Cardiac Haemodynamics: Next Step in Fetal Monitoring

MBChB(Ntl), B.SC (UDW), DA (SA), Dip Mid COG (SA), FCOG (SA), PhD.

Subspecialist:Fetal –Maternal Medicine

Head: Fetal Medicine, Dept of Obstetrics and Gynaecology, Nelson R

Mandela School of Medicine, University of Kwa-Zulu Natal, Durban, South Africa

Cardiac Haemodynamics:

Next Step in Fetal Monitoring

Dr IE Bhorat

Outline of Presentation

• 1. Pathophysiology of Gestational Diabetes, IUGR and PET –> Different pathways Link to Cardiac Dysfunction

• 2. Methodologies and Techniques to Assess Fetal Cardiac Function: Mod MPI and E/A ratio

• 3. Studies Supporting Use of Functional Cardiac Assessment - ? Integration in Routine Fetal Assessment

Outline of Presentation

Pathophysiology of Diabetic Pregnancy

• Maternal hyperglycaemia

• fetal hyperglycaemia

• fetal pancreatic hyperplasia

• fetal hyperinsulinaemia

• macrosomia

Pathophysiology

Diabetic Pregnancy

Pathopysiology – Diabetic Pregnancy

• Fetal hyperinsulinaemiaincreased glucose oxidation + oxygen consumption

• fetus has reduced capacity for oxidative metabolism and low pyruvate dehydrogenase

activity

• when capacity is reached anaerobic metabolism lacticaemia fetal acidosis

death

• Bradley and Salvesan (early 90’s) –cordocentesis - fetuses of diabetic pregnancies

SIGNIFICANT ACIDEMIA AND HYPERLACTICAEMIA IN ABSENCE OF HYPOXAEMIA - offers an

explanation of so-called “unexplained” fetal deaths consequence of increased metabolic

rate

• DIABETES: Concept of: ACIDOSIS IN ABSENCE OF HYPOXIA

• Implications for antenatal surveillance

Pathophysiology

Diabetic Pregnancy

Gestational Diabetes

• Macrosomia

• Increased metabolic demand

• Larger vascular cross sections

• FETO-MATERNAL METABOLIC PROBLEM AND

NOT A PLACENTAL PROBLEM

Gestational Diabetes

Gestational Diabetes

• What antenatal tools do we presently have in fetal

surveillance?

• Umbilical Artery Doppler velocimetry – widely used

method of antenatal surveillance in high risk

pregnancies including diabetic pregnancies.

• But what does Umbilical Artery Doppler velocimetry

measure?- resistance to placental blood flow

Gestational Diabetes

Gestational Diabetes

• Most of our conventional antenatal surveillance techniques

– Umbilical artery PI/RI, Middle cerebral artery PI/RI and

Ductus venosus PIV – revolve around placental insufficiency

– NOT THE PROBLEM IN DIABETIC PREGNANCIES

• CONCLUSION: NOT APPROPRIATE OR SUFFICIENT AS A

MONITORING MODEL IN DIABETES.

• What about cardiac dysfunction?

Gestational Diabetes

Literature Survey

Literature: Cardiac Haemodynamics:

• 1. Fetal interventricular septal thickness increases – alterations in diastole (occur

even in well controlled diabetics)-Rizzo G et al – (1991)

• 2. Impaired ventricular compliance in fetuses of diabetic pregnancie Rizzo G et al

(1994), Weiner Z et al (1999)

• 3. LV and RV hypertrophy – Weiner et al

• 4. Hypertrophic CMO

• 5. Increased Preload Index in IVC – associated with lower pH at birth and

polycythaemia – Nicolaides KH et al

• 6. Abnormal metabolism – direct cardiac effect on function

Literature Survey

Summary –Gestational Diabetes

• 1. Pathophysiology – metabolic problem and not placental insufficiency.

