- Email: [email protected]
Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis
Journal of Neonatal Nursing (2016) xxx, xxxexxx
www.elsevier.com/jneo
ORIGINAL ARTICLE
Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis Philippa Mann, RN, MN(ClinLead), Registered Nursea,*, Janet Green, RN, PhD, MBioethics, Coordinator Postgraduate Neonatal Nursing, UTS, Karen Walker, PhD MN BAppSc (Nsg) RGN RSCN, Clinical Research Officer, Grace Centre for Newborn Careb a
The Children’s Hospital at Westmead, Australia The Children’s Hospital at Westmead, The University of Sydney, The University of Technology Sydney, Cerebral Palsy Alliance, Australia
b
Available online - - -
KEYWORDS Twin-to-twin transfusion syndrome; Barker hypothesis; Foetal; Development; Outcomes
Abstract Twin-to-Twin Transfusion Syndrome (TTTS) carries significant risk of morbidity and mortality in affected monozygotic twin sets. As research into TTTS progresses, the effects of the adverse intrauterine environment on the long-term morbidities of TTTS survivors, is becoming more apparent. In TTTS, there is impaired vascular development and significant cardiac change in both foetuses, leading to high risk of long-term cardiac and neurologic morbidities in survivors. This appears to reflect the Barker Hypothesis of the Developmental Origins of Disease. This review will discuss the Barker Hypothesis and its potential applicability to TTTS. It will outline foetal development in TTTS and subsequent consequences for the neonate. Current TTTS research will be discussed in addition to relevant neonatal care provision. It will become evident that in order to improve long-term outcomes for TTTS survivors, a significant body of research focussing upon the correlation between foetal development in TTTS and associated adult disease states is required. ª 2016 Published by Elsevier Ltd on behalf of Neonatal Nurses Association.
* Corresponding author. 2 Ashcroft Street, Ermington, NSW, 2115, Australia. Tel.: þ61 406553935. E-mail address: [email protected] (P. Mann). http://dx.doi.org/10.1016/j.jnn.2016.03.002 1355-1841/ª 2016 Published by Elsevier Ltd on behalf of Neonatal Nurses Association.
Please cite this article in press as: Mann, P., et al., Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis, Journal of Neonatal Nursing (2016), http://dx.doi.org/10.1016/j.jnn.2016.03.002
2
Introduction Twin-to-Twin Transfusion Syndrome (TTTS) is a rare but life threatening condition affecting a proportion of monozygotic pregnancies. Monozygotic pregnancies arise from the division of a single zygote after fertilisation, with the resulting foetuses sharing similar genetic material (Silva et al., 2011) e commonly referred to as identical twins. It has a significant risk of functional and structural cardiac changes to the affected foetuses, increased risk of adverse neurological outcomes, carries a high chance of premature delivery, and if untreated, carries an exceptionally high risk of foetal demise. As such, understanding and developing appropriate interventions to treat TTTS is a significant priority. As more research is emerging, it is becoming evident that the effects of the intrauterine environment on TTTS survivors development is having a significant impact upon long-term morbidities, particularly in relation to impaired vascular development in-utero and longterm cardiac and neurologic morbidities. This appears to relate to the Barker hypothesis of the developmental origins of adult disease, which postulates that adverse influences during perinatal development can impact upon the risk of adult disease states. The following review will discuss the origins of the Barker hypothesis and its potential applicability to Twin-to-Twin Transfusion Syndrome, with reference to current evidence and the possible mechanisms that may be involved. It will outline foetal development of TTTS and the short and long term consequences for neonates. The role of the neonatal nurse in care provision will also be identified. It will be evident that although links between TTTS and the Barker hypothesis are emerging, an increasing body of research is required to understand and further develop best practice to improve outcomes both in the acute care setting and across the lifespan.
Methodology Medical Subject Heading (MeSH) terms were utilised for the purposes of obtaining relevant literature on the topic. The databases of choice for this review were CINAHL, Medline, PubMed, and Informit. Literature searches were conducted in three parts, using Boolean search types. The first search conducted utilised the MeSH terms of “Barker”, “Hypothesis”, “Twin-To-Twin” “Transfusion” “Syndrome” and yielded no relevant literature. The topic then was separated into two
P. Mann et al. search focuses, with the resulting literature analysed together to review potential applicability of the Barker Hypothesis to Twin-To-Twin Transfusion Syndrome. The search for “Barker” “Hypothesis” yielded 290 results. The search for “Twin-To-Twin” “Transfusion” “Syndrome” yielded 3563 results, which were further filtered to results from the last five years, generating 1330 results. The resultant literature utilised in this review were hand selected based upon relevance to the topic, highlighting potential for links to be made between Twin-To-Twin Transfusion Syndrome and The Barker Hypothesis.
