Journal of Obstetrics and Gynaecology
ISSN: 0144-3615 (Print) 1364-6893 (Online) Journal homepage: http://www.tandfonline.com/loi/ijog20
Congenital Anomalies Presenting In Utero as TTTS: A case series report and review of literature M.P. Oostveen, K.E.A. Hack, L.R. Pistorius, P.G.J. Nikkels & C. KoopmanEsseboom To cite this article: M.P. Oostveen, K.E.A. Hack, L.R. Pistorius, P.G.J. Nikkels & C. KoopmanEsseboom (2013) Congenital Anomalies Presenting In Utero as TTTS: A case series report and review of literature, Journal of Obstetrics and Gynaecology, 33:8, 901-903 To link to this article: http://dx.doi.org/10.3109/01443615.2013.821969
Published online: 12 Nov 2013.
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Obstetric Case Reports 901 6.8 mg/dl and 54 pg/ml, respectively. He showed no evidence of PHP-1a at 2 years of age. She did not resume menstruation for a year after delivery because of low oestradiol levels (20 pg/ml) accompanied by normal gonadotropin levels (FSH, 6.70 mIU/ml; LH, 7.10 mIU/ml). She was therefore administered hormone replacement therapy.
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Discussion The treatment of PHP-1a in pregnancy should be carefully considered, especially in the 3rd trimester, to avoid inducing maternal convulsions and neonatal hyperparathyroidism with severe skeletal changes, because a full-term infant requires 25–30 g of calcium during pregnancy for new bone mineralisation, and this accumulation occurs mainly in this period (Mestman 1998; Wills et al. 1982). However, it remains controversial as to whether the treatment of hypocalcaemia in pregnant patients with PHP is aggravated by vitamin D and/or calcium administration (Mestman 1998; Seki et al. 1999). In our case, calcium carbonate administration was raised in response to a decrease in protein-adjusted calcium levels and an increase in intact PTH levels. Conversely, vitamin D supplementation was unchanged, because 1,25(OH)2 vitamin D levels were maintained within normal range. As for the fetus, the serum levels of calcium, phosphate and intact PTH measured in the umbilical artery, indicated that calcium regulation remained normal. Therefore, this treatment was appropriate for the mother and the fetus. The slight increase in 1,25(OH)2 vitamin D detected in the 3rd trimester was consistent with a previous study showing enhanced 1,25(OH)2 vitamin D production by the placenta of pregnant women with PHP (Zerwekh and Breslau 1986). In our case, a lack of disease inheritance by the fetus might have permitted sensitivity of the placental 25(OH)D3-1α-hydroxylase and increased 1,25(OH)2 vitamin D levels (Zerwekh and Breslau 1986). The mechanisms regulating maternal intact PTH during pregnancy remain unclear. The intact PTH levels remained low during the first two trimesters, but they increased during the 3rd trimester despite the higher protein-adjusted calcium levels. Similar phenomenon has been reported in a case of pregnancy complicated by PHP-1b (Seki et al. 1999), which is a disorder in the alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gsα), the same causative molecule as in PHP-1a. Altogether, this case and ours suggest that Gsα may be involved in the regulation of maternal intact PTH during pregnancy by a mechanism independent of protein-adjusted calcium levels. Our case exhibited infertility and secondary amenorrhoea after pregnancy. Namnoum et al. (1998) reported that reproductive dysfunction was common in women with PHP-1a because of partial resistance to gonadotropin in the ovary. In their series, only two of the 17 females with AHO and PHP-1a had conceived previously. Females with PHP-1a should be aggressively treated for reproductive dysfunction. In conclusion, women with PHP-1a display multiple hormonal alterations. Treatment of PHP-1a during pregnancy should be closely regulated to avoid adverse perinatal outcomes. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References Levine MA. 2000. Clinical spectrum and pathogenesis of pseudohypoparathyroidism. Reviews in Endocrine and Metabolic Disorders 1:265–274. Mestman JH. 1998. Parathyroid disorders of pregnancy. Seminars in Perinatology 22:485–496. Namnoum AB, Merriam GR, Moses AM et al. 1998. Reproductive dysfunction in women with Albright’s hereditary osteodystrophy. Journal of Clinical Endocrinology and Metabolism 83:824–829. Seki K, Osada H, Yasuda T et al. 1999. Pseudohypoparathyroidism type 1b in pregnancy. Gynecologic and Obstetric Investigation 47:278–280. Wills MR, Bruns DE, Savory J. 1982. Disorders of calcium homeostasis in the fetus and neonate. Annals of Clinical and Laboratory Science 12:79–88. Zerwekh JE, Breslau NA. 1986. Human placental production of 1 alpha,25dihydroxyvitamin D3: biochemical characterization and production in normal subjects and patients with pseudohypoparathyroidism. Journal of Clinical Endocrinology and Metabolism 62:192–196.
Congenital Anomalies Presenting In Utero as TTTS: A case series report and review of literature M.P. Oostveen1, K.E.A. Hack1, L.R. Pistorius1, P.G.J. Nikkels2 & C. Koopman-Esseboom3 1University Medical Centre Utrecht, Department of Obstetrics and
Gynecology, Utrecht, The Netherlands, 2University Medical Centre Utrecht, Department of Pathology, Utrecht, The Netherlands, 3University Medical Centre Utrecht, Department of Neonatology, Utrecht, The Netherlands DOI: 10.3109/01443615.2013.821969 Correspondence: Dr. K.E.A. Hack, Department of Obstetrics, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, KE.04.123.1, P. O. Box 85090, 3508 AB Utrecht, The Netherlands, Tel. 0031-88-7556426, E-mail: [email protected], Fax: 0031-88-7555320
Keywords: Congenital anomaly, intestinal atresia, renal agenesis, twin-to-twin transfusion syndrome.
Introduction Monochorionic diamniotic (MCDA) twin pregnancies are at risk for twin-to-twin transfusion syndrome (TTTS) and congenital structural anomalies, which can also occur in only one infant of a twin pair despite their monozygosity (Sperling et al 2007). An oligohydramnios/ polyhydramnios sequence (TOPS) is an essential criterion for the diagnosis of TTTS. Discrepant amniotic fluid volumes can however also be seen in several congenital anomalies which cause an imbalance in the production and absorption of amniotic fluid, as well as in selective intra-uterine growth restriction (sIUGR) or viral infections with discrepant viral transmission (O’Brien et al. 1986, Von Kaisenberg et al. 2007, Chalouhi et al. 2008, Harman et al. 2008, Baschat et al. 2011). We identified through a retrospective review of obstetric and neonatal databases from the University Medical Center of Utrecht (2000-2010), two monochorionic twin pairs with congenital malformations diagnosed after birth, which were interpreted as TTTS during pregnancy. The cases illustrate the importance of a correct diagnosis of congenital anomaly or TTTS since the treatments in both scenarios are different. The diagnostic challenge to distinguish a TTTS from congenital anomalies presenting with discrepant amniotic fluid volumes is discussed and a review of the recent literature is given.