• 2. Acidosis in absence of hypoxia

• 3. Fetal monitoring models revolve –hypoxia detection

• 4. Evidence of cardiac dysfunction

• 5. Possible –channel cardiac dysfunction into a monitoring model

Summary

Gestational Diabetes

Early Onset IUGR

• Fetal growth impairment

• Oligohydramnios

• Good fetal monitoring models

• Haemodynamic changes: alterations flow velocities in UA, MCA, DV, AoI Doppler

Early Onset IUGR

IUGR

• Ductus venosus and Aortic Isthmus – Late Doppler changes – cascade of deterioration

• DV Doppler anomaly fetal acidosis anomalies in forward flow cardiac haemodynamics.

• DV and AoI flow anomalies extrapolations compromised cardiac state

IUGR

Place for Additional Monitoring Parameters

• Hypoxia MCA RI < p5

• Tracking myocardial function

• Acidosis DV anomalies – myocardial necrosis + late compromised state

Place for Additional Monitoring

Parameters

IUGR

• Pivotal role intrinsic myocardial function Compensatory mechanism of the IUGR fetus establishment of arterial redistribution or Brain –Sparing effect

• Direct functional assessment of fetal heart based on pathophysiology clinical value

IUGR

Pre-Eclampsia

• Cardiac dysfunction not conclusively demonstrated in Pre-Eclampsia

• Studies not distinguished early from late pre-eclampsia

• Not homogeneous group

• Early onset PET –part of Great Obstetric Syndromes

PRE-ECLAMPSIA

EO-PRE-ECLAMPSIA

Placental maladaptation + Vascular Transformation

Reduced perfusion

Placental Ischaemia------------------------------------------ PLGF + VEGF / sFLT -1

Vessel Injury + vasoconstriction

Increased PVR

Increased Fetal Cardiac Afterload

EO-PRE-ECLAMPSIA

Spiral Artery In Junctional Zone Myometrium Classification of Defective Deep Placentation- Brosens et al – Am J Obstet Gynecol :2011

PRE-ECLAMPSIA

• EO-PET >> placental pathological state >> IUGR -more serious clinical phenotype

• IUGR intrinsic myocardial function pivotal role - compensatory mechanisms

• Hypothesise - alterations in cardiac function in PET – Increased Cardiac Afterload

•

PRE-ECLAMPSIA

Different Pathophysiologies Cardiac Dysfunction

• Diabetes IUGR PET

• AbnormalMetabolic milieu Hypoxia LV afterload

Cardiac Dysfunction

Different Pathophysiologies

Cardiac Dysfunction

Methodologies

Myocardial Performance Index

E/A ratio

Methodologies

Myocardial Performance Index

• The Myocardial Performance Index (MPI)

– Tei et al (TEI Index) – in adults to assess ventricular dysfunction (1995)

• Ratio between the duration of the isovolumetric periods (composed of 2

periods: contraction and relaxation ie ICT and IRT) and duration of ejection

(ET)

• MPI= (ICT+IRT)/ET

• Tei Index- used in fetus and newborn (Tsutsumi and Ichizuka )

• Valve –click method: Hernandez-Andrade = Mod MPI

Myocardial Performance Index

Myocardial Performance Index

The time cursor is placed at the beginning of each Doppler click.

Myocardial Performance Index

Studies in Fetal Myocardial Performance –Research Group at UKZN

• 1. Reference Ranges of MPI – normograms -5th, 50th

and 95th percentiles.

• 2. MPI in Diabetes

• 3. MPI in IUGR

• 4. MPI in Pre-eclampsia

Studies in Fetal Myocardial Performance –

Research Group at UKZN

Reference Intervals of MPI –normal pregnancies

0.3

00

.35

0.4

00

.45

MP

I

20 25 30 35 40Gestational age (weeks)

Reference Intervals of MPI –

Normal Pregnancies

Reference Intervals of MPI – Normal Pregnancies

• Reference intervals of the Mod-MPI evaluating

fetal cardiac function have been established.