The Barker hypothesis In the late 1980’s, David Barker identified relationships between low birth weight neonates who survived infancy and an increased risk of disease in adulthood. This led him to further research and hypothesize that adverse influences during intrauterine life and early development could lead to permanent physiologic and metabolic changes, which increase the risk of disease later in life (De Boo and Harding, 2006). The hypothesis was called “developmental origins of adult disease” and is often referred to as the “Barker Hypothesis” (De Boo and Harding, 2006). A number of conditions have been linked to the hypothesis such as hypertension, ischaemic heart disease and diabetes (Poulter, 2001), as well as stroke, coronary heart disease and obesity (Kimm, 2004). However, the hypothesis has been met with scepticism at times due to a lack of compounding evidence of the mechanisms involved in the relationship, the links identified being largely observational, and the impact of other factors such as prematurity or multiple gestations influencing the results. Although not yet proven, a number of mechanisms have been proposed which support the Barker Hypothesis. According to De Boo and Harding (2006), the most likely mechanism involved is the process of foetal programming whereby insults or specific stimuli during critical or sensitive periods of development, result in long-term, irreversible, adverse consequences affecting subsequent development. These could be related to altered foetal nutrition, exposure to excess glucocorticoids, the thrifty phenotype hypothesis and predictive adaptive responses, the foetal insulin hypothesis, genetic and epigenetic links, intergenerational effects, and periconceptional events (De Boo and Harding, 2006). For example, Daniels (2007) suggests that for hypertension, it appears that the combination of a
Please cite this article in press as: Mann, P., et al., Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis, Journal of Neonatal Nursing (2016), http://dx.doi.org/10.1016/j.jnn.2016.03.002
Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis smaller birth weight followed by a rapid weight increase in the first six months of life (indicating a significant increase in adiposity), influences a higher blood pressure by three years of age. Again, the issue is that the evidence is not strong enough to understand and support the mechanics postulated definitively at present. One condition where research into the intrauterine environment and ensuing foetal development could potentially provide tangibility and validity to the understanding of the mechanisms involved in the Barker Hypothesis, is Twin-to-Twin Transfusion Syndrome and its relationship with subsequent adult disease states.
Twin-to-twin transfusion Twin-to-Twin Transfusion Syndrome (TTTS) is a rare condition occurring in approximately 9e15% of monozygotic twin sets (Chmait et al., 2010) which, if left untreated, results in a risk of foetal death of approximately 90% (Graeve et al., 2012). It is caused by significant arterial-venous anastomoses in a shared placenta, which leads to shunting of arterial blood from one twin (the donor) through the anastomoses into the venous circulation of the other twin (the recipient) (Moore et al., 2013). As stated by Blackburn (2013) the recipient will respond to the higher blood volume by increasing atrial natriuretic peptide leading to an increased glomerular filtration rate, decreased tubular reabsorption as well as suppression of arginine vasopressin and polyuria e all of which may lead to the development of hydrops and cardiomegaly. The reduced circulating blood volume in the donor twin stimulates the renin-angiotensin system which in turn stimulates vasoconstriction in order to increase vascular volume often resulting in hypertension leading to foetal growth restriction due to a decrease in placental and renal perfusion (Blackburn, 2013). The donor twin is at risk of developing congestive heart failure and is smaller, anaemic and hypovolemic, often with decreased urine output leading to oligohydramnios, whereby conversely, the recipient is larger, polycythaemic, hypervolemic and hypertensive with excessive urination leading to polyhydramnios (Blackburn, 2013). Structural and functional cardiac changes result in the recipient twin, which can include unilateral or bilateral ventricular hypertrophy, tricuspid regurgitation, mitral regurgitation, increased cardiothoracic ratio, ventricular dilation, systolic dysfunction, and sometimes right ventricular outflow tract obstruction, and pulmonary valve stenosis or atresia (Habli et al., 2010). TTTS places both foetuses at an
3
increased risk of brain injury, prematurity, and foetal demise (Merhar et al., 2013), with worsening outcomes associated with a more rapid progression of the clinical course at earlier gestations.
