Article Text

Potential benefits of prenatal diagnosis of TGA in Australia may be outweighed by the adverse effects of earlier delivery: likely causation and potential solutions
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  1. Siva P Namachivayam1,2,3,4,
  2. Warwick Butt1,2,3,4,
  3. Christian Brizard3,4,5,
  4. Johnny Millar1,2,3,4,
  5. Jenny Thompson1,4,
  6. Susan P Walker6,7,
  7. Michael M H Cheung3,4,8
  1. 1 Cardiac Intensive Care Unit, Royal Children's Hospital, Parkville, Victoria, Australia
  2. 2 Department of Critical Care, The University of Melbourne—Parkville Campus, Melbourne, Victoria, Australia
  3. 3 Department of Paediatrics, The University of Melbourne—Parkville Campus, Melbourne, Victoria, Australia
  4. 4 Clinical Sciences, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
  5. 5 Department of Cardiac Surgery, Royal Children's Hospital Melbourne, Parkville, Victoria, Australia
  6. 6 Department of Obstetrics and Gynaecology, The University of Melbourne—Parkville Campus, Melbourne, Victoria, Australia
  7. 7 Mercy Perinatal, Mercy Hospital for Women, Melbourne, Victoria, Australia
  8. 8 Department of Cardiology, Royal Children's Hospital Melbourne, Parkville, Victoria, Australia
  1. Correspondence to Dr Siva P Namachivayam, Cardiac Intensive Care Unit, Royal Children's Hospital, Parkville, VIC 3052, Australia; siva.namachivayam{at}rch.org.au

Abstract

Objective Prenatal diagnosis of transposition of great arteries (TGA) is expected to improve postoperative outcomes after neonatal arterial switch operation (ASO); however, published reports give conflicting results. We aimed to determine the association between prenatal diagnosis and early postoperative outcomes after neonatal ASO.

Methods Cohort study involving 243 newborns who underwent ASO (70% prenatally diagnosed) between 2010 and 2019. Multivariable regression was used to determine the association between prenatal diagnosis and (a) birth characteristics and (b) postoperative outcomes.

Results Gestational age and birthweight centile were lower and small-for-gestational-age more common (11.8% vs 1.4%) in those diagnosed prenatally. Among births which followed labour induction or prelabour caesarean, prenatal diagnosis was associated with earlier gestation at birth (mean (SD), 38.5 (1.6) vs 39.2 (1.4), p=0.01). Among births which followed spontaneous labour, prenatal diagnosis was associated with earlier gestation at labour onset (38.2 (1.8) vs 39.2 (1.4), p=0.01). Prenatal diagnosis was associated with longer postoperative mechanical ventilation (incidence rate ratio 1.74, 95% CI 1.37 to 2.21), intensive care (1.70, 1.31 to 2.21) and hospital length of stay (1.37, 1.14 to 1.66) after ASO. Gestational age mediated up to 60% of the effect of prenatal diagnosis on postoperative outcomes.

Conclusion Among newborns undergoing ASO for TGA, prenatal diagnosis is associated with poorer early postoperative outcomes. In addition to minimising iatrogenic factors (such as planned births) resulting in earlier births, evaluation of other dynamics following a prenatal diagnosis which may result in poor fetal growth and earlier onset of spontaneous labour is important.

  • cardiology
  • intensive care units, paediatric

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Crucial cardiovascular and other organ maturation is ongoing till a fetus reaches full-term (40–41 weeks).

  • Prenatal diagnosis rates for congenital heart disease is continuing to increase and following prenatal diagnosis a high proportion of planned births occur, resulting in earlier gestational age at birth.

WHAT THIS STUDY ADDS

  • Prenatal diagnosis is associated with earlier gestation due to planned births and earlier onset of spontaneous labour.

  • Prenatal diagnosis is associated with a higher proportion of small-for-gestational age newborns.

  • Newborns with prenatal diagnosis displayed poorer postoperative performance.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • In addition to minimising iatrogenic factors (such as planned birth) contributing to earlier gestation, potential additional dynamics such as maternal stress (due to knowledge of prenatal diagnosis) and its influence on newborn outcomes after cardiac operation need further evaluation.