Case report Case I A 30-year-old multipara was referred to our hospital at 31⫹1 weeks of gestation. The ultrasound of fetus A showed an oligohydramnios (deepest vertical pocket of amniotic fluid (DVP) 0.9 cm) with normal fetal growth (40th centile). Fetus B had a polyhydramnios (DVP 12.7 cm) with normal stomach- and bladderfilling and an estimated weight of 1443 grams (⬍ 10th centile). They both had normal Doppler studies of the umbilical artery and middle cerebral artery. A single umbilical artery (SUA) was found in fetus B. Ultrasound findings are shown in Figure 1. No structural anomalies were seen. TTTS Quintero stage I was diagnosed, with fetus A considered to be the donor and fetus B considered to be the recipient. Two days later, after steroid therapy, a caesarean section was performed because of abnormal fetal heart rate tracings in the larger twin. Two daughters were born (birth weights 1865g and 1500g, and haemoglobin levels of 9,9 mmol/L and 9,4 mmol/L respectively). Injection study of the placental vessels (Figure 2A) showed a medium-sized arterio-arterial anastomosis and a large arteriovenous anastomosis from child B to A, combination of anastomoses not found in TTTS-placentas (Hack et al. (a) 2008). An oesophageal atresia with fistula above the vena azygos was diagnosed in the second twin. A partial resection of the distended oesophagus was performed, and continuity was restored
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Figure 1. Sonographic findings of a) a poly- and oligohydramnios, b) stomach- and bladder filling, and c) amniotic membranes in a MCDA twin pregnancy (case 1).
with an end to end anastomosis. The neurodevelopmental outcome at five years corrected age is normal in both children. Case II A 35-year-old multipara was admitted to our hospital at 18 weeks gestation with discrepant amniotic fluid volumes (DVP fetus A 0.5 cm and fetus B 7.0 cm), and discordant growth (fetus A 10th centile and fetus B 90th centile). Sonographically there was an empty bladder and doubt about the presence of both kidneys in fetus A, however in follow-up scans both kidneys seemed visible. Doppler assessment of the umbilical artery showed no abnormalities in both infants. DVP in the healthy twin gradually increased to 11.0 cm at 29 weeks with moderate to small amounts of amniotic fluid in the smaller twin (DVP 0.5 to 3.2 cm) and TTTS Quintero stage II was diagnosed. Because of the technical challenges of laser therapy in this twin with an anterior placenta, laser therapy was not performed (early 2000’s) and amniodrainage was done at 29⫹2 weeks gestation removing 3500 mL of amniotic fluid. After the amniodrainage, the amount of amniotic fluid in twin B remained normal for several weeks. At 33 weeks of gestation the DVP in twin B was 9.0 cm and Doppler abnormalities of the umbilical artery were seen. The patient was admitted at the ward. An L/S punction was performed (no amniodrainage since the patient did not have any mechanical complaints), which showed normal lung maturation and a caesarean section was planned at 34 weeks. Two sons were born (birth weights 2020g and 2400g respectively and Hb 10.1mmol/l and 12,5mmol/L respectively.) The first infant died four days after birth. Autopsy demonstrated a combination of congenital anomalies in this child, including bilateral renal agenesis, bladder agenesis, anusatresia, cryptorchism, absence of a penis, pulmonary hypoplasia. The second infant was healthy without any congenital anomalies. We found no explanation for the polyhydramnios in this infant. Placental injection study showed a large arterioarterial anastomosis as well as a few bidirectional arteriovenous anastomoses (Figure 2B), which rejects a diagnosis of TTTS as mentioned before.
Discussion TTTS is a severe complication of MCDA twin pregnancies, caused by a net inter twin transfusion of blood from one fetus, defined as the donor, towards the other fetus, defined as the recipient, through placental anastomoses (Baschat et al. 2011). Principally TOPS is an essential characteristic for the diagnosis of TTTS. TTTS may be falsely diagnosed if a difference in amniotic fluid volumes is caused by congenital anomalies which cause an imbalance in the production and absorption of amniotic fluid, or viral infections or growth restriction (Table I; O’Brien et al.1986, Von Kaisenberg et al. 2007, Harman et al. 2008, Chalouhi et al. 2010, Baschat et al. 2011). Both cases show that conflicting results from ultrasound studies need to be addressed more carefully and should make the clinician alert to confusing diagnosis. In Case I the polyhydramnios was the result of the reduced absorption of amniotic fluid due to the oesophageal atresia. Indeed, pathology findings also supported the conclusion that no TTTS occurred in this case. Retrospectively, there were incompatible ultrasound findings. Although a size discrepancy is not required for the diagnosis of TTTS, typically the donor presents as the smaller twin with an oligohydramnios and the recipient presents as the larger twin with a polyhydramnios (Harman et al. 2008, Chalouhi et al. 2010, Baschat et al. 2011). In case I this was opposite. Furthermore, the presence of a SUA should have made us alert for a different diagnosis. A fetus with a SUA is at greater risk for congenital anomalies, polyhydramnios, growth restriction and adverse neonatal outcomes (Murphy-Kaulback et al. 2010, Burshtein et al. 2011). In Case II the oligohydramnios was caused by a (lethal) urinary tract anomaly, which was doubted at first anomaly scan. It is known that fetal ultrasound may be limited due to fetal position, maternal obesity, overlying bone, and oligohydramnios (Hendrix et al. 1998). Many studies evaluate the role of antenatal magnetic resonance imaging (MRI) to improve sonographic prenatal diagnosis of congenital anomalies (Breysem et al. 2003, Pistorius et al. 2008, Gupta et al. 2010). The oligohydramnios, presenting in TTTS as well as in congenital renal anomalies, can make sonographical evaluation difficult. Above this, the characteristics of the TTTS
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Table I. Causes of polyhydramnios and oligohydramnios. Polyhydramnios Fetal Aneuploidy Neurological anomalies (anencephaly) Neuromuscular disorders Skeletal dysplasia Gastrointestinal obstruction (oesophageal atresia, intestinal atresia, gastroschisis) Maternal Diabetes mellitis Medication Infections Placenta/membranes Chorioangioma of the placenta Twin-to-twin transfusion syndrome Oligohydramnios Fetal Urogenital tract anomalies Aneuploidy Placenta/Membranes Preterm Rupture Of Membranes (PROM) Uteroplacental insufficiency/(selective) intrauterine growth restriction Twin-to-twin transfusion syndrome
Figure 2 (A, B). Monochorionic diamniotic (MCDA) placentas after injection with coloured dye. The veins are coloured yellow or orange, and the arteries are blue. (A) Placenta of MCDA twin from Case I, delivered at 31 3/7 weeks of gestation. Twin I (birth weight 1865g) has a paracentral cord insertion and a placenta territory of 56%, whereas twin II (birth weight 1500g) has a velamentous cord insertion with a single umbilical artery and a placenta territory of 44%. The artery-to-artery anastomosis is indicated by arrowheads and the artery-to-vein anastomosis ( from child B to A) is indicated by an arrow. Very small artery-to-vein anastomoses from twin A to twin B are situated close to the artery-toartery anastomosis. (B) Placenta of MCDA twin from Case II, delivered at 34 weeks of gestation. Twin A (birth weight 2020g, multiple lethal congenital malformations) has a central cord insertion with single umbilical artery and a placenta territory of 40%, whereas twin B (birth weight 2400g) has a marginal cord insertion and a placenta territory of 60%. The artery-to-artery anastomosis is indicated by arrowheads and the arteryto-vein anastomosis from twin B to twin A is indicated by a white arrow and the artery-to-vein anastomosis from twin A to twin B is indicated by a black arrow.