Potential links As yet, there is no literature available directly linking TTTS to the Barker hypothesis. However, it can be inferred that if the recipient twin survives, he/she will be at greater risk for ongoing cardiac concerns in adulthood due to the significant vascular changes occurring during intrauterine development. It could also be said that even though acute care is often focused upon the recipient twin as they often present more acutely ill, it is the donor twin who may be at the greatest risk of adult disease due to their small size at birth compared to the placenta and recipient twin as well as potential insults occurring during significant periods such as the formation of the foetal vasculature (Stirnemann et al., 2010). TTTS is diagnosed via ultrasound prenatally by identifying a monochorionic diamniotic (MCDA) pregnancy with presence of oligohydramnios (maximum vertical pocket <2 cm) in one sac and polyhydramnios (maximum vertical pocket >8 cm) in the other sac (Simpson and Medicine, 2013). This is normally identified and diagnosed during the second trimester of pregnancy (Lopriore et al., 2014). Current evidence, as discussed by Van Mieghem et al. (2010), shows that cardiac function of the twin foetuses is increasingly being assessed comprehensively through ultrasound techniques such as intracardiac Doppler assessment of transvalvular blood flow, the myocardial performance (“Tei”) index, praecordial venous Doppler’s, and M-mode assessment of ventricular contractility. The research is suggesting that these tools for cardiac functional assessment could be utilised to predict survival of the foetuses, particularly the recipient, as well as identifying issues and the requirements for intervention at earlier stages. Therefore it could be inferred that in relation to the Barker hypothesis, these tools may play a larger role in the future of predicting the foetuses risk of developing adverse cardiac outcomes and related diseases in adulthood.
Twin-to-twin transfusion intervention Due to the high risk of foetal death if TTTS is left untreated, intervention is necessary to reduce the
Please cite this article in press as: Mann, P., et al., Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis, Journal of Neonatal Nursing (2016), http://dx.doi.org/10.1016/j.jnn.2016.03.002
4 risk of poor outcomes in the short term as well as long term disease and disability. In order to identify when intervention is required, the Quintero classification is used to stage the clinical course of TTTS from Stage I (mild) to Stage V (foetal death) (Hoopmann et al., 2010). An increasing amount of data being collected is demonstrating that the quicker the progression between the stages, the greater the risk of adverse outcomes. The prenatal management of TTTS is aimed at decreasing this high risk of morbidity and mortality and can include treatment options such as amnioreduction, septostomy, and foetoscopic laser photocoagulation (Giconi, 2013). Research has shown that foetoscopic laser photocoagulation is current best practice and now considered to be the gold standard of intervention for TTTS. Graeve et al. (2012) state that this is because it is the only intervention that offers a causal therapy by interrupting the placental anastomoses between the donor and recipient twins, giving the best chance to slowing disease progression and allowing improved perinatal development to proceed, with a resulting survival rate of nearly 70%.
Research In regards to current research, Skupski (2014) identified that one of the most vexing issues in treatment of TTTS via laser coagulation is recurrent TTTS and Twin Anaemia Polycythaemia Sequence (TAPS), which often develop post laser surgery and with no accurate method of prediction at present. Evidence has also suggested that survivors of TTTS treated by foetoscopic laser surgery have a higher likelihood of displaying visible abnormalities on head ultrasound in the first day of life, indicating that the insult occurred antenatally (Crombleholme, 2012). The mechanisms involved require further investigation but is thought to be a result of dilated cerebral sinuses and increased central venous pressure which potentially contribute to the development of intraventricular haemorrhage (IVH) (Crombleholme, 2012). An interesting point noted by Crombleholme (2012) in his literature review is that over the past decade or so, there has been a decrease in the incidences of CNS abnormalities in TTTS survivors treated with foetoscopic laser photocoagulopathy, perhaps suggestive of the improved experience, techniques and expertise of the teams performing the intervention. Under the Barker hypothesis, this could improve long term outcomes in TTTS survivors into adulthood as it would suggest that intervening with
P. Mann et al. the placental anastomoses more accurately and at earlier gestations, would mean that the vasculature of both the recipient and donor would develop healthier and decrease the risk of further insults during significant periods of intrauterine development. This would in turn minimise or ameliorate the risks of adult disease states in addition to the reduction of adverse outcomes in both the perinatal and neonatal periods.