Introduction

Prenatal diagnosis of transposition of great arteries (TGA) allows for parental counselling, earlier stabilisation after birth (eg, commencement of prostaglandin infusion), planned access to intensive care and early intervention in a cardiac centre.1 2 It also offers families the option of termination of pregnancy if desired. Among pregnancies which progress to birth, prenatal diagnosis is expected to improve outcomes after neonatal arterial switch operation (ASO); however, published reports give conflicting results.3 4 Prenatal diagnosis also introduces additional challenges to the unborn fetus. For example, it is known that prenatal diagnosis is associated with an earlier birth1 3 5 often due to the practice of electively scheduling delivery around availability of high-intensity postnatal cardiac care. The resultant combination of reduced gestational age and lower birth weight is known to contribute to poorer outcomes after cardiac surgery.6 Moreover, the maternal stress associated with prenatal diagnosis of a serious fetal abnormality may itself contribute to poorer outcomes, through increased risks of spontaneous preterm birth7 and/or programming effects. High levels of psychological distress in expectant mothers due to knowledge of prenatal diagnosis of congenital heart disease (CHD)8–10 may impact the fetus and newborn negatively2 and this, too, may influence the subsequent postoperative outcome.

Newborns diagnosed with TGA typically undergo surgery in the early neonatal period and recent data show relatively good outcomes after neonatal ASO.11 12 Over the last two decades, the rate of prenatal detection of TGA has steadily increased and current rates in some regions vary around 70%–80%.3 13 However, a comprehensive understanding of the influence that prenatal diagnosis of TGA has on outcomes after ASO in this current period of relatively high prenatal detection rates is unclear.

The main questions addressed in this study are as follows: among newborns undergoing ASO for TGA (1) What is the effect of prenatal diagnosis of TGA on birth weight, birthweight centile and gestational age at birth? (2) What is the effect of prenatal diagnosis on early postoperative outcomes after neonatal ASO? (3) To what extent is the effect of prenatal diagnosis on early postoperative outcomes mediated through gestational age at birth? (4) What is the effect of gestational age at birth on early postoperative outcomes after accounting for the influence of prenatal diagnosis?

Methods

The study was conducted at the Royal Children’s Hospital (RCH) in Melbourne, Australia and included neonates with a diagnosis of TGA who underwent ASO within the first 30 days of life. The hospital is a tertiary cardiac centre and newborns with severe CHD from the Australian states of Victoria, South Australia, Western Australia, Tasmania, Northern Territory and southern New South Wales undergo cardiac surgery in this centre. For the TGA population, following prenatal diagnosis the local policy involves planned delivery (by induction of labour or in some cases caesarean) at one the major perinatal centres capable of providing emergency septostomy after birth. Mothers and family units may be relocated (if they do not live in close proximity) closer to the perinatal centre in the third trimester before a planned induction date and this often includes several interstate patients as well moving to Melbourne (Victoria). All newborns are eventually transferred to undergo ASO at RCH Melbourne (Victoria).

Study data

Study variables were collected from pre-existing information in the intensive care unit (ICU) database. Additional study information was collected from medical records. Birth details were collected from neonatal discharge and transfer records. The following were obtained: gestational age, birth weight, delivery factors and risk factors for premature birth. Gestational age in Australia is estimated based on information that includes early ultrasound estimation and the last normal menstrual period. The following were considered as risk factors for premature birth and included in the analysis: smoking, drug or alcohol use during pregnancy, known maternal stress/depression/anxiety/psychosis, advanced maternal age, maternal diabetes (gestational or pre-existing), maternal obesity, pre-eclampsia, maternal hypertension, twin-pregnancy, in vitro fertilisation, maternal infection, history of premature labour, maternal autoimmune disorders, hypothyroidism, fibroids and placental bleeding. Birthweight centiles for gestation and sex were calculated using published centiles for Australian newborn singletons14 and twins.15 Small-for-gestational-age was defined as birth weight less than 10th centile for gestational age. Socio-economic position of the family (based on Australian-derived Index of Relative Socio-economic Disadvantage (IRSD)16), postnatal management (provision of septostomy, preoperative ventilation, preoperative brain injury based on cranial ultrasound examination, preoperative creatinine), diagnosis, extracardiac congenital abnormality, peri-operative variables (nature of cardiac surgery, perfusion, postoperative extracorporeal membrane oxygenation (ECMO), postoperative ventilation duration, ICU and hospital length of stay and death in hospital) were also obtained.