donor twin with a very small or non visible bladder makes it difficult to distinguish a renal agenesis or severe renal hypoplasia from TTTS. MRI is preferable since MRI is not significantly affected by diminished amniotic fluid on T2- weighted images. MRI might have a supplemental role since it provides a more detailed description and insight into fetal anatomy, pathology and etiology (Breysem et al. 2003, Pistorius et al. 2008, Gupta et al. 2010). In the future, an additional MRI-scan might give more information when sonographic findings are inconclusive, particularly when oligohydramnios is present. The cases illustrate the importance of a correct diagnosis. The treatments in both scenarios are different. In TTTS an invasive treatment could be necessary and fetal deterioration often necessitates iatrogenic preterm delivery. If the physicians in charge would have been consequent, an unnecessary laser treatment would have been performed with all combined risks. This in contrast to the more preferred scenario of continuing pregnancy in case of a congenital anomaly, since prematurity may have considerable consequences, also for the healthy sibling. The white matter of the immature brain is sensitive for haemodynamic imbalances and anaesthetic procedures
when acute surgery is necessary after birth (Harman et al. 2008, Chalouhi et al. 2010, Baschat et al. 2011). Other possible causes for discrepant amniotic fluid should therefore be ruled out. Structural anomalies have been reported to occur more often in monozygotic twins compared with dizygotic twins, with a relative risks of 1.4 to 2.7 (Myrianthopoulos et al. 1978). Despite monozygosity, the incidence of discrepant occurrence of congential malformations is increased. Discordance in monozygotic twins is usually due to a consequence of the underlying stimulus to zygote splitting, variation in gene expression, or abnormal placentation (Hendrix et al. 1998). Selective intrauterine growth restriction (sIUGR) has to be considered as a distinct entity (O’Brien et al. 1986, Baschat et al. 2011). Careful Doppler analysis may help in distinguishing in differential diagnosis, mainly in MC twins with growth restriction. Also TORCH serology needs to be determined to rule out a viral infection (e.g. parvovirus), which can also provoke this pattern (Von Kaisenberg et al. 2007). Another distinct entity is ‘the MC twins discordant for amniotic fluid’ (Harman et al. 2008, Baschat et al. 2011). These twins present with subjective difference in amniotic fluid which fail to comply with the criteria of TTTS. These pregnancies are at high risk for TTTS and should therefore be followed up on a weekly basis until subjective normalization of the amniotic fluid level is observed (Baschat et al. 2011). It may however be possible that TTTS is combined with congenital malformations, which can make the indication for invasive fetal surgery more sophisticated dependent on the future prognosis of the siblings. The relationship between intestinal atresia and TTTS has already been reported in the literature (Arul et al. 2001; Schanter et al. 2005; Morikawa et al 2008; Saura et al. 2010). It has been suggested that the aetiological factor is the fetoscopic laser photocoagulation therapy, with an embolic phenomenon causing ischaemia as the cause of this malformation (Arul et al. 2001; Schanter et al. 2005; Morikawa et al 2008; Saura et al. 2010). Morikawa et al. (2008) suggests that TTTS itself may cause the intestinal atresia. Data supporting this last hypothesis show a higher rate of small intestinal atresia among monozygotic twins than in singletons (Cragan et al. 1994). This significantly accounts for jejunoileal atresia, suggesting a vascular cause (Louw et al. 1955; Van der Pol et al. 1992). In addition, lesions in several organs caused by ischaemia, especially the brain, have been reported in twins affected by TTTS irrespective of the kind of treatment employed (Morikawa et al. 2008). Mesenteric ischaemia due to haemodynamic alterations causing hypoperfu-
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sion and hyperviscosity associated with TTTS, might cause these (gastro-) intestinal malformations (Arul et al. 2001; Schanter et al. 2005; Morikawa et al 2008; Saura et al. 2010). The same mechanism may also be the cause of the higher incidence of necrotising enterocolitis found in MC twins (Hack et al. (b) 2008). Conclusion and recommendation These case series clearly show that the diagnosis of TTTS should not be easily confused with other reasons of discrepant amniotic fluid volumes or discrepant size. A detailed anomaly scan (even when previous scans did not show any abnormalities), TORCH serology and Doppler velocimetry of fetal vessels should be applied in third line centers. In the future, an additional MRI scan might give more information when sonographic findings are inconclusive, particularly when oligohydramnios is present.