Neonatal care As TTTS is a syndrome of pregnancy, there is no definitive treatment once neonates with the condition have been delivered (Giconi, 2013). Neonatal Intensive Care Unit (NICU) teams should treat each neonate for the specific complications of TTTS that each may have suffered. In the donor, this could be fluid resuscitation for hypovalaemia, blood transfusions if profound anaemia is present, monitoring urine output if the infant has poor renal function, and treating respiratory distress secondary to severe oligohydramnios (Giconi, 2013). The recipient twin may need significant cardiovascular and respiratory support such as inotropes to increase contractility and output of the heart due to severe cardiomyopathy, significant ventilatory support, exchange transfusion for the profound polycythaemia in addition to aggressive phototherapy management for the corresponding hyperbilirubinaemia (Giconi, 2013). In addition to understanding and treating the individual complications that each neonate may suffer, neonatal nurses must understand the long-term sequela that survivors of TTTS are at risk for. Evidence individually collated by Giconi (2013), Salomon et al. (2010), Bidzan et al. (2013), Memmo et al. (2012), and Jawish et al. (2015) among many others, has shown that poor outcomes, particularly high neurologic morbidities, occur in approximately 25% of survivors of TTTS. This has an enormous impact on the neonates and their families for the rest of their lives and highlights the importance of comprehensive developmental follow up and information provision to families to maximise the chances of a healthier and higher quality of life across the lifespan. In order to minimise the risk of adverse outcomes both short and long term, significant research is required to improve early identification and management of TTTS as well as investigating TTTS in relation to the Barker hypothesis, to identify and understand the mechanisms involved between intrauterine development and adult disease states.
Please cite this article in press as: Mann, P., et al., Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis, Journal of Neonatal Nursing (2016), http://dx.doi.org/10.1016/j.jnn.2016.03.002
Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis
Conclusion In order for long-term outcomes to be improved for survivors of TTTS, a large amount of research is required with a focus on the links between intrauterine development and disease states in later life. The paucity of data for TTTS and the Barker hypothesis is testament to the rarity of the disease and the relatively young understanding of it. Future longitudinal follow up studies of TTTS survivors, following the Barker Hypothesis, may demonstrate that adult disease states such as hypertension, diabetes and coronary heart disease in TTTS survivors will be correlated to the mechanisms involved in TTTS and subsequent foetal development.
References Bidzan, M., Bieleninik, q., Lipowska, M., 2013. The development of speech in early childhood in children from twin pregnancies with twin-twin transfusion syndrome (TTTS). Pol. Psychol. Bull. 44, 9e20. Blackburn, S.T., 2013. Maternal, Fetal, & Neonatal Physiology. Elsevier Saunders, Amsterdam. Chmait, R., Assaf, S., Benirschke, K., 2010. Residual vascular communications in twin-twin transfusion syndrome treated with sequential laser surgery: frequency and clinical implications. Placenta 31, 611e614. Crombleholme, T., 2012. Central nervous system injury in twinetwin transfusion syndrome: opportunity for improvement? Obstet. Gynecol. 120, 7e8. Daniels, S.R., 2007. The Barker hypothesis revisited. J. Pediatr. 151, A3. De Boo, H.A., Harding, J.E., 2006. The developmental origins of adult disease (Barker) hypothesis. Aust. N. Z. J. Obstet. Gynaecol. 46, 4e14. Giconi, S.S., 2013. Twin-to-twin transfusion syndrome: a case study. Adv. Neonatal Care 13, 31e37. Graeve, P., Banek, C., Stegmann-Woessner, G., Maschke, C., Hecher, K., Bartmann, P., 2012. Neurodevelopmental outcome at 6 years of age after intrauterine laser therapy for twin-twin transfusion syndrome. Acta Paediatr. 101, 1200e1205. Habli, M., Cnota, J., Michelfelder, E., Salisbury, S., Schnell, B., Polzin, W., Lim, F.Y., Crombleholme, T.M., 2010. The relationship between amniotic fluid levels of brain-type natriuretic peptide and recipient cardiomyopathy in twinetwin
