0.9) in a sub-population of 52 twin pregnancies. These findings should be confirmed in trials aimed at investigating the effect of progesterone in women with twin pregnancies and a short CL. Several placebo-controlled trials have been published examining the effect of progesterone in women with twin pregnancies varying in size from 24 to 675 included twin pregnancies. Some studies have used vaginal progesterone ( mg/ day) and others 17-OHPC ( mg/day) Despite the differences, none of the published trials have shown a significant effect of progesterone in twin pregnancies. One RCT with twin pregnancies using 200 mg or 400 mg progesterone found no advantages of 400 mg over 200 mg. 70 A collaboration between all published and ongoing RCTs including twin pregnant women, has been initiated in the Netherlands. 77 This individual patient data meta-analysis will include data from 13 studies randomising more than 3500 women with twin pregnancies and perform subgroup analyses to compare effects of 9

10 KARDIO PRENATAL, 2014, 3 (14) vaginal progesterone treatment with 17-OHPC treatment. A recent meta-analysis suggested that progesterone may have adverse effects in multiple pregnancies. 78 The risk for perinatal death was 1.6 (95% CI 1.01 to 2.4), and the risk ratio for composite adverse outcome was 1.2 (95% CI 1.03 to 1.4). A safety signal has been proposed for 17-OHCP 79, but not for vaginal progesterone, because a triplet study comparing 17-OHPC with placebo showed significantly increased risk of midtrimester fetal loss (P < 0.02) 80. In addition Caritis et al. observed higher levels of CRP and even of SPB in twin pregnancies. 76 Cervical surveillance in cases with progressive dilatation Cervical assessment has not yet been integrated into the population-based routine surveillance of twin pregnancies. Unfortunately, it is still common practice to wait until clinical symptoms such as uterine contractility, bulging membranes or PROM are unpredictably present although the condition might have been apparent earlier or even been preventable. One of the most frequent indications for in-utero transfer of a multifetal pregnancy to level III facilities is threatened preterm delivery with progressive dilatation when the first symptoms have been missed or unsuccessfully treated. In twin pregnancies with a cervical dilatation of >4 cm we have successfully postponed pregnancy for up to 4 weeks. 81. In these patients, TVS is useful to detect the degree of protrusion ( ballooning ), the position of the first or even both twins, as well as the umbilical cord, and whether there is a dissociation of membranes. In our first 30 patients (20 pregnancies with twin gestations) with progressive dilatation and ballooning < 28 weeks at admission, we could prolong the interval to delivery for two weeks (mean) and a maximum of up to 4 weeks. In those patients longitudinal TVS is a noninvasive procedure used in the surveillance of progression. Delayed interval delivery Delayed interval delivery of twin pregnancies, is the last option to help at least one twin to survive if delivery of the first twin before viability cannot be prevented. TVS is used for cervical assessment before and even more after the delivery of the first twin 82 and helps to predict the success of the procedure. In the twin pregnancy with the longest interval between the delivery of the first and the second twin (106 days), we observed that the umbilical cord of the first twin had completely disappeared above the internal os and that the cervix restored to a length of more than 3 cm. The survival chance of the second twin was approximately 50%. CONCLUSIONS Very few interventions have been shown to be effective in twin gestations to prevent SPB, some might even do more harm than good. Progesterone does not reduce the rate of SPB in twins in general, subgroup analysis might evaluate the impact in twin gestations with a short CL. Tocolytics are not indicated as long-term treatment and a cerclage does not reduce but possibly increases SPB. The cervical pessary is still further evaluated but has shown some benefit in published and non-published trials. Cervical assessment should be incorporated in the routine care of twin pregnancies from 15 weeks onwards to recognize first symptoms of SPB, to reduce physical stress and possibly apply a pessary or take part in further studies. Specially trained staff and twin clinics are desirable. 