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Financial disclosure absence of any interest to disclosure Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References Arul GS, Carrol S, Kyle PM, Soothill PW, Spicer RD. 2001. Intestinal complications associated with twin-to-twin transfusion syndrome after antenatal laser treatment: report of two cases. Journal of Pediatric Surgery ; 36:301–302. Baschat A. Chmait RH, Deprest J, Gratacós E, Hecher K, Kontopoulos E et al. 2011. Twin-to-twin transfusion syndrome (TTTS) Journal of Perinatal Medicine; 39:107–112. Breysem L, Bosmans H, Dymarkowski S, Van Schoubroeck D, Witters I, Deprest J et al. 2003. The value of fast MR imaging as an adjunct to ultrasound in prenatal diagnosis. Eurepean Radiology 13:1538–1548. Burshtein S, Levy A, Holcberg G, Zlotnik A, Sheiner E. 2011. Is single umbilical artery an independent risk factor for perinatal mortality? Arch Gynecol Obstet. 283:191–194. Chalouhi GE, Stirneman JJ, Salomon LJ, Essaoui M, Quibel T, Ville Y. 2010. Specific complications of monochorionic twin pregnancies: twin- twin transfusion syndrome and twin reversed arterial perfusion sequence. Seminars in fetal & Neonatal Medicine 15:349–356. Cragan JD, Martin ML, Waters GD, Khoury MJ. 1994. Increased risk of small intestinal atresia among twins in the United States. Archives of Pediatric Adolescense Medicine 148:733–739. Gupta R, Kumar S, Sharma R, Gadodia A, Roy KK, Sharma JB. 2010. The role of magnetic resonance imaging in fetal renal anomalies. International Journal of Gynaecology and Obstetrics 111:209–212. Hack KEA (a), Nikkels PG, Koopman-Esseboom C, Derks JB, Elias SG, van Gemert MJ et al. 2008. Placental characteristics of monochorionic diamniotic twin pregnancies in relation to perinatal outcome. Placenta 29: 976–981. Hack KEA (b), Derks JB, Elias SG, Franx A, Roos EJ, Voerman SK et al. 2008. Increased perinatal mortality and morbidity in monochorionic versus dichorionic twin pregnancies: clinical implications of a large Dutch cohort study. British Journal of Obstetrics and Gynaecology. 115:141–143. Harman, CR. 2008. Amniotic Fluid Abnormalities. Seminars in Perinatology 32:288–294. Hendrix NW, Chauhan SP. 1998. Sonographic examination of twins. From first trimester to delivery of second fetus. Obstet Gynecol Clin North Am. 25: 609–621. Louw JH, Barnard CN. 1955. Congenital intestinal atresia: observations on its origin. Lancet 2:1065–1069. Morikawa M, Sago H. Yamada T, Hayashi S, Yamada T, Cho K et al. 2008. Ileal atresia after fetoscopic laser photocoagulation for twin-to-twin transfusion syndrome- a case report. Prenatal Diagnosis 28:1072–1074. Murphy-Kaulback L, Dodds L, Joseph KS, van den Hof M. 2010. Single umbilical artery risk factors and pregnancy outcomes. Obstetrics and Gynecology 116:843–850. Myrianthopoulos NC. 1978 Congenital malformations: the contribution of twin studies. Birth Defects Orig Artic Ser 14:151–165. O’Brien WF, Knuppel RA, Scerbo JC, Rattan PK. 1986. Birth weight in twins: an analysis of discordancy and growth retardation. Obstetrics and Gynecology 67: 483–486.
Pistorius LR, Hellmann PM, Visser GHA, Malinger G, Prayer D. 2008. Fetal neuroimaging: ultrasound, MRI, or both? Obstetrics and Gynecology Survey 63:733–745. Schanter JM, Zalen-Sprock RM, Schaap AHP, Festen S, Aronson DC. 2005 Ileal atresia and thrombo-embolic liver calcifications diagnosed after treatment with intrauterine laser coagulation therapy for twin-to-twin transfusion syndrome. Report of two casus. Journal of Pediatric Surgery 40: 875–876. Saura L, Muñoz ME, Castañón M, Eixarch E, Corradini M, Aguilar C et al. 2010. Intestinal complications after antenatal fetoscopic laser ablation in twin-to-twin transfusion syndrome. Journal of Pediatric Surgery 45: E5–E8. Sperling L, Kiil C, Larsen LU et al. 2007. Detection of chromosomal abnormalities, congenital abnormalities and transfusion syndrome in twins. Utrasound Obstet Gynecol 29: 517–526. Van der Pol JG, Wolf H, Boer K, Treffers PE, Leschot NJ, Hey HA et al. 1992. Jejunal atresia related to the use of methylene blue in genetic amniocentesis in twins.British Journal of Obstetrics and Gynaecology 99:141–143. Von Kaisenberg CS, Grebe S, Schleider S, Kühling-vonKaisenberg H, Venhoff L, Meinhold-Heerlein I. 2007. Successful Intrauterine Intracardiac Transfusion in Mono-chorionic Twins Affected by Parvovirus B19. Fetal Diagn Ther 22:420–424.
Impaired DNA methylation leading to heterotrisomy M. Turgal, A. Yazicioglu, O. Ozyuncu & M. S. Beksac Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Hacettepe University School of Medicine, Ankara, Turkey DOI: 10.3109/01443615.2013.838547 Correspondence: A. Yazicioglu, Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Hacettepe University, School of Medicine, Sihhiye, Ankara, Turkey. E-mail: [email protected]
Introduction To date, it is known that approximately 15–20% of all clinically recognised pregnancies result in spontaneous abortion (Robinson et al. 2001). The American Society for Reproductive Medicine defines recurrent pregnancy loss (RPL) as two or more failed pregnancies (Practice Committee of the American Society for Reproductive Medicine 2008). Some 2% of pregnant women experience two consecutive pregnancy losses and only 0.4–1% have three consecutive pregnancy losses (Salat-Baroux 1988). Major chromosomal rearrangement accounts for only 3–5% of RPL cases (Franssen et al. 2005; De Braekeleer and Dao 1990). Here, we describe a unique case of a 46-year-old woman having a different trisomy at each of four pregnancies (21, 15, 6, 2), with impaired DNA methylation as the only identified risk factor.
Case report A 46-year-old woman was admitted to our department for the follow-up of her fourth pregnancy. Her obstetric history was remarkable, with two previous terminated pregnancies and one spontaneous abortion. The first pregnancy (42 years) was terminated after a cytogenetic finding of fetal trisomy 21 and the second (43 years) was terminated due to trisomy 15. During genetic counselling, the couple expressed their fear that they were at high risk for recurrent trisomy for any future pregnancy. They preferred to have their third pregnancy (44 years) via an in-vitro fertilisation (IVF) protocol, with intracytoplasmic sperm injection (ICSI) and subsequent embryo biopsy and fluorescent in situ hybridisation (FISH) analysis for chromosomes 13, 15, 16, 17, 18, 21, 22, X and Y. After ICSI, three blastomeres developed and FISH was performed. The result was bizarre: the first had monosomy 16, the second had both monosomy 16 and 21 and the third was considered to be normal. The woman’s third pregnancy was that remaining blastomere, subsequently ending with a spontaneous abortion at 8 weeks’ gestation.