Data analysis

Postoperative outcomes

All of the study outcomes are postoperative outcomes after ASO. The primary variable of interest (prenatal diagnosis or not) and its association with early postoperative outcomes (length of mechanical ventilation, ICU and hospital stay) was evaluated using a negative-binomial regression model (with robust SEs); estimates are reported as incidence rate ratio (IRR) with 95% CIs. The IRR can be interpreted as the per cent change (increase or decrease) in the outcome for each unit increase in the exposure variable, with an IRR of 1 indicating no change. The association between prenatal diagnosis and binary outcomes (postoperative ECMO and death) was evaluated using multivariable logistic regression. All analyses were adjusted for potentially confounding or prognostic variables: premature birth risk, sex, preoperative ventilation, Paediatric Index of Mortality-217 (an admission severity of illness score), cardiopulmonary-bypass time (min) and type of cardiac surgery (0—ASO; 1—ASO with ventricular septal defect (VSD) repair; 2—ASO with aortic-arch repair; 3—ASO with VSD repair and aortic-arch repair). Prenatal diagnosis rates were not related to social-economic disadvantage (IRSD) nor did inclusion of IRSD influence the study outcomes; so IRSD was excluded from the final model (online supplemental table S1).

Gestational age as a mediator

In a separate mediation analysis, gestational age was included as a mediator to evaluate its role in the causal path between prenatal diagnosis and early postoperative outcomes. Mediation analysis in this context helps to determine the extent to which prenatal diagnosis impacts outcomes due to its effect on gestational age which then influences the outcome. It divides the total effect of the exposure into a natural direct effect (it bypasses the mediator) and a natural indirect effect (through the mediator). From these measures, the proportion of the effect of prenatal diagnosis mediated through gestational age can be calculated18: proportion mediated=Embedded Image .

Three post hoc sensitivity analyses were conducted. This was performed by checking for heterogeneity of exposure (prenatal diagnosis) effect across state of prenatal care (Victoria vs other states), birth year (2010–2014 vs 2015–2019) and type of operation (ASO vs ASO±VSD repair±coarctation of aorta repair). All analyses were conducted in Stata/MP (V.16.1).

Results

Overall, 243 newborns underwent the ASO within the first 30 days of life; 70% (169) had a prenatal diagnosis of TGA (table 1). The rate of prenatal diagnosis increased from 56% in 2010–11 to 82% in 2018–19 (time-series trend p<0.001).

Table 1

Birth characteristics (n=243)

Birth characteristics (aim 1)

The gestational age at birth was lower for those prenatally diagnosed compared with a postnatal diagnosis (mean (SD) 38.4 (1.7) vs 39.2 (1.4), p<0.001). A higher percentage of babies were delivered following labour-induction or prelabour caesarean in the prenatal group (76% vs 58%, p=0.006); in these births which followed induction of labour or prelabour caesarean, prenatal diagnosis was associated with earlier gestational age at birth (mean (SD), 38.5 (1.6) vs 39.2 (1.4), p=0.01). Second, in the prenatal group, spontaneous onset of labour occurred in 24% compared with 42% in the postnatal group (p=0.004); the mean (SD) gestational age for newborns following a spontaneous onset of labour was 38.2 (1.8) for prenatal diagnosis and 39.2 (1.4) for postnatal diagnosis (p=0.01). Additional birth details are shown in online supplemental figure S1 and online supplemental table S2.

Birthweight centile

The mean (SD) birthweight centile in the prenatal versus postnatal groups were 49 (29) and 57 (28), respectively (p=0.03). Overall, 20 (11.8%) in the prenatal and 1 (1.4%) in the postnatal group were small-for-gestational age (p=0.008) (figure 1). Patient characteristics. The weight at the time of surgery was lower in the prenatal diagnosis group. There were no other major differences in demographic and preoperative characteristics between the study groups (table 2).

Figure 1

Scatter plot of birthweight centile and gestation, shown by those with and without prenatal diagnosis. Green dashed line represents 10th centile for birth weight (cut-off for small-for-gestational age).

Table 2

Patient characteristics

Prenatal diagnosis and early postoperative outcomes (aim 2)

In a multivariable analysis, after adjusting for study covariates, the postoperative duration of mechanical ventilation was 74% longer for neonates who had a prenatal diagnosis (IRR (95% CI) 1.74 (1.37 to 2.21)) (table 3) (statistical model performance, online supplemental table S3). Similarly, neonates with a prenatal diagnosis spent longer time in intensive care (1.70, 1.31 to 2.21) and in hospital (1.37, 1.14 to 1.66) compared with those diagnosed postnatally. Postoperative ECMO was necessary in 10.7% (18 out of 169) in those diagnosed prenatally and in 4.1% (3 out of 74) diagnosed postnatally. In the adjusted analysis, the odds for requiring postoperative ECMO were higher with prenatal diagnosis (adjusted OR 5.87; 95% CI 1.12 to 30.7).