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12 KARDIO PRENATAL, 2014, 3 (14) 60. Arabin B, Halbesma JR, Vork F, Hubener M, van Eyck J. Is treatment with vaginal pessaries an option in patients with a sonographically detected short cervix? J Perinat Med 2003;31(2): Carreras E, Arevalo S, Bello-Munoz JC, Goya M, Rodo C, Sanchez-Duran MA, et al. Arabin cervical pessary to prevent preterm birth in severe twin-to-twin transfusion syndrome treated by laser surgery. Prenat Diagn 2012;32(12): Liem S, Schuit E, Hegeman M, Bais J, de Boer K, Bloemenkamp K, et al. Cervical pessaries for prevention of preterm birth in women with a multiple pregnancy (ProTWIN): a multicentre, open-label randomised controlled trial. Lancet Arabin B, Alfirevic Z. Cervical pessaries for prevention of spontaneous preterm birth: past, present and future. Ultrasound Obstet Gynecol 2013;42(4): Cannie MM, Dobrescu O, Gucciardo L, Strizek B, Ziane S, Sakkas E, et al. Arabin cervical pessary in women at high risk of preterm birth: a magnetic resonance imaging observational follow-up study. Ultrasound Obstet Gynecol 2013;42(4): Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O Brien JM, Cetingoz E, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 2012;206(2):124 e Schuit E, Stock S, Groenwold RH, Maurel K, Combs CA, Garite T, et al. Progestogens to prevent preterm birth in twin pregnancies: an individual participant data meta-analysis of randomized trials. BMC Pregnancy Childbirth 2012;12: Sotiriadis A, Papatheodorou S, Makrydimas G. Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis. Ultrasound Obstet Gynecol 2012;40(3): O Brien JM. The safety of progesterone and 17-hydroxyprogesterone caproate administration for the prevention of preterm birth: an evidence-based assessment. Am J Perinatol 2012;29(9): Combs CA, Garite T, Maurel K, Das A, Porto M. Failure of 17-hydroxyprogesterone to reduce neonatal morbidity or prolong triplet pregnancy: a double-blind, randomized clinical trial. Am J Obstet Gynecol 2010;203(3):248 e Arabin B, Kuizenga K, van Zoeren D, Eyck JV. Long-term epidural block treatment in patients with early threatening preterm delivery and vaginal fetal engagement. J Perinat Med 2008;36(6): Arabin B, van Eyck J. Delayed-interval delivery in twin and triplet pregnancies: 17 years of experience in 1 perinatal center. Am J Obstet Gynecol 2009;200(2):154 e Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007;357(5): Aboulghar MM, Aboulghar MA, Amin YM, Al-Inany HG, Mansour RT, Serour GI. The use of vaginal natural progesterone for prevention of preterm birth in IVF/ICSI pregnancies. Reprod Biomed Online 2012;25(2): Norman JE, Shennan AH. Prevention of preterm birth--why can t we do any better? Lancet 2013;381(9862): Rode L, Klein K, Nicolaides KH, Krampl-Bettelheim E, Tabor A. Prevention of preterm delivery in twin gestations (PREDICT): a multicenter, randomized, placebo-controlled trial on the effect of vaginal micronized progesterone. Ultrasound Obstet Gynecol 2011;38(3): Serra V, Perales A, Meseguer J, Parrilla JJ, Lara C, Bellver J, et al. Increased doses of vaginal progesterone for the prevention of preterm birth in twin pregnancies: a randomised controlled double-blind multicentre trial. Bjog 2013;120(1): Wood S, Ross S, Tang S, Miller L, Sauve R, Brant R. Vaginal progesterone to prevent preterm birth in multiple pregnancy: a randomized controlled trial. J Perinat Med Briery CM, Veillon EW, Klauser CK, Martin RW, Chauhan SP, Magann EF, et al. Progesterone does not prevent preterm births in women with twins. Southern medical journal 2009;102(9): Combs CA, Garite T, Maurel K, Das A, Porto M. 17-hydroxyprogesterone caproate for twin pregnancy: a double-blind, randomized clinical trial. Am J Obstet Gynecol 2011;204(3):221 e Lim AC, Schuit E, Bloemenkamp K, Bernardus RE, Duvekot JJ, Erwich JJ, et al. 17alpha-hydroxyprogesterone caproate for the prevention of adverse neonatal outcome in multiple pregnancies: a randomized controlled trial. Obstet Gynecol 2011;118(3): Rouse DJ, Caritis SN, Peaceman AM, Sciscione A, Thom EA, Spong CY, et al. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med 2007;357(5): Caritis SN, Simhan HN, Zhao Y, Rouse DJ, Peaceman AM, Sciscione A, et al. Relationship between 17-hydroxyprogesterone caproate concentrations and gestational age at delivery in twin gestation. Am J Obstet Gynecol 2012;207(5):396 e1-8. Conflict of interest Authors do not report any financial or personal links with other persons or organizations, which might affect negatively the content of this publication and/or claim authorship rights to this publication 12

13 / September 2014 Original report DORV IN FETUSES: HOW TO CONSULT FUTURE PARENTS AT A PRENATAL CARDIOLOGY CENTER? RETROSPECTIVE ANALYSIS OF 39 CASES Authors: Małgorzata Soroka 1, Maciej Słodki 2,3, Hanna Moczulska 2,4, Maria Respondek-Liberska 2,5 1 Oddział Ginekologii i Położnictwa - Szpital Św. Trójcy w Płocku, 2 Zakład Kardiologii Prenatalnej Instytut Centrum Zdrowia Matki Polki w Łodzi, 3 Instytut Nauk o Zdrowiu PWSZ w Płocku, 4 Zakład Genetyki, Instytut Centrum Zdrowia Matki Polki w Łodzi, 5 Zakład Diagnostyki i Profilaktyki Wad Wrodzonych Uniwersytetu Medycznego w Łodzi Abstract KARDIO PRENATAL, 2014, 3 (14), DOI /09142 DORV [double outlet right ventricle] is defined as a defect in which the great vessels leave entirely or mostly from above the morphologically right ventricle. The proposed by us new prenatal classification of heart defects for the DORV defect including the division into isolated and coexisting with extracardiac defect, facilitates consultation and predicting prognosis for the fetus and newborn. Isolated DORV in fetuses is classified as a severe elective defect (expected cardiac intervention or surgery