ISSN: 0144-3615 (Print) 1364-6893 (Online) Journal homepage: http://www.tandfonline.com/loi/ijog20
Congenital Anomalies Presenting In Utero as TTTS: A case series report and review of literature M.P. Oostveen, K.E.A. Hack, L.R. Pistorius, P.G.J. Nikkels & C. KoopmanEsseboom To cite this article: M.P. Oostveen, K.E.A. Hack, L.R. Pistorius, P.G.J. Nikkels & C. KoopmanEsseboom (2013) Congenital Anomalies Presenting In Utero as TTTS: A case series report and review of literature, Journal of Obstetrics and Gynaecology, 33:8, 901-903 To link to this article: http://dx.doi.org/10.3109/01443615.2013.821969
Published online: 12 Nov 2013.
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Article views: 40
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijog20 Download by: [Nanyang Technological University]
Date: 11 November 2015, At: 00:01
Obstetric Case Reports 901 6.8 mg/dl and 54 pg/ml, respectively. He showed no evidence of PHP-1a at 2 years of age. She did not resume menstruation for a year after delivery because of low oestradiol levels (20 pg/ml) accompanied by normal gonadotropin levels (FSH, 6.70 mIU/ml; LH, 7.10 mIU/ml). She was therefore administered hormone replacement therapy.
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Discussion The treatment of PHP-1a in pregnancy should be carefully considered, especially in the 3rd trimester, to avoid inducing maternal convulsions and neonatal hyperparathyroidism with severe skeletal changes, because a full-term infant requires 25–30 g of calcium during pregnancy for new bone mineralisation, and this accumulation occurs mainly in this period (Mestman 1998; Wills et al. 1982). However, it remains controversial as to whether the treatment of hypocalcaemia in pregnant patients with PHP is aggravated by vitamin D and/or calcium administration (Mestman 1998; Seki et al. 1999). In our case, calcium carbonate administration was raised in response to a decrease in protein-adjusted calcium levels and an increase in intact PTH levels. Conversely, vitamin D supplementation was unchanged, because 1,25(OH)2 vitamin D levels were maintained within normal range. As for the fetus, the serum levels of calcium, phosphate and intact PTH measured in the umbilical artery, indicated that calcium regulation remained normal. Therefore, this treatment was appropriate for the mother and the fetus. The slight increase in 1,25(OH)2 vitamin D detected in the 3rd trimester was consistent with a previous study showing enhanced 1,25(OH)2 vitamin D production by the placenta of pregnant women with PHP (Zerwekh and Breslau 1986). In our case, a lack of disease inheritance by the fetus might have permitted sensitivity of the placental 25(OH)D3-1α-hydroxylase and increased 1,25(OH)2 vitamin D levels (Zerwekh and Breslau 1986). The mechanisms regulating maternal intact PTH during pregnancy remain unclear. The intact PTH levels remained low during the first two trimesters, but they increased during the 3rd trimester despite the higher protein-adjusted calcium levels. Similar phenomenon has been reported in a case of pregnancy complicated by PHP-1b (Seki et al. 1999), which is a disorder in the alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gsα), the same causative molecule as in PHP-1a. Altogether, this case and ours suggest that Gsα may be involved in the regulation of maternal intact PTH during pregnancy by a mechanism independent of protein-adjusted calcium levels. Our case exhibited infertility and secondary amenorrhoea after pregnancy. Namnoum et al. (1998) reported that reproductive dysfunction was common in women with PHP-1a because of partial resistance to gonadotropin in the ovary. In their series, only two of the 17 females with AHO and PHP-1a had conceived previously. Females with PHP-1a should be aggressively treated for reproductive dysfunction. In conclusion, women with PHP-1a display multiple hormonal alterations. Treatment of PHP-1a during pregnancy should be closely regulated to avoid adverse perinatal outcomes. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References Levine MA. 2000. Clinical spectrum and pathogenesis of pseudohypoparathyroidism. Reviews in Endocrine and Metabolic Disorders 1:265–274. Mestman JH. 1998. Parathyroid disorders of pregnancy. Seminars in Perinatology 22:485–496. Namnoum AB, Merriam GR, Moses AM et al. 1998. Reproductive dysfunction in women with Albright’s hereditary osteodystrophy. Journal of Clinical Endocrinology and Metabolism 83:824–829. Seki K, Osada H, Yasuda T et al. 1999. Pseudohypoparathyroidism type 1b in pregnancy. Gynecologic and Obstetric Investigation 47:278–280. Wills MR, Bruns DE, Savory J. 1982. Disorders of calcium homeostasis in the fetus and neonate. Annals of Clinical and Laboratory Science 12:79–88. Zerwekh JE, Breslau NA. 1986. Human placental production of 1 alpha,25dihydroxyvitamin D3: biochemical characterization and production in normal subjects and patients with pseudohypoparathyroidism. Journal of Clinical Endocrinology and Metabolism 62:192–196.
Congenital Anomalies Presenting In Utero as TTTS: A case series report and review of literature M.P. Oostveen1, K.E.A. Hack1, L.R. Pistorius1, P.G.J. Nikkels2 & C. Koopman-Esseboom3 1University Medical Centre Utrecht, Department of Obstetrics and
Gynecology, Utrecht, The Netherlands, 2University Medical Centre Utrecht, Department of Pathology, Utrecht, The Netherlands, 3University Medical Centre Utrecht, Department of Neonatology, Utrecht, The Netherlands DOI: 10.3109/01443615.2013.821969 Correspondence: Dr. K.E.A. Hack, Department of Obstetrics, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, KE.04.123.1, P. O. Box 85090, 3508 AB Utrecht, The Netherlands, Tel. 0031-88-7556426, E-mail: [email protected], Fax: 0031-88-7555320
Keywords: Congenital anomaly, intestinal atresia, renal agenesis, twin-to-twin transfusion syndrome.
Introduction Monochorionic diamniotic (MCDA) twin pregnancies are at risk for twin-to-twin transfusion syndrome (TTTS) and congenital structural anomalies, which can also occur in only one infant of a twin pair despite their monozygosity (Sperling et al 2007). An oligohydramnios/ polyhydramnios sequence (TOPS) is an essential criterion for the diagnosis of TTTS. Discrepant amniotic fluid volumes can however also be seen in several congenital anomalies which cause an imbalance in the production and absorption of amniotic fluid, as well as in selective intra-uterine growth restriction (sIUGR) or viral infections with discrepant viral transmission (O’Brien et al. 1986, Von Kaisenberg et al. 2007, Chalouhi et al. 2008, Harman et al. 2008, Baschat et al. 2011). We identified through a retrospective review of obstetric and neonatal databases from the University Medical Center of Utrecht (2000-2010), two monochorionic twin pairs with congenital malformations diagnosed after birth, which were interpreted as TTTS during pregnancy. The cases illustrate the importance of a correct diagnosis of congenital anomaly or TTTS since the treatments in both scenarios are different. The diagnostic challenge to distinguish a TTTS from congenital anomalies presenting with discrepant amniotic fluid volumes is discussed and a review of the recent literature is given.