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transfusion syndrome. Am. J. Obstet. Gynecol. 203, 404. e401e404. e407. Hoopmann, M., Abele, H., Wallwiener, D., Kagan, K.O., 2010. Management of twinetwin transfusion syndrome. Gynecol. Surg. 7, 329e333. Jawish, R., Lim, F.-Y., Lababidi, A., Zaid, M., Polzin, W., Habli, M. , 2015. 590: long term neurodevelopmental outcome in twin twin transfusion syndrome (TTTS) from a single institution in the USA. Am. J. Obstet. Gynecol. 212, S294. Kimm, S.Y., 2004. Fetal origins of adult disease: the Barker hypothesis revisitedd2004. Curr. Opin. Endocrinol. Diabetes Obes. 11, 192e196. Lopriore, E., Holtkamp, N., Sueters, M., Middeldorp, J.M., Walther, F.J., Oepkes, D., 2014. Acute peripartum twinetwin transfusion syndrome: incidence, risk factors, placental characteristics and neonatal outcome. J. Obstet. Gynaecol. Res. 40, 18e24. Memmo, A., Dias, T., Mahsud-Dornan, S., Papageorghiou, A., Bhide, A., Thilaganathan, B., 2012. Prediction of selective fetal growth restriction and twin-to-twin transfusion syndrome in monochorionic twins. BJOG Int. J. Obstet. Gynaecol. 119, 417e421. Merhar, S., Kline-Fath, B., Meinzen-Derr, J., Schibler, K., Leach, J., 2013. Fetal and postnatal brain MRI in premature infants with twinetwin transfusion syndrome. J. Perinatol. 33, 112e118. Moore, K.L., Persaud, T.V.N., Torchia, M.G., 2013. The Developing Human: Clinically Oriented Embryology. Elsevier Saunders, Philadelphia. Poulter, N.R., 2001. Birthweights, maternal cardiovascular events, and Barker hypothesis. Lancet 357, 1990e1991. ¨ rtqvist, L., Aegerter, P., Bussieres, L., Salomon, L.J., O Staracci, S., Stirnemann, J.J., Essaoui, M., Bernard, J.-P., Ville, Y., 2010. Long-term developmental follow-up of infants who participated in a randomized clinical trial of amniocentesis vs laser photocoagulation for the treatment of twin-to-twin transfusion syndrome. Am. J. Obstet. Gynecol. 203, 444. e441e444. e447. Silva, S., Martins, Y., Matias, A., Blickstein, I., 2011. Why are monozygotic twins different? J. Perinatal Med. 39, 195e202. Simpson, L.L., Medicine, S.f.M.-F., 2013. Twin-twin transfusion syndrome. Am. J. Obstet. Gynecol. 208, 3e18. Skupski, D.W., 2014. Twin-to-twin transfusion syndrome: knowing our boundaries. Lancet 383, 2108e2109. Stirnemann, J., Mougeot, M., Proulx, F., Nasr, B., Essaoui, M., Fouron, J., Ville, Y., 2010. Profiling fetal cardiac function in twinetwin transfusion syndrome. Ultrasound Obstet. Gynecol. 35, 19e27. Van Mieghem, T., Done ´, E., Gucciardo, L., Klaritsch, P., Allegaert, K., Van Bree, R., Lewi, L., Deprest, J., 2010. Amniotic fluid markers of fetal cardiac dysfunction in twinto-twin transfusion syndrome. Am. J. Obstet. Gynecol. 202, 48. e41e48. e47.
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Please cite this article in press as: Mann, P., et al., Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis, Journal of Neonatal Nursing (2016), http://dx.doi.org/10.1016/j.jnn.2016.03.002
www.elsevier.com/jneo
ORIGINAL ARTICLE
Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis Philippa Mann, RN, MN(ClinLead), Registered Nursea,*, Janet Green, RN, PhD, MBioethics, Coordinator Postgraduate Neonatal Nursing, UTS, Karen Walker, PhD MN BAppSc (Nsg) RGN RSCN, Clinical Research Officer, Grace Centre for Newborn Careb a
The Children’s Hospital at Westmead, Australia The Children’s Hospital at Westmead, The University of Sydney, The University of Technology Sydney, Cerebral Palsy Alliance, Australia
b
Available online - - -
KEYWORDS Twin-to-twin transfusion syndrome; Barker hypothesis; Foetal; Development; Outcomes
Abstract Twin-to-Twin Transfusion Syndrome (TTTS) carries significant risk of morbidity and mortality in affected monozygotic twin sets. As research into TTTS progresses, the effects of the adverse intrauterine environment on the long-term morbidities of TTTS survivors, is becoming more apparent. In TTTS, there is impaired vascular development and significant cardiac change in both foetuses, leading to high risk of long-term cardiac and neurologic morbidities in survivors. This appears to reflect the Barker Hypothesis of the Developmental Origins of Disease. This review will discuss the Barker Hypothesis and its potential applicability to TTTS. It will outline foetal development in TTTS and subsequent consequences for the neonate. Current TTTS research will be discussed in addition to relevant neonatal care provision. It will become evident that in order to improve long-term outcomes for TTTS survivors, a significant body of research focussing upon the correlation between foetal development in TTTS and associated adult disease states is required. ª 2016 Published by Elsevier Ltd on behalf of Neonatal Nurses Association.
* Corresponding author. 2 Ashcroft Street, Ermington, NSW, 2115, Australia. Tel.: þ61 406553935. E-mail address: [email protected] (P. Mann). http://dx.doi.org/10.1016/j.jnn.2016.03.002 1355-1841/ª 2016 Published by Elsevier Ltd on behalf of Neonatal Nurses Association.