at 1 month of age) with a relatively good prognosis for newborns, regardless of the type of intracardiac anomalies (in our series of cases 100% survival). DORV in the fetus with coexisting extracardiac defects (ECM) regardless of type of anomaly had poor prognosis (in our study group 100% demise rate). Key words: congenital heart defect, CHD double outlet right ventricle, DORV, fetal echocardiography prenatal diagnosis BACKGROUND DORV [double outlet right ventricle] is defined as a defect in which the great vessels leave entirely or mostly from above the morphologically right ventricle. [1,2,3] Anatomical classification of the defect by Van Praagh [4] or Lev [5] used in pediatric cardiology is of little clinical utility for the youngest patients (fetuses) in the prenatal period. Aim: Which data is essential for proper consultation of prospective parents and perinatologists in relation to the fetus with DORV? MATERIALS AND METHODS This was retrospective analysis of the data from a single institution: the medical documentation of 39 gravidas and their fetuses with a diagnosis of DORV, among 632 patients with fetal heart defects from the Prenatal Cardiology Department of the Institute of Polish Mother s Memorial Hospital, in the years The study group of 39 patients was divided into two groups: Isolated heart defect (n = 19) DORV ; Heart defect coexisting with extracardiac congenital malformation ECM (n = 20) DORV + ECM. We retrospectively analyzed echocardiographic and digital documentation of registered examinations. The following data was analyzed and compared between groups: the reason for referral for echocardiography, gestational age at which the fetal abnormalities were detected, heart size, the presence of problems such as non-cardiac structural defects, the presence of extracardiac anomalies: dysmorphy (no nasal bone, hypoteloryzm, abnormal profile), amniotic fluid index, fetal size based on biometrics in relation to gestational age according to the LMP, sex of the fetus, fetal karyotype, day in which cardiac surgery was performed, demises. Examinations were performed using the ATL HDI 5000 ultrasound and Voluson 730 Expert Pro equipped with ultrasound probe heads of 5MHz frequency, 7.5 MHz and 9MHz. Digital recordings of examinations were collected in the MedArchive and 4Dview. The selection of studies were derived from the Department database. Statistical comparison was performed using the chi-square test of independence and Fisher s exact test, assuming the significance level of P <0.05. Indications Isolated DORV n=19 DORV + ECM n=20 Cardiac Extracardiac 0 2 P 0,49 Table 1. The reason for referral for investigation to the reference center, in the subgroup of fetuses with isolated double outlet right ventricle [DORV isolated] and fetuses with associated additional non-cardiac defect [DORV + ECM]. Kontakt: dr hab. n. med. Maciej Słodki, Instytut Nauk o Zdrowiu PWSZ, Pl. Dąbrowskiego 2; Płock, tel. (24) , mail: maciejslodki@op.pl Data wpłynięcia artykułu: ; data zaakceprowania artykułu:

14 KARDIO PRENATAL, 2014, 3 (14) DORV REMAINING CHD Predominantly the indication to perform echocardiography in the referral center was suspected heart defects in the obstetric screening ultrasound: 19/19 cases in the DORV subgroup and 18/20 in DORV + ECM subgroup. In two cases, no heart defect was noted upon screening: in one case with extreme oligohydramnios in the other oligohydramnios and hiperechogenic bowel. Figure 1. Percentage distribution of occurrence double outlet right ventricle [DORV] n = 39 in the group of all congenital heart disease [CHD] n = 632, in the material of the Department of Prenatal Cardiology ICZMP in the years Figure 2. Analysis of labeled (n = 14) fetal karyotype in each group: DORV (n = 6) and DORV + ECM (n = 8). NUMBER OF FETUSES BIRTH WEIGHT Figure. 3. Birth weight of newborns with DORV and DORV+ECM. RESULTS: Number of selected fetuses with DORV [39/632] accounted for 6% of all CHD examined in (Figure 1) in the Department of Prenatal Cardiology at the Institute of Polish Mother s Memorial Hospital. Summary of comparative data are presented in Table 1. There were no significant statistical differences between the two subgroups in regard to: mean age of gravida, mean age of the fetus at the time of diagnosis and during diagnostic testing at the referral center, the gender of the fetus (Table 2) and in the evaluation of the karyotype (Figure 2). There were no differences between DORV and DORV + ECM in the frequency of co-occurrence of additional intracardiac anomalies such as septal defect [VSD], transposition of the great arteries [TGA], pulmonary stenosis [PS], mitral atresia, common atrioventricular canal [AV canal ], coarctation of the aorta [CoA], hypoplasia of the aortic arch [HAA], hypoplasia of the left ventricle, the total anomalous pulmonary venous return [TAPVR], partial anomalous pulmonary venous return [PAPVR], patent left superior vena cava [bilateral SVC]. There were also no significant statistical differences of functional anomalies (cardiomegaly, tricuspid regurgitation) between