Case report Case I A 30-year-old multipara was referred to our hospital at 31⫹1 weeks of gestation. The ultrasound of fetus A showed an oligohydramnios (deepest vertical pocket of amniotic fluid (DVP) 0.9 cm) with normal fetal growth (40th centile). Fetus B had a polyhydramnios (DVP 12.7 cm) with normal stomach- and bladderfilling and an estimated weight of 1443 grams (⬍ 10th centile). They both had normal Doppler studies of the umbilical artery and middle cerebral artery. A single umbilical artery (SUA) was found in fetus B. Ultrasound findings are shown in Figure 1. No structural anomalies were seen. TTTS Quintero stage I was diagnosed, with fetus A considered to be the donor and fetus B considered to be the recipient. Two days later, after steroid therapy, a caesarean section was performed because of abnormal fetal heart rate tracings in the larger twin. Two daughters were born (birth weights 1865g and 1500g, and haemoglobin levels of 9,9 mmol/L and 9,4 mmol/L respectively). Injection study of the placental vessels (Figure 2A) showed a medium-sized arterio-arterial anastomosis and a large arteriovenous anastomosis from child B to A, combination of anastomoses not found in TTTS-placentas (Hack et al. (a) 2008). An oesophageal atresia with fistula above the vena azygos was diagnosed in the second twin. A partial resection of the distended oesophagus was performed, and continuity was restored
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Figure 1. Sonographic findings of a) a poly- and oligohydramnios, b) stomach- and bladder filling, and c) amniotic membranes in a MCDA twin pregnancy (case 1).
with an end to end anastomosis. The neurodevelopmental outcome at five years corrected age is normal in both children. Case II A 35-year-old multipara was admitted to our hospital at 18 weeks gestation with discrepant amniotic fluid volumes (DVP fetus A 0.5 cm and fetus B 7.0 cm), and discordant growth (fetus A 10th centile and fetus B 90th centile). Sonographically there was an empty bladder and doubt about the presence of both kidneys in fetus A, however in follow-up scans both kidneys seemed visible. Doppler assessment of the umbilical artery showed no abnormalities in both infants. DVP in the healthy twin gradually increased to 11.0 cm at 29 weeks with moderate to small amounts of amniotic fluid in the smaller twin (DVP 0.5 to 3.2 cm) and TTTS Quintero stage II was diagnosed. Because of the technical challenges of laser therapy in this twin with an anterior placenta, laser therapy was not performed (early 2000’s) and amniodrainage was done at 29⫹2 weeks gestation removing 3500 mL of amniotic fluid. After the amniodrainage, the amount of amniotic fluid in twin B remained normal for several weeks. At 33 weeks of gestation the DVP in twin B was 9.0 cm and Doppler abnormalities of the umbilical artery were seen. The patient was admitted at the ward. An L/S punction was performed (no amniodrainage since the patient did not have any mechanical complaints), which showed normal lung maturation and a caesarean section was planned at 34 weeks. Two sons were born (birth weights 2020g and 2400g respectively and Hb 10.1mmol/l and 12,5mmol/L respectively.) The first infant died four days after birth. Autopsy demonstrated a combination of congenital anomalies in this child, including bilateral renal agenesis, bladder agenesis, anusatresia, cryptorchism, absence of a penis, pulmonary hypoplasia. The second infant was healthy without any congenital anomalies. We found no explanation for the polyhydramnios in this infant. Placental injection study showed a large arterioarterial anastomosis as well as a few bidirectional arteriovenous anastomoses (Figure 2B), which rejects a diagnosis of TTTS as mentioned before.
Discussion TTTS is a severe complication of MCDA twin pregnancies, caused by a net inter twin transfusion of blood from one fetus, defined as the donor, towards the other fetus, defined as the recipient, through placental anastomoses (Baschat et al. 2011). Principally TOPS is an essential characteristic for the diagnosis of TTTS. TTTS may be falsely diagnosed if a difference in amniotic fluid volumes is caused by congenital anomalies which cause an imbalance in the production and absorption of amniotic fluid, or viral infections or growth restriction (Table I; O’Brien et al.1986, Von Kaisenberg et al. 2007, Harman et al. 2008, Chalouhi et al. 2010, Baschat et al. 2011). Both cases show that conflicting results from ultrasound studies need to be addressed more carefully and should make the clinician alert to confusing diagnosis. In Case I the polyhydramnios was the result of the reduced absorption of amniotic fluid due to the oesophageal atresia. Indeed, pathology findings also supported the conclusion that no TTTS occurred in this case. Retrospectively, there were incompatible ultrasound findings. Although a size discrepancy is not required for the diagnosis of TTTS, typically the donor presents as the smaller twin with an oligohydramnios and the recipient presents as the larger twin with a polyhydramnios (Harman et al. 2008, Chalouhi et al. 2010, Baschat et al. 2011). In case I this was opposite. Furthermore, the presence of a SUA should have made us alert for a different diagnosis. A fetus with a SUA is at greater risk for congenital anomalies, polyhydramnios, growth restriction and adverse neonatal outcomes (Murphy-Kaulback et al. 2010, Burshtein et al. 2011). In Case II the oligohydramnios was caused by a (lethal) urinary tract anomaly, which was doubted at first anomaly scan. It is known that fetal ultrasound may be limited due to fetal position, maternal obesity, overlying bone, and oligohydramnios (Hendrix et al. 1998). Many studies evaluate the role of antenatal magnetic resonance imaging (MRI) to improve sonographic prenatal diagnosis of congenital anomalies (Breysem et al. 2003, Pistorius et al. 2008, Gupta et al. 2010). The oligohydramnios, presenting in TTTS as well as in congenital renal anomalies, can make sonographical evaluation difficult. Above this, the characteristics of the TTTS
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Table I. Causes of polyhydramnios and oligohydramnios. Polyhydramnios Fetal Aneuploidy Neurological anomalies (anencephaly) Neuromuscular disorders Skeletal dysplasia Gastrointestinal obstruction (oesophageal atresia, intestinal atresia, gastroschisis) Maternal Diabetes mellitis Medication Infections Placenta/membranes Chorioangioma of the placenta Twin-to-twin transfusion syndrome Oligohydramnios Fetal Urogenital tract anomalies Aneuploidy Placenta/Membranes Preterm Rupture Of Membranes (PROM) Uteroplacental insufficiency/(selective) intrauterine growth restriction Twin-to-twin transfusion syndrome
Figure 2 (A, B). Monochorionic diamniotic (MCDA) placentas after injection with coloured dye. The veins are coloured yellow or orange, and the arteries are blue. (A) Placenta of MCDA twin from Case I, delivered at 31 3/7 weeks of gestation. Twin I (birth weight 1865g) has a paracentral cord insertion and a placenta territory of 56%, whereas twin II (birth weight 1500g) has a velamentous cord insertion with a single umbilical artery and a placenta territory of 44%. The artery-to-artery anastomosis is indicated by arrowheads and the artery-to-vein anastomosis ( from child B to A) is indicated by an arrow. Very small artery-to-vein anastomoses from twin A to twin B are situated close to the artery-toartery anastomosis. (B) Placenta of MCDA twin from Case II, delivered at 34 weeks of gestation. Twin A (birth weight 2020g, multiple lethal congenital malformations) has a central cord insertion with single umbilical artery and a placenta territory of 40%, whereas twin B (birth weight 2400g) has a marginal cord insertion and a placenta territory of 60%. The artery-to-artery anastomosis is indicated by arrowheads and the arteryto-vein anastomosis from twin B to twin A is indicated by a white arrow and the artery-to-vein anastomosis from twin A to twin B is indicated by a black arrow.