Please cite this article in press as: Mann, P., et al., Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis, Journal of Neonatal Nursing (2016), http://dx.doi.org/10.1016/j.jnn.2016.03.002
2
Introduction Twin-to-Twin Transfusion Syndrome (TTTS) is a rare but life threatening condition affecting a proportion of monozygotic pregnancies. Monozygotic pregnancies arise from the division of a single zygote after fertilisation, with the resulting foetuses sharing similar genetic material (Silva et al., 2011) e commonly referred to as identical twins. It has a significant risk of functional and structural cardiac changes to the affected foetuses, increased risk of adverse neurological outcomes, carries a high chance of premature delivery, and if untreated, carries an exceptionally high risk of foetal demise. As such, understanding and developing appropriate interventions to treat TTTS is a significant priority. As more research is emerging, it is becoming evident that the effects of the intrauterine environment on TTTS survivors development is having a significant impact upon long-term morbidities, particularly in relation to impaired vascular development in-utero and longterm cardiac and neurologic morbidities. This appears to relate to the Barker hypothesis of the developmental origins of adult disease, which postulates that adverse influences during perinatal development can impact upon the risk of adult disease states. The following review will discuss the origins of the Barker hypothesis and its potential applicability to Twin-to-Twin Transfusion Syndrome, with reference to current evidence and the possible mechanisms that may be involved. It will outline foetal development of TTTS and the short and long term consequences for neonates. The role of the neonatal nurse in care provision will also be identified. It will be evident that although links between TTTS and the Barker hypothesis are emerging, an increasing body of research is required to understand and further develop best practice to improve outcomes both in the acute care setting and across the lifespan.
Methodology Medical Subject Heading (MeSH) terms were utilised for the purposes of obtaining relevant literature on the topic. The databases of choice for this review were CINAHL, Medline, PubMed, and Informit. Literature searches were conducted in three parts, using Boolean search types. The first search conducted utilised the MeSH terms of “Barker”, “Hypothesis”, “Twin-To-Twin” “Transfusion” “Syndrome” and yielded no relevant literature. The topic then was separated into two
P. Mann et al. search focuses, with the resulting literature analysed together to review potential applicability of the Barker Hypothesis to Twin-To-Twin Transfusion Syndrome. The search for “Barker” “Hypothesis” yielded 290 results. The search for “Twin-To-Twin” “Transfusion” “Syndrome” yielded 3563 results, which were further filtered to results from the last five years, generating 1330 results. The resultant literature utilised in this review were hand selected based upon relevance to the topic, highlighting potential for links to be made between Twin-To-Twin Transfusion Syndrome and The Barker Hypothesis.
The Barker hypothesis In the late 1980’s, David Barker identified relationships between low birth weight neonates who survived infancy and an increased risk of disease in adulthood. This led him to further research and hypothesize that adverse influences during intrauterine life and early development could lead to permanent physiologic and metabolic changes, which increase the risk of disease later in life (De Boo and Harding, 2006). The hypothesis was called “developmental origins of adult disease” and is often referred to as the “Barker Hypothesis” (De Boo and Harding, 2006). A number of conditions have been linked to the hypothesis such as hypertension, ischaemic heart disease and diabetes (Poulter, 2001), as well as stroke, coronary heart disease and obesity (Kimm, 2004). However, the hypothesis has been met with scepticism at times due to a lack of compounding evidence of the mechanisms involved in the relationship, the links identified being largely observational, and the impact of other factors such as prematurity or multiple gestations influencing the results. Although not yet proven, a number of mechanisms have been proposed which support the Barker Hypothesis. According to De Boo and Harding (2006), the most likely mechanism involved is the process of foetal programming whereby insults or specific stimuli during critical or sensitive periods of development, result in long-term, irreversible, adverse consequences affecting subsequent development. These could be related to altered foetal nutrition, exposure to excess glucocorticoids, the thrifty phenotype hypothesis and predictive adaptive responses, the foetal insulin hypothesis, genetic and epigenetic links, intergenerational effects, and periconceptional events (De Boo and Harding, 2006). For example, Daniels (2007) suggests that for hypertension, it appears that the combination of a
Please cite this article in press as: Mann, P., et al., Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis, Journal of Neonatal Nursing (2016), http://dx.doi.org/10.1016/j.jnn.2016.03.002
Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis smaller birth weight followed by a rapid weight increase in the first six months of life (indicating a significant increase in adiposity), influences a higher blood pressure by three years of age. Again, the issue is that the evidence is not strong enough to understand and support the mechanics postulated definitively at present. One condition where research into the intrauterine environment and ensuing foetal development could potentially provide tangibility and validity to the understanding of the mechanisms involved in the Barker Hypothesis, is Twin-to-Twin Transfusion Syndrome and its relationship with subsequent adult disease states.