subgroups ( Chart 1). Intrauterine growth restriction occurred in most parts [14/16] in fetuses with DORV + ECM (p=0,01) (Table 2). Regarding the follow-up of fetuses and neonates, no significant statistical differences in the mean duration of pregnancy, the percentage of vaginal deliveries or Apgar score were noted. The majority of the 16/19 neonates from the DORV subgroup had a birth weight> 3000 g, and delivery in 18/19 cases took place> 37 weeks of gestation. In the DORV + ECM subgroup birth weight> 3000g occurred only 1 x ( Figure 3). All 16 neonates in the isolated DORV subgroup required cardiac surgery in the first month of life on average day 16 ( Chart 2 ). In the DORV + ECM subgroup cardiac surgery was performed in only one case in a neonate with coexisting cleft upper lip and palate. Demise of the child occurred on day 100 of postnatal life. The prognosis of fetuses with DORV is shown in Figure 4. In the subgroup with isolated DORV (n=16/19) and known follow-up, survival was noted in 100%. In DORV 14

15 / September 2014 Demography Karyotype Congenital Heart Defect Functional changes Extracardiac anomalies Dismorphia Extracardiac defects DORV, DORV+ECM, n=19 n=20 p Mean 29,9 27,9 Mother's age Mediana Min Max Gestational age at which the fetal Mediana 22,5 23 Min abnormalities were detected Max. 33,1 34 Mean 29,2 28,2 Gestational age at diagnostic testing at Mediana 31 28,05 the referral center Min. 18,6 20,2 Max. 36,4 38,1 Sex Male ,4 Female ,55 Correct Microdeletion 22q Incorrect Trisomy Trisomy Deletion of chromosome Ventricular Septal Defect Transposition of the Great Arteries ,46 Pulmonary stenosis Mitral atresia 0 1 Atrioventricular canal defect 1 3 0,61 Coarctation of the aorta Hypoplastic aortic arch 3 0 Hypoplastic left heart syndrome Total anomalous pulmonary venous return 1 0 Partial anomalous pulmonary venous return 0 1 Persistent left superior vena cava 0 1 Cardiomegaly 2 9 0,09 Tricuspid insufficiency 3 5 0,7 Hyperechogenic bowel 2 4 0,66 Hydronephrosis 1 7 0,11 Single umbilical artery 1 5 0,2 Cyst of umbilical cord 0 1 Oligohydramnios 2 5 0,42 Incorrect volume of amniotic fluid Anhydramnios 0 3 Polyhydramnios 2 6 0,26 Summary ,01 Intrauterine Growth Restriction ,01 Hypotelorism 0 4 Micrognathia 0 1 Low set ears 0 1 Hypoplastic nasal bone 0 1 Abnormal profil 0 2 Summary 0 9 Hypoplastic chest 0 5 Club foot 0 2 Defects of the skeletal system Foot heel 0 1 Polydactyly 0 1 Absence of femur 0 2 Unspecified defect in hands and feet 0 3 Dandy-Walker syndrome 0 7 Defects of central nervous system Hydrocephalus 0 4 Agenesis of the corpus callosum 0 2 Holoprosencephaly 0 1 Multicystic dysplastic kidney 0 6 Defects of urinary system Renal agenesis 0 3 Agenesis of bladder 0 2 Megacystis 0 1 Craniofacial defects Cleft lip and palate 0 3 Abdominal wall defects Omphalocele 0 2 Defects of the spine Spina bifida 0 2 Other Spina bifida 0 4 Situs inversus 0 2 Summary 0 53 Mean 38,5 34 Week of gestation at the time of Mediana delivery Min Max Vaginal delivery ,43 Newborns with birth weight above 3000 g ,001 Number of points in the Apgar scale in the first minute of life Mean 8,6 3 Mediana 9 1 Min. 5 0 Max Cardiac surgery in first month of life ,001 Demise , ECM subgroup follow-up of fetuses was known in 16/20 cases, all of which proved fatal ( Figure 4 ). The most of them died in the first week of age (n=10), at the latest death in this group was noted in 104 days of life. DISCUSSION The incidence of the double outlet right ventricle according to various sources is 1-3% of all detected congenital heart malformations, which is an average of 1: live births. [7,8,9,15,16] According to the National Registry for Fetal Heart Pathologies in the occurrence of DORV was 4.69% ( The formation of defects in the outflow tract is associated with impaired rotation of the primary outflow tract and its abnormal division, which conveys the wrong formation of the aorta and pulmonary trunk, and the relationship of the great arteries. [8,10,12,13,17,18,19,20,21,22] In the literature we found several patterns of classification of DORV, where the common denominator is the departure of large vessels from the right ventricle. So far, DORV has been classified depending on the relationship of the great arteries and VSD. [8,11,14,23,24,25,26,27] The existing structural divisions of heart defects, including DORV, are relevant to the strategic planning for the child, but they are scarcely useful before birth, especially in mid-pregnancy, or even before, when the prospective parents and team of perinatologists would like to establish not merely the diagnosis for the patient but also prognosis. For this purpose, in our center we have developed a prenatal division of heart defects such as DORV into two groups depending on whether it is an isolated defect or concomitant with extracardiac defects. [6] Comparing the frequency of coexisting additional intracardiac anomalies in the two subgroups DORV and DORV + ECM statistically Table 2. Comparison of the tested subgroups (DORV n = 19 and DORV + ECM = 20), in the material of the Department of Prenatal Cardiology ICZMP in the years