donor twin with a very small or non visible bladder makes it difficult to distinguish a renal agenesis or severe renal hypoplasia from TTTS. MRI is preferable since MRI is not significantly affected by diminished amniotic fluid on T2- weighted images. MRI might have a supplemental role since it provides a more detailed description and insight into fetal anatomy, pathology and etiology (Breysem et al. 2003, Pistorius et al. 2008, Gupta et al. 2010). In the future, an additional MRI-scan might give more information when sonographic findings are inconclusive, particularly when oligohydramnios is present. The cases illustrate the importance of a correct diagnosis. The treatments in both scenarios are different. In TTTS an invasive treatment could be necessary and fetal deterioration often necessitates iatrogenic preterm delivery. If the physicians in charge would have been consequent, an unnecessary laser treatment would have been performed with all combined risks. This in contrast to the more preferred scenario of continuing pregnancy in case of a congenital anomaly, since prematurity may have considerable consequences, also for the healthy sibling. The white matter of the immature brain is sensitive for haemodynamic imbalances and anaesthetic procedures
when acute surgery is necessary after birth (Harman et al. 2008, Chalouhi et al. 2010, Baschat et al. 2011). Other possible causes for discrepant amniotic fluid should therefore be ruled out. Structural anomalies have been reported to occur more often in monozygotic twins compared with dizygotic twins, with a relative risks of 1.4 to 2.7 (Myrianthopoulos et al. 1978). Despite monozygosity, the incidence of discrepant occurrence of congential malformations is increased. Discordance in monozygotic twins is usually due to a consequence of the underlying stimulus to zygote splitting, variation in gene expression, or abnormal placentation (Hendrix et al. 1998). Selective intrauterine growth restriction (sIUGR) has to be considered as a distinct entity (O’Brien et al. 1986, Baschat et al. 2011). Careful Doppler analysis may help in distinguishing in differential diagnosis, mainly in MC twins with growth restriction. Also TORCH serology needs to be determined to rule out a viral infection (e.g. parvovirus), which can also provoke this pattern (Von Kaisenberg et al. 2007). Another distinct entity is ‘the MC twins discordant for amniotic fluid’ (Harman et al. 2008, Baschat et al. 2011). These twins present with subjective difference in amniotic fluid which fail to comply with the criteria of TTTS. These pregnancies are at high risk for TTTS and should therefore be followed up on a weekly basis until subjective normalization of the amniotic fluid level is observed (Baschat et al. 2011). It may however be possible that TTTS is combined with congenital malformations, which can make the indication for invasive fetal surgery more sophisticated dependent on the future prognosis of the siblings. The relationship between intestinal atresia and TTTS has already been reported in the literature (Arul et al. 2001; Schanter et al. 2005; Morikawa et al 2008; Saura et al. 2010). It has been suggested that the aetiological factor is the fetoscopic laser photocoagulation therapy, with an embolic phenomenon causing ischaemia as the cause of this malformation (Arul et al. 2001; Schanter et al. 2005; Morikawa et al 2008; Saura et al. 2010). Morikawa et al. (2008) suggests that TTTS itself may cause the intestinal atresia. Data supporting this last hypothesis show a higher rate of small intestinal atresia among monozygotic twins than in singletons (Cragan et al. 1994). This significantly accounts for jejunoileal atresia, suggesting a vascular cause (Louw et al. 1955; Van der Pol et al. 1992). In addition, lesions in several organs caused by ischaemia, especially the brain, have been reported in twins affected by TTTS irrespective of the kind of treatment employed (Morikawa et al. 2008). Mesenteric ischaemia due to haemodynamic alterations causing hypoperfu-
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sion and hyperviscosity associated with TTTS, might cause these (gastro-) intestinal malformations (Arul et al. 2001; Schanter et al. 2005; Morikawa et al 2008; Saura et al. 2010). The same mechanism may also be the cause of the higher incidence of necrotising enterocolitis found in MC twins (Hack et al. (b) 2008). Conclusion and recommendation These case series clearly show that the diagnosis of TTTS should not be easily confused with other reasons of discrepant amniotic fluid volumes or discrepant size. A detailed anomaly scan (even when previous scans did not show any abnormalities), TORCH serology and Doppler velocimetry of fetal vessels should be applied in third line centers. In the future, an additional MRI scan might give more information when sonographic findings are inconclusive, particularly when oligohydramnios is present.