Twin-to-twin transfusion Twin-to-Twin Transfusion Syndrome (TTTS) is a rare condition occurring in approximately 9e15% of monozygotic twin sets (Chmait et al., 2010) which, if left untreated, results in a risk of foetal death of approximately 90% (Graeve et al., 2012). It is caused by significant arterial-venous anastomoses in a shared placenta, which leads to shunting of arterial blood from one twin (the donor) through the anastomoses into the venous circulation of the other twin (the recipient) (Moore et al., 2013). As stated by Blackburn (2013) the recipient will respond to the higher blood volume by increasing atrial natriuretic peptide leading to an increased glomerular filtration rate, decreased tubular reabsorption as well as suppression of arginine vasopressin and polyuria e all of which may lead to the development of hydrops and cardiomegaly. The reduced circulating blood volume in the donor twin stimulates the renin-angiotensin system which in turn stimulates vasoconstriction in order to increase vascular volume often resulting in hypertension leading to foetal growth restriction due to a decrease in placental and renal perfusion (Blackburn, 2013). The donor twin is at risk of developing congestive heart failure and is smaller, anaemic and hypovolemic, often with decreased urine output leading to oligohydramnios, whereby conversely, the recipient is larger, polycythaemic, hypervolemic and hypertensive with excessive urination leading to polyhydramnios (Blackburn, 2013). Structural and functional cardiac changes result in the recipient twin, which can include unilateral or bilateral ventricular hypertrophy, tricuspid regurgitation, mitral regurgitation, increased cardiothoracic ratio, ventricular dilation, systolic dysfunction, and sometimes right ventricular outflow tract obstruction, and pulmonary valve stenosis or atresia (Habli et al., 2010). TTTS places both foetuses at an
3
increased risk of brain injury, prematurity, and foetal demise (Merhar et al., 2013), with worsening outcomes associated with a more rapid progression of the clinical course at earlier gestations.
Potential links As yet, there is no literature available directly linking TTTS to the Barker hypothesis. However, it can be inferred that if the recipient twin survives, he/she will be at greater risk for ongoing cardiac concerns in adulthood due to the significant vascular changes occurring during intrauterine development. It could also be said that even though acute care is often focused upon the recipient twin as they often present more acutely ill, it is the donor twin who may be at the greatest risk of adult disease due to their small size at birth compared to the placenta and recipient twin as well as potential insults occurring during significant periods such as the formation of the foetal vasculature (Stirnemann et al., 2010). TTTS is diagnosed via ultrasound prenatally by identifying a monochorionic diamniotic (MCDA) pregnancy with presence of oligohydramnios (maximum vertical pocket <2 cm) in one sac and polyhydramnios (maximum vertical pocket >8 cm) in the other sac (Simpson and Medicine, 2013). This is normally identified and diagnosed during the second trimester of pregnancy (Lopriore et al., 2014). Current evidence, as discussed by Van Mieghem et al. (2010), shows that cardiac function of the twin foetuses is increasingly being assessed comprehensively through ultrasound techniques such as intracardiac Doppler assessment of transvalvular blood flow, the myocardial performance (“Tei”) index, praecordial venous Doppler’s, and M-mode assessment of ventricular contractility. The research is suggesting that these tools for cardiac functional assessment could be utilised to predict survival of the foetuses, particularly the recipient, as well as identifying issues and the requirements for intervention at earlier stages. Therefore it could be inferred that in relation to the Barker hypothesis, these tools may play a larger role in the future of predicting the foetuses risk of developing adverse cardiac outcomes and related diseases in adulthood.
Twin-to-twin transfusion intervention Due to the high risk of foetal death if TTTS is left untreated, intervention is necessary to reduce the
Please cite this article in press as: Mann, P., et al., Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis, Journal of Neonatal Nursing (2016), http://dx.doi.org/10.1016/j.jnn.2016.03.002
4 risk of poor outcomes in the short term as well as long term disease and disability. In order to identify when intervention is required, the Quintero classification is used to stage the clinical course of TTTS from Stage I (mild) to Stage V (foetal death) (Hoopmann et al., 2010). An increasing amount of data being collected is demonstrating that the quicker the progression between the stages, the greater the risk of adverse outcomes. The prenatal management of TTTS is aimed at decreasing this high risk of morbidity and mortality and can include treatment options such as amnioreduction, septostomy, and foetoscopic laser photocoagulation (Giconi, 2013). Research has shown that foetoscopic laser photocoagulation is current best practice and now considered to be the gold standard of intervention for TTTS. Graeve et al. (2012) state that this is because it is the only intervention that offers a causal therapy by interrupting the placental anastomoses between the donor and recipient twins, giving the best chance to slowing disease progression and allowing improved perinatal development to proceed, with a resulting survival rate of nearly 70%.