Table 3

Study outcomes and association with prenatal diagnosis

Time-series analysis: for every 10% increase in prenatal diagnosis rate, the duration of mechanical ventilation increased by 21% (95% CI 11.3 to 30.8, p-trend<0.001) for those with prenatal diagnosis compared with those with a postnatal diagnosis. Similarly, ICU stay increased by 15.7% (95% CI 10.7 to 20.9, p-trend<0.001) and hospital stay increased by 25.3% (95% CI 20.5 to 30.1, p-trend<0.001) for every 10% increase in prenatal diagnosis rate (online supplemental figure S2).

Finally, post hoc sensitivity analyses showed that there was no evidence of interaction between (i) prenatal diagnosis and Australian state of prenatal care (Victoria vs other states, p=0.73), (ii) across time (2010–14 vs 2015–19, p=0.60) and (iii) type of surgery (online supplemental figure S3).

Gestational age as a mediator (aim 3)

On the basis of known associations between prenatal diagnosis and gestational age at birth, and gestational age at birth and postoperative outcomes, the mediation path of prenatal diagnosis (yes/no) on postoperative outcomes through gestational age at birth was evaluated. This showed that gestational age mediated 45% of the effect of prenatal diagnosis on postoperative ventilation, 47% on ICU stay and more than half (62%) on hospital length of stay (table 4). In a separate analysis, we did not find evidence for mediation of the effect of prenatal diagnosis on postoperative outcomes through birthweight centile (data not shown).

Table 4

Prenatal diagnosis and postoperative outcomes: natural direct effect, natural indirect effect and proportion mediated through gestational age

Maturation (gestational age) as a primary exposure (aim 4)

A separate analysis with gestation as the main exposure and adjusting for previously mentioned covariates and prenatal diagnosis was conducted. On average, birth at 37 weeks was associated with hospital length of stay which was at least 7 days longer than birth at 40 weeks: 19.6 (95% CI, 16.1 to 23) days at 37 weeks vs 13.1 (11.7 to 14.4) days at 40 weeks (table 5). Similar reductions were identified in postoperative length of mechanical ventilation and ICU stay (online supplemental table S4).

Table 5

Mean hospital length of stay for selected gestational ages at birth

Discussion

Given prenatal diagnosis currently encompasses the majority of newborns with TGA undergoing cardiac surgery in several regions and is expected to increase globally in many other regions, it is important to systematically analyse the role of prenatal diagnosis on postoperative outcomes. In this study of newborns who underwent the ASO for TGA, we show that prenatal diagnosis is associated with poorer early postoperative performance. Prenatal diagnosis is connected with earlier gestation (due to planned births and earlier onset of spontaneous labour) and earlier gestation is associated with poorer outcomes. Although additional mechanisms remain unclear, maternal stress (due to knowledge of prenatal diagnosis) may also adversely influence fetal programming and subsequent postoperative performance and this hypothesis needs further evaluation.

Prenatal diagnosis and gestational age at birth

It is well known that appropriate length of intrauterine maturation is important for postnatal outcomes and this is particularly true for those newborns with CHD.6 19 20 Even among term-births (≥37 weeks), there is a substantial reduction in the risk of death after surgery for CHD with increasing gestational age (up to 40–41 weeks) at birth.20 Prenatal diagnosis of a CHD often leads to a planned birth. In such babies there is a greater risk of being born earlier (ie, 37–39 weeks), and delivery even a week or two earlier is associated with a greater number of complications and death in intensive care.19 Maturational deficiencies in the cardiovascular21 22 and other organ systems23 24 are likely to explain these findings.

A prenatal diagnosis of CHD should not in itself be considered an indication for medically induced early delivery.25 Importantly, we propose (a) greater consideration of the adverse impact of early delivery is made and avoidance of this, as far as possible, with review of local management protocols for this group of patients and (b) avoiding routine induction of labour for planning (so as to have planned access to intensive care and managing operational work flow of treating teams). The advantage conferred by maximising gestation far exceeds any proposed benefit of elective early birth. It is also likely that with prenatal diagnosis, increased fetal surveillance may be undertaken in late pregnancy, which may itself prompt iatrogenic early birth. Every effort should be made to minimise birth before full term (40–41 weeks) unless there are clear maternal and fetal indications for early delivery.