16 KARDIO PRENATAL, 2014, 3 (14) this subgroup in term newborns (birth> 37 tyg.ciąży) only in 1 case out of 20, birth weight was> 3000 g. Figure 4. The number of cases in the analyzed material by reference to ending of pregnancy in the group with DORV (n = 16) and in the group with DORV and ECM (n=20) in the material of the Department of Prenatal Cardiology ICZMP through period. *including : intrauterine death (n = 2), termination of pregnancy (n = 3) death after delivery (n = 11) significant differences were detected. These anomalies regarded the coexistence of VSD [89,7%], TGA [76,9%] and pulmonary stenosis [30,7%]. The most frequent concomitant extracardiac defects regarded the musculo-skeletal system [41%], central nervous system [35,7%] and urinary tract [30,7%]. In previous publications attention was drawn only to the type of accompanying defects and their prevalence. [19,28,30,31,32,33,34] As resulted from our observation the type of extracardiac defects in fetuses with DORV had no effect on the survival of the newborn (in DORV + ECM subgroup 100% mortality in our series). Presumably, the very coexistence of extracardiac defects together with a heart malformation in the form of DORV is associated with severe prognosis not only for the fetus but the neonate as well. The neonate theoretically requiring two independent operations: cardiac and surgical, has very little chance of survival. Another factor, whose role has not been evaluated in the available literature is the volume of amniotic fluid. A significant number [46%] of cases among our study subgroup ( fetuses with DORV and abnormal amniotic fluid volume) had extracardiac anomalies, such as two-vessel umbilical cord, pyelectasis, umbilical cord cyst. Both polyhydramnios [75%], oligohydramnios [71%] and anhydramnios [100%] accompanied mainly fetuses with DORV and ECM ( Table 2). According to the prenatal classification of heart defects used in our center, DORV is regarded as a severe elective defect, i.e. meaning the necessity for cardiac surgery intervention in the first month of life. In the subgroup with isolated DORV 66.6% of interventions took place in the first two weeks of life, and 100% in the first month of life. The presence of extracardiac malformations was the only factor significantly influencing the prognosis of the newborn. Neonatal survival was not affected by the type of coexisting VSD, nor was it affected by the way the vessels departed, or even the type of coexisting extracardiac malformation. In contrast, the very fact of its co-occurrence was significant. DORV + ECM subgroup comprised 100% mortality. The proposed prenatal classification of heart defects for the DORV defect including the division into isolated and coexisting with extracardiac defect, facilitates consultation and predicting prognosis for the fetus and newborn. The limitation of this work may be present small study group fetuses (n = 39), a small amount of labeled karyotypes (n = 14) and no long-term follow-up. CONCLUSIONS 1.Isolated DORV classified as a severe elective defect (expected cardiac intervention during the first month of postnatal life) had a relatively good prognosis for newborns, irrespective of the type of intracardiac anomalies (in our series of cases 100% survival). 2. DORV in the fetus with coexisting extracardiac defects (ECM) irrespective of type of anomaly had poor prognosis (in our study group 100% demise rate). The neonates birth weight differed significantly (p=0,001) between DORV and DORV + ECM subgroups. In part this was due to a statistically significant higher prevalence of IUGR (p=0,01) in the subgroup of fetuses with DORV + ECM. In Chart 1. Coexisted cardiac anomalies with DORV and DORV+ECM in fetuses. Detailed description in the text. VSD- ventricular septal defect, TGA- transposition of the great arteries, PS- pulmonary stenosis, AV-canal- atrioventricular canal defect, TAPVR- total anomalous pulmonary venous return, PAPVR -partial anomalous pulmonary venous return, BILATERAL SVC- persistent left superior vena cava. 16

17 / September Goldmuntz E, Bamford R, Karkera JD, dela Cruz J, Roessler E, Muenke M: CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle; Am J Hum Genet;2002;70: Ferencz C, Rubin JD, McCarter RJ, Clark EB: Maternal diabetes and cardiovascularmalformations: predominance of double outlet right ventricle and truncusarteriosus; Teratology;1990;41: Chart 2. The percentage of neonates that underwent cardiac surgery in the first month of life, in two groups of newborns: the first group with DORV and the second group with DORV+ECM. References 1. Respondek Liberska M: Echokardiografia i kardiologia płodu. Wydawnictwo Medyczne MAKmed; Respondek Liberska M: Kardiologia prenatalna dla położników i kardiologów dziecięcych; Czelej; Szymkiewicz-Dangel J: Kardiologia Płodu. Zasady diagnostyki i terapii; Poznań; Ośrodek Wydawnictw Naukowych; Van Praagh S, Davidoff A, Chin A, Shiel FS, Reynolds J, Van Praagh R: Double outlet right ventricle: anatomic types and developmental implications based on a study of 