Research In regards to current research, Skupski (2014) identified that one of the most vexing issues in treatment of TTTS via laser coagulation is recurrent TTTS and Twin Anaemia Polycythaemia Sequence (TAPS), which often develop post laser surgery and with no accurate method of prediction at present. Evidence has also suggested that survivors of TTTS treated by foetoscopic laser surgery have a higher likelihood of displaying visible abnormalities on head ultrasound in the first day of life, indicating that the insult occurred antenatally (Crombleholme, 2012). The mechanisms involved require further investigation but is thought to be a result of dilated cerebral sinuses and increased central venous pressure which potentially contribute to the development of intraventricular haemorrhage (IVH) (Crombleholme, 2012). An interesting point noted by Crombleholme (2012) in his literature review is that over the past decade or so, there has been a decrease in the incidences of CNS abnormalities in TTTS survivors treated with foetoscopic laser photocoagulopathy, perhaps suggestive of the improved experience, techniques and expertise of the teams performing the intervention. Under the Barker hypothesis, this could improve long term outcomes in TTTS survivors into adulthood as it would suggest that intervening with
P. Mann et al. the placental anastomoses more accurately and at earlier gestations, would mean that the vasculature of both the recipient and donor would develop healthier and decrease the risk of further insults during significant periods of intrauterine development. This would in turn minimise or ameliorate the risks of adult disease states in addition to the reduction of adverse outcomes in both the perinatal and neonatal periods.
Neonatal care As TTTS is a syndrome of pregnancy, there is no definitive treatment once neonates with the condition have been delivered (Giconi, 2013). Neonatal Intensive Care Unit (NICU) teams should treat each neonate for the specific complications of TTTS that each may have suffered. In the donor, this could be fluid resuscitation for hypovalaemia, blood transfusions if profound anaemia is present, monitoring urine output if the infant has poor renal function, and treating respiratory distress secondary to severe oligohydramnios (Giconi, 2013). The recipient twin may need significant cardiovascular and respiratory support such as inotropes to increase contractility and output of the heart due to severe cardiomyopathy, significant ventilatory support, exchange transfusion for the profound polycythaemia in addition to aggressive phototherapy management for the corresponding hyperbilirubinaemia (Giconi, 2013). In addition to understanding and treating the individual complications that each neonate may suffer, neonatal nurses must understand the long-term sequela that survivors of TTTS are at risk for. Evidence individually collated by Giconi (2013), Salomon et al. (2010), Bidzan et al. (2013), Memmo et al. (2012), and Jawish et al. (2015) among many others, has shown that poor outcomes, particularly high neurologic morbidities, occur in approximately 25% of survivors of TTTS. This has an enormous impact on the neonates and their families for the rest of their lives and highlights the importance of comprehensive developmental follow up and information provision to families to maximise the chances of a healthier and higher quality of life across the lifespan. In order to minimise the risk of adverse outcomes both short and long term, significant research is required to improve early identification and management of TTTS as well as investigating TTTS in relation to the Barker hypothesis, to identify and understand the mechanisms involved between intrauterine development and adult disease states.
Please cite this article in press as: Mann, P., et al., Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis, Journal of Neonatal Nursing (2016), http://dx.doi.org/10.1016/j.jnn.2016.03.002
Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis
Conclusion In order for long-term outcomes to be improved for survivors of TTTS, a large amount of research is required with a focus on the links between intrauterine development and disease states in later life. The paucity of data for TTTS and the Barker hypothesis is testament to the rarity of the disease and the relatively young understanding of it. Future longitudinal follow up studies of TTTS survivors, following the Barker Hypothesis, may demonstrate that adult disease states such as hypertension, diabetes and coronary heart disease in TTTS survivors will be correlated to the mechanisms involved in TTTS and subsequent foetal development.
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Please cite this article in press as: Mann, P., et al., Twin-to-twin transfusion syndrome and potential applicability to the Barker hypothesis, Journal of Neonatal Nursing (2016), http://dx.doi.org/10.1016/j.jnn.2016.03.002