Other postulated pathways

Prenatal diagnosis of CHD can trigger maternal stress.2 10 26–28 Psychological distress, anxiety and depression are higher in mothers with a prenatal diagnosis.27–29 Maternal stress is known to be associated with increased risks of spontaneous preterm birth7; it is not known whether the higher rates of spontaneous premature labour noticed in our study is related to maternal stress, but has to be considered as a potential factor (online supplemental figure S4). Additionally, high levels of circulating glucocorticoids in the maternal circulation coupled with the downregulation of placental membrane enzyme 11β-hydroxysteroid dehydrogenase type 230 in the setting of stress may allow excess cortisol to freely reach the fetal circulation. Elevated fetal cortisol leads to secondary dysregulation of the fetal hypothalamic-adrenal-pituitary axis system.31 Finally, an increasing body of literature has shown that epigenetic alterations such as genome-wide DNA methylation in the neonate secondary to maternal stress modifies the effects of stress on fetal immune and metabolic function32 33.

Strengths and weaknesses of the study

(1) This study population comes from a vast geographical area and this enhances the representativeness of a population level sample. Surgery and postoperative care however was performed in a single centre due to the highly centralised nature of cardiac services in Australia. This limitation may be important as it is not known whether similar findings will be noted from other centres. (2) While maternal stress may be associated with adverse perinatal outcomes, these are more commonly seen in the setting of significant other psychosocial stresses and other major confounders; while we adjusted for maternal factors for preterm birth in our analysis, the full extent of these factors need to be considered further in future studies. (3) The numbers of stillbirths or neonatal deaths presurgery is not known for our full study cohort. But this information is available for the state of Victoria where 73% of the study cohort births occurred (shown in online supplemental table S5); in this cohort, there were four preoperative neonatal deaths (two with a prenatal diagnosis and two with postnatal diagnosis). (4) We did not have long-term developmental outcomes in our study; earlier evidence has shown that lower gestational age and longer length of stay after cardiac surgery to be associated with poorer neurodevelopment.34 35 (5) Distances travelled by families in Australia and logistics of care may be different in Australia compared with other countries, but our findings should remain of interest to other regions.

Implications: (1) Given the clear advantages of maximising gestation, obstetric care providers should be cautioned against birth before full term (40–41 weeks), unless there are clear maternal or fetal indications for earlier delivery. For families living within a reasonable distance from the major perinatal cardiac centre we propose allowing spontaneous onset of labour. For families living far away, moving nearer to the major perinatal cardiac centre closer to the delivery date and allowing spontaneous labour. (2) More studies are needed to assess the interconnected pathways between the psychological impact of prenatal diagnosis and its effect on the newborn.

Conclusion

In newborns undergoing ASO for TGA, those diagnosed prenatally had poorer early postoperative performance compared with those with a postnatal diagnosis. A large proportion of this effect is mediated by gestational age at birth. Additional factors such as maternal stress and its effects on fetal programming need further evaluation. Finally, gestational age at planned birth is modifiable and every effort must be placed to minimise elective planned delivery in newborns with prenatally diagnosed CHD.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Ethics statements

Patient consent for publication

Ethics approval

The study was approved by the institutional ethics board (QA/74871/RCHM-2021).

Acknowledgments

We are grateful to CCOPMM for providing access to the data used for this project and for the assistance of the staff at the Safer Care Victoria.

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • Contributors SPN conceptualised and designed the study, obtained data, had full access to the dataset and performed the analyses, drafted the initial manuscript and reviewed and revised the manuscript. SPN acts as guarantor of the study. MC conceptualised and designed the study, obtained data, drafted the initial manuscript and reviewed and revised the manuscript. JT obtained data, had access to the dataset, provided initial data merging and important intellectual content. KJM, WB, CB and SPW provided important intellectual content to the study and critically reviewed the manuscript. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

  • Funding SPN is supported by a health professional research scholarship from the National Heart Foundation of Australia (award number 101003).

  • Disclaimer The conclusions, findings, opinions and views or recommendations expressed in this paper are strictly those of the author(s). They do not necessarily reflect those of CCOPMM.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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