101 autopsied cases; Coeur 1982;XIII: Lev M, Bharati S, Meng CC, Liberthson RR, Paul MH, Idriss F: A concept of doubleoutletright ventricle; J Thorac Cardiosc; 1972;64: Słodki M: Opracowanie modelu opieki nad ciężarną z wrodzoną wadą serca u płodu na podstawie nowego prenatalnego podziału wad serca. Rozprawa habilitacyjna. Wydawnictwo PWSZ; Obler D, Juraszek A L, Smoot L B, Natowicz M R: Double outlet right ventricle: aetiologies and associations;j Med Genet 2008;45: Demir M T, Amasyali Y, Kopuz C, Aydin M E, Çorumlu U: The double outlet right ventricle with additional cardiac malformations: an anatomic and echocardiographic study; Folia Morphol.Vol. 68, No. 2, pp Zidere V,Pushparajah K, Allan L D, Simpson J M : Three-dimensional fetal echocardiography for predictionof postnatal surgical approach in double outlet rightventricle: a pilot study; Ultrasound Obstet Gynecol;2013; 42: Wilkinson J: Double outlet right ventricle; Orphanet encyclopedia; Feb Pushparajah K, Med Sci B, Barlow A, Hons B A, Vi-Hue Tran, Phil M, Miller Owen I, Zidere Vita, Vaidyanathan B, Simpson J M:A Systematic Three- Dimensional Echocardiographic Approach to Assist Surgical Planning in Double Outlet Right Ventricle; Echocardiography;2013;30: Silvestri LM, Scarabotti A, Marino B Challenges of classifying double outlet right ventricle: Importance for genotype phenotypeanalyses; Am J Med Genet Part A; 2014;164A: Hartge D, Niemeyer L, Axt-Fliedner R, Krapp M, Gembruch U, Germer U, Weichert J: Prenatal detection and postnatal management of double outlet rightventricle (DORV) in 21 singleton pregnancies;j Matern Fetal Neonatal Med;2012; 25(1): Kim N, Friedberg M, Silverman N H: Diagnosis and prognosis of fetuses with double outlet right ventricle;prenat Diagn;2006; 26: Gedikbasi A, Oztarhan K, Gul A, Sargin A, Ceylan Y: Diagnosis and prognosis in double-outlet right ventricle; Am J Perinatol;2008;25: Harris JA, Francannet C, Pradat P, Robert E: The epidemiology of cardiovascular defects, part 2: a study based on data from three large registries of congenital malformations; Pediatr Cardiol;2003;24: Berishvili II, Mitina IN, Ragimov FR: Origin of theaorta and pulmonary artery from the right ventricle:anatomic and echocardiographic comparisons; Kardiologia;1992;32: Paladini D, Rustico M, Todros T, Palmieri S, Gaglioti P, Benettoni A, Russo MG, Chiappa E, D Ottavio G: Conotruncal anomalies in prenatal life; Ultrasound Obstet Gynecol;1996;8: Allan LD, Sharland GK, Chita SK, Lockhart S, Maxwell DJ: Chromosomal anomalies in fetal congenital heart disease; Ultrasound Obstet Gynecol;1991;1: Khositseth A, Tocharoentanaphol C, Khowsathit P, Ruangdaraganon N: Chromosome 22q11 deletions in patients with conotruncal heart defects; Pediatr Cardiol;2005;26: Pitka nen OM, Hornberger LK, Miner SE, Mondal T, Smallhorn JF, Jaeggi E, Nield LE: Borderline left ventricles in prenatally diagnosed atrioventricular septal defect or double outlet right ventricle: echocardiographic predictors of biventricular repair; Am Heart J; 2006;152: Walters HL, III, Mavroudis C, Tchervenkov CI, Jacobs JP, Lacour- Gayet F, Jacobs ML: Congenital Heart Surgery Nomenclature and Database Project: double outlet right ventricle; Ann Thorac Surg; 2000; 69: S249 S Lacour-Gayet F: Intracardiac repair of double outlet right ventricle; Semin Thorac Cardiovasc Surg Pediatr Card Surg Ann; 2008: Stellin G, Ho SY, Anderson RH, Zuberbuhler JR, Siewers RD: The surgical anatomy of double-outlet right ventricle with concordant atrioventricular connection and noncommitted ventricular septal defect; J Thorac Cardiovasc Surg; 1991; 102: Smallhorn JF: Double-outlet right ventricle: an echocardiographic approach.; Semin Thorac Cardiovasc Surg Pediatr Card Surg Ann ;2000; 3: Serraf A, Lacour-Gayet F, Houyel L, et al.:subaortic obstruction in double outlet right ventricles. Surgical considerations for anatomic repair; Circulation 1993; 88 (5 Pt 2): II177 II Bradley TJ, Karamlou T, Kulik A, et al.: Determinants of repair type, reintervention, and mortality in 393 children with double- outlet right ventricle; J Thorac Cardiovasc Surg 2007; 134: Macartney FJ, Rigby ML, Anderson RH, Stark J, Silverman NH: Double outlet right ventricle. Cross sectional echocardiographic findings, their anatomical explanation, and surgical relevance; Br Heart J 1984; 52: Baslaim GM: Is preoperative delineation of coronary artery pattern a prerequisite for arterial switch operation? J Card Surg 2006; 21: Uemura H, Yagihara T, Kadohama T, Kawahira Y, Yoshikawa Y: Repair of double outlet right ventricle with doubly-committed ventricular septal defect; Cardiol Young 2001; 11: Belli E, Serraf A, Lacour-Gayet F, et al: Double-outlet right ventricle with non-committed ventricular septal defect; Eur J Cardiothorac Surg 1999; 15: Barbero-Marcial M, Tamanati C, Jatene MB, et al: Double-outlet right ventricle with nonrelated ventricular septal defect: surgical results using the multiple patches technique. Heart Surg Forum 1998; 1: Authors and the division of work: M. Soroka: collecting data, data analysis, choice of literature, text of the article in Polish, sending the article for publication, M. Słodki: the idea of the research, correction article, text of the article in Polish and English H. Moczulska: collecting data, text of the article in Polish M. Respondek-Liberska: correction article, final version of the article Financing: The research was not financed from the external sources Conflict of interest: The authors declare no conflict of interest and did not receive any remuneration related to the creation of this work. 17