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Financial disclosure absence of any interest to disclosure Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References Arul GS, Carrol S, Kyle PM, Soothill PW, Spicer RD. 2001. Intestinal complications associated with twin-to-twin transfusion syndrome after antenatal laser treatment: report of two cases. Journal of Pediatric Surgery ; 36:301–302. Baschat A. Chmait RH, Deprest J, Gratacós E, Hecher K, Kontopoulos E et al. 2011. Twin-to-twin transfusion syndrome (TTTS) Journal of Perinatal Medicine; 39:107–112. Breysem L, Bosmans H, Dymarkowski S, Van Schoubroeck D, Witters I, Deprest J et al. 2003. The value of fast MR imaging as an adjunct to ultrasound in prenatal diagnosis. Eurepean Radiology 13:1538–1548. Burshtein S, Levy A, Holcberg G, Zlotnik A, Sheiner E. 2011. Is single umbilical artery an independent risk factor for perinatal mortality? Arch Gynecol Obstet. 283:191–194. Chalouhi GE, Stirneman JJ, Salomon LJ, Essaoui M, Quibel T, Ville Y. 2010. Specific complications of monochorionic twin pregnancies: twin- twin transfusion syndrome and twin reversed arterial perfusion sequence. Seminars in fetal & Neonatal Medicine 15:349–356. Cragan JD, Martin ML, Waters GD, Khoury MJ. 1994. Increased risk of small intestinal atresia among twins in the United States. Archives of Pediatric Adolescense Medicine 148:733–739. Gupta R, Kumar S, Sharma R, Gadodia A, Roy KK, Sharma JB. 2010. The role of magnetic resonance imaging in fetal renal anomalies. International Journal of Gynaecology and Obstetrics 111:209–212. Hack KEA (a), Nikkels PG, Koopman-Esseboom C, Derks JB, Elias SG, van Gemert MJ et al. 2008. Placental characteristics of monochorionic diamniotic twin pregnancies in relation to perinatal outcome. Placenta 29: 976–981. Hack KEA (b), Derks JB, Elias SG, Franx A, Roos EJ, Voerman SK et al. 2008. Increased perinatal mortality and morbidity in monochorionic versus dichorionic twin pregnancies: clinical implications of a large Dutch cohort study. British Journal of Obstetrics and Gynaecology. 115:141–143. Harman, CR. 2008. Amniotic Fluid Abnormalities. Seminars in Perinatology 32:288–294. Hendrix NW, Chauhan SP. 1998. Sonographic examination of twins. From first trimester to delivery of second fetus. Obstet Gynecol Clin North Am. 25: 609–621. Louw JH, Barnard CN. 1955. Congenital intestinal atresia: observations on its origin. Lancet 2:1065–1069. Morikawa M, Sago H. Yamada T, Hayashi S, Yamada T, Cho K et al. 2008. Ileal atresia after fetoscopic laser photocoagulation for twin-to-twin transfusion syndrome- a case report. Prenatal Diagnosis 28:1072–1074. Murphy-Kaulback L, Dodds L, Joseph KS, van den Hof M. 2010. Single umbilical artery risk factors and pregnancy outcomes. Obstetrics and Gynecology 116:843–850. Myrianthopoulos NC. 1978 Congenital malformations: the contribution of twin studies. Birth Defects Orig Artic Ser 14:151–165. O’Brien WF, Knuppel RA, Scerbo JC, Rattan PK. 1986. Birth weight in twins: an analysis of discordancy and growth retardation. Obstetrics and Gynecology 67: 483–486.
Pistorius LR, Hellmann PM, Visser GHA, Malinger G, Prayer D. 2008. Fetal neuroimaging: ultrasound, MRI, or both? Obstetrics and Gynecology Survey 63:733–745. Schanter JM, Zalen-Sprock RM, Schaap AHP, Festen S, Aronson DC. 2005 Ileal atresia and thrombo-embolic liver calcifications diagnosed after treatment with intrauterine laser coagulation therapy for twin-to-twin transfusion syndrome. Report of two casus. Journal of Pediatric Surgery 40: 875–876. Saura L, Muñoz ME, Castañón M, Eixarch E, Corradini M, Aguilar C et al. 2010. Intestinal complications after antenatal fetoscopic laser ablation in twin-to-twin transfusion syndrome. Journal of Pediatric Surgery 45: E5–E8. Sperling L, Kiil C, Larsen LU et al. 2007. Detection of chromosomal abnormalities, congenital abnormalities and transfusion syndrome in twins. Utrasound Obstet Gynecol 29: 517–526. Van der Pol JG, Wolf H, Boer K, Treffers PE, Leschot NJ, Hey HA et al. 1992. Jejunal atresia related to the use of methylene blue in genetic amniocentesis in twins.British Journal of Obstetrics and Gynaecology 99:141–143. Von Kaisenberg CS, Grebe S, Schleider S, Kühling-vonKaisenberg H, Venhoff L, Meinhold-Heerlein I. 2007. Successful Intrauterine Intracardiac Transfusion in Mono-chorionic Twins Affected by Parvovirus B19. Fetal Diagn Ther 22:420–424.
Impaired DNA methylation leading to heterotrisomy M. Turgal, A. Yazicioglu, O. Ozyuncu & M. S. Beksac Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Hacettepe University School of Medicine, Ankara, Turkey DOI: 10.3109/01443615.2013.838547 Correspondence: A. Yazicioglu, Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Hacettepe University, School of Medicine, Sihhiye, Ankara, Turkey. E-mail: [email protected]
Introduction To date, it is known that approximately 15–20% of all clinically recognised pregnancies result in spontaneous abortion (Robinson et al. 2001). The American Society for Reproductive Medicine defines recurrent pregnancy loss (RPL) as two or more failed pregnancies (Practice Committee of the American Society for Reproductive Medicine 2008). Some 2% of pregnant women experience two consecutive pregnancy losses and only 0.4–1% have three consecutive pregnancy losses (Salat-Baroux 1988). Major chromosomal rearrangement accounts for only 3–5% of RPL cases (Franssen et al. 2005; De Braekeleer and Dao 1990). Here, we describe a unique case of a 46-year-old woman having a different trisomy at each of four pregnancies (21, 15, 6, 2), with impaired DNA methylation as the only identified risk factor.
Case report A 46-year-old woman was admitted to our department for the follow-up of her fourth pregnancy. Her obstetric history was remarkable, with two previous terminated pregnancies and one spontaneous abortion. The first pregnancy (42 years) was terminated after a cytogenetic finding of fetal trisomy 21 and the second (43 years) was terminated due to trisomy 15. During genetic counselling, the couple expressed their fear that they were at high risk for recurrent trisomy for any future pregnancy. They preferred to have their third pregnancy (44 years) via an in-vitro fertilisation (IVF) protocol, with intracytoplasmic sperm injection (ICSI) and subsequent embryo biopsy and fluorescent in situ hybridisation (FISH) analysis for chromosomes 13, 15, 16, 17, 18, 21, 22, X and Y. After ICSI, three blastomeres developed and FISH was performed. The result was bizarre: the first had monosomy 16, the second had both monosomy 16 and 21 and the third was considered to be normal. The woman’s third pregnancy was that remaining blastomere, subsequently ending with a spontaneous abortion at 8 weeks’ gestation.