18 KARDIO PRENATAL, 2014, 3 (14) Case report - cardiac FIRST TRIMESTER DIAGNOSIS OF ABSENT PULMONARY VALVE (APV): A CASE REPORT OF PRENATAL TREATMENT WITH A REVIEW OF LITERATURE AND DATA FROM THE POLISH NATIONAL REGISTRY OF FETAL CARDIAC PATHOLOGY Authors: Agnieszka Nawara 1, Beata Radzymińska-Chruściel 2, Maria Respondek Liberska 3,4, Katarzyna Januszewska 5, Edward Malec 6 1 Centrum Medyczne Ujastek, 2 Pracownia Echokardiografii Płodu Centrum Medycznego Ujastek w Krakowie, 3 Zakład Kardiologii Prenatalnej Instytut Centrum Zdrowia Matki Polki, 4 Zakład Diagnostyki i Profilaktyki Wad Wrodzonych Uniwersytetu Medycznego w Łodzi, 5 University Hospital Muenstern Division of Pediatric Heart Surgeryn Albert-Schweitzer-Campus 1, Geb.A1n48149 Münster, 6 University Hospital Muenstern Director of Division of Pediatric Heart Surgeryn Albert-Schweitzer-Campus 1, Geb.A1n48149 Münster Abstract KARDIO PRENATAL, 2014, 3 (14), DOI /09143 Absent of pulmonary valve syndrome is a rare congenital heart defect, which is diagnosed prenataly in 0,8% of fetuses with congenital heart defect based on the data from National Polish Registry Of Fetal Cardiac Anomalies. We present a case of pregnat woman and fetus with that heart defect, which was detected in the 1st trimester and treated prenatally with digoxin, amnioreduction, tocolysis and steroids following by the cardiac sugery in the neonatal period. Despite an intensive therapy, the infant died on the 3rd month of age. We belive that the main reason of poor outcome was premature delivery at the 35th week of gestation. We present unique cardiac images proving the changing characterists of this type anomay since 1 st trimester. Key words: twin pregnancy, prevention of sponatenous preterm birth, cervical assessment INTRODUCTION Absent pulmonary valve is a rare congenital heart defect that may be diagnosed prenatally but is typically associated with poor prognosis. This anomaly was found in 0.8% of fetuses with heart defects in the Polish National Registry of Fetal Cardiac Pathology (ORPKP) between the years , ( It is less commonly seen nowadays after birth due to the decision to terminate the pregnancy after prenatal diagnosis 1,2,3,4. We present a case of this anomaly provisionally diagnosed at 12 weeks gestation. CASE PRESENTATION 33-year-old patient, G3P1 underwent ultrasound screening at 12 weeks gestation which showed normal nuchal translucency (1,2 mm) and normal heart size but with an abnormal heart axis of 95 degrees. On pulsed Doppler, there was a reversal of flow at the ductus venosus (DV) and pulmonary valve. A two-vessel umbilical cord was identified. The patient declined both biochemical marker and diagnostic genetic testing and would not consider termination of the pregnancy. Fetal echocardiography (FECHO) at 16 weeks showed cardiomegaly, right> left chamber size disproportion, severe heart axis deviation (90 degrees), a malalignment type ventricular septal defect with an overriding aorta and significantly dilated main pulmonary artery and branches of the pulmonary arteries (5mm). No ductus arteriosus was identified. Doppler examination, showed holosystolic regurgitation of the tricuspid valve and turbulent, accelerated flow across the pulmonary annulus (150cm/s) with reverse flow in diastole. The diagnosis of Tetralogy of Fallot (ToF) with absent pulmonary valve ( APV) was made. Flow velocities in both the umbilical artery and the middle cerebral artery were normal. The circulatory system was assessed at 8/10 points in the Cardiovascular Profile Score (CVPS) 5. Nuchal fold was 3 mm. Amniotic fluid index (AFI) was normal. Parents received counseling from the fetal / pediatric cardiologist along with description of multi-stage heart surgery (in case of delivery at term) and potential complications. The patient was informed, relative to Polish law, that termination of pregnancy was possible. Corresponding author: Agnieszka Nawara, anawarabaran@gmail.com Data wpłynięcia artykułu: ; data zaakceprowania artykułu:

19 / September 2014 systolic velocity was 225 cm/s, diastolic reversal flow velocity was 200 cm/s. CVS= 9 points (Table 1). Amnioreduction with tocolysis for decreasing AFI was performed and steroids were administered at 26 weeks. The condition of the fetus was good after amnioreduction, but in the following week, increasing cardiomegaly and dilatation of hepatic vessels were observed. Maternal hyperoxygenation test was performed at 34 weeks which showed normal pulmonary vascular reactivity. Figure 1. The four chamber view in 1 st trimester, size of the heart 8mm. Figure 2. Fetal cardiomegaly at 22nd week of gestation and abnormal heart axis. The 22 week FECHO showed continued cardiomegaly, continued dilatation of the branch pulmonary arteries and increased main pulmonary artery velocity. The CVPS was set at 7 / 10 and AFI 16 cm. Transplacental digoxin treatment to prevent further cardiomegaly and in attempt to slow down further signs of circulatory insufficiency 6,7 was administered. At 25 th week FECHO again showed cardiomegaly, with a double increase in the main and pulmonary artery branches diameter. The left lung appeared to be compressed by the heart. Pulmonary Spontaneous birth occurred at 35 weeks gestation following premature rupture of membranes. A female infant weighing 1970 g with Apgar scores of 5,6,6,8 at 1,3,5,10 minutes, respectively was delivered. Immediately after birth the newborn required intubation and mechanical ventilation and on the 2 nd day was transferred in critical condition to the pediatric cardiology ward. In spite of intensive ventilation the child chronically manifested severe hypoxemia and hypercapnia. On day 30, a rescue heart surgery was performed: VSD was closed, pulmonary trunc was resected, the size of the proximal pulmonary arteries was reduced and the right ventricular outflow tract was reconstructed using a xenograft (Contegra). The distal pulmonary arteries were multiple and severely hypoplastic. After surgery the baby was 7 days on ECMO due to hypoxemia. Based on angiography and angio CT hypoplasia of left lung and left bronchus was confirmed, as well as severe hypoplasia of the distal pulmonary arteries. Artificial ventilation was continued, however despite intensive therapy the baby died in the fourth month of life. DISCUSSION According to Sauer 8 absent pulmonary valve (APV) for the first time described in 1847 by Chevers, constitutes about 0.9% of heart defects 2 and corresponds to the 0.8 % in the Polish National Registry of Fetal Cardiac Pathology (Table 3). This defect is characterized by the partial or complete absence of pulmonary valve leaflets. Various versions of this defect have been described. In all forms, the ring of the valve is narrowed and the pulmonary trunk and branches are aneurysmally dilated. This dilatation can exert pressure on the main stem bronchi and intrapulmonary branches already in fetal life which may result in necrotic changes in the lungs. APV most commonly occurs with tetralogy of 19

20 KARDIO PRENATAL, 2014, 3 (14) Fallot (3 % of all ToF cases) and with intact ventricular septum 9. APV with ToF may be associated with cardiomegaly, axis shift severely to the left or right (dextroposition). Agenesis of the ductus arteriosus has been implicated in the dilation of the pulmonary arteries. This version of APV is associated with chromosome 22q deletion in 20 to 25 % of affected fetuses 10. Absent pulmonary valve with intact septum has been seen with tricuspid valve atresia and with double chambered right ventricle. The ductus arteriosus may be patent in this variant 11,12. Figure 3. Dilatation of pulmonary branches up to 28 mm in fetus with APV at 32nd week of gestation The etiology is unknown, however, association with genetic syndromes is common. APV with VSD (Fallot type) is linked to microdeletion of chromosome 22 (22q11.2) 10. CATCH, a mutation in the TBX1 gene which is responsible for the development of DG/VCFS, deletion of the long arm of chromosome 6. Some other cases of APV without VSD (non Fallot type) with deletion of the long arm of chromosome 18 have also been described. 13 Figure 4. Fetal heart with APV at 34 week, heart size 37 mm, (power angio); 6 weeks on digoxin...compare the heart size in fig. 2 from 22nd week GESTATIONAL AGE PLACE OF EXAM DATE FETAL WEIGHT Ha/Ca AP mm Disproportion RV>> LV 13 wks Kraków 3.VII 0, wks Kraków 5.VII 183g 0, wks Kraków 5.IX 422g 0, wks Łódź 11.IX 527 g 0, wks Kraków 26.IX 655g 0, wks Łódź 14.X 1033g 0, wks Łódź 14.XI 1590g APV may be complicated by congestive heart failure, non-immunological hydrops fetalis, fetal hypotrophy and death in utero. The ORPKP shows more cases of APV diagnosed in utero than in live born newborns, due to termination of pregnancies and in utero demises (table 3). The first prenatal diagnosis of APV was published by Fouron in The 4-chamber view shows cardiomegaly and aneurysmal dilatation of the 0, wks Łódź 29.XI 2297g no Heart axis PV ( mm) RPA & LPA ( mm) No dilatation PA V max PA cm/s PR cm/s CVS AFI (cm) normal normal * Table 1: Data from echocardiographic monitoring of the fetus with absent pulmonary valve in Kraków and Łódź, last exam at 34 wks and 10 days later premature rapture of membranes and spontaneous delivery in Kraków 0,3 37 pulmonary trunk and its branches (Mickey Mouse sign). Growth restriction, polyhydramnios and signs of hydrops fetalis may be present after the 2 nd trimester. The leaflets of the pulmonary valve are difficult to visualize. The Doppler flow patterns in the right ventricular outflow display a bidirectional waveform and the sound of sawing wood. In our case, the observed evolutionary changes of the heart were identified at the 20