Maturational and developmental alterations in

the myocardial performance in utero resulting in

better ventricular compliance is most likely

responsible for the decreasing trend of the Mod-

MPI noted with advancing gestation.

Reference Intervals of MPI –

Normal Pregnancies

Bhorat I, Bagratee R, Reddy T. Prenatal Diagnosis:2014;34 (11): 1031-1036

Gestational Diabetes

• Fetal myocardial performance in Gestational Diabetes and links to perinatal outcome

Gestational Diabetes

MPI and Gestational Diabetes

• To determine whether the MPI is altered in fetuses in

pregnancies complicated by severe gestational

diabetes (GDM)

• To determine whether MPI is of value in fetal

surveillance in Diabetic pregnancy

• To determine whether MPI is of value in predicting

adverse perinatal outcome

MPI and Gestational Diabetes

MPI and Gestational Diabetes0

.30

.40

.50

.60

.7

MP

I

Control IDDM

MPI in Controls vs IDDM

MPI and Gestational Diabetes

Scatterplot of MPI vs Gestational age with linear predictions from quantile regression superimposed.

0.3

0.4

0.5

0.6

0.7

MP

I

31 32 33 34 35 36Gestational age (weeks)

Control IDDM

Linear prediction Linear prediction

Outcomes in Study and Control Groups

Outcomes Study Group (n=29) Controls (n=29)

Stillbirth 1 -

Neonatal death 1 -

NICU admission 16 -

Tachypnoea + pulmonary oedema

8 -

Apgar < 7 (5 min) 13 -

pH <7.15 13 -

Cardiomyopathy 1 -

Normal outcome 12 29

Distribution of MPI between normal and abnormal outcomes in the study group and correlation to the 95th percentile of MPI from normal ranges

study

Results – MPI and Gestational Diabetes

All 17 fetuses showing abnormal outcome had:

MPI’s > 0.52 - sensitivity of 1 (0.8-1), specificity of

91.67% (0.61-0.998)

Additional risk factors: Increased Birthweight and low

E/A ratios and increased AFI

Results

MPI and Gestational Diabetes

MPI and Gestational Diabetes

• To our knowledge this is the first study to demonstrate a clear relationship between an altered MPI and adverse fetal and neonatal outcome in diabetic pregnancies.

MPI and Gestational Diabetes

Bhorat I, Bagratee J, Pillay M, Reddy T. Prenatal Diagnosis 2014; 34 (13): 1301-1306

IUGR and Fetal Myocardial Performance

• Question 1: Is MPI altered in IUGR

• Question 2: Does MPI correlate with degree of IUGR

• Question 3: Is MPI a prognostic indicator of APO?

IUGR and Fetal Myocardial

Performance

MPI and IUGR

Question 1: Is MPI altered in IUGR?

MPI and IUGR

MPI and IUGRMPI and IUGR

Demographic, Sonographic Data and Cardiac Doppler Data between Control and Study Groups

Control (n=43) IUGR (n=43) p-value

Median (IQR) Median (IQR)

Maternal age (mean(SD)) 29.62 (3.61) 29.67(3.59) 0.9535

Gestational age (weeks) 33 (31 -34) 33 (31-34) 1

Gestational age of delivery (mean

SD)

39.20 (0.45) 36.76 (1.18) <0.0001

AFI (cm) 12.8 (12.2 - 13.4) 8.95 (7.95 - 10.1) <0.0001

EWF (g) 2214 (1788 – 2436) 1559.5 (1042 - 1897.5) <0.0001

E/A ratio 0.79 (0.78-08) 0.63 (0.57-0.67) <0.0001

Median MPI (IQR) 0.37 (0.36-0.38) 0.59 (0.52-0.69) <0.001

MPI and IUGR

• Question 2: Does MPI correlate with degree of IUGR ?

MPI and IUGR

Methods

• Uncompensated IUGR: AC < 10th percentile for gestational age, elevated umbilical artery RI at > 2 standard deviations for gestational age with no arterial redistribution and normal venous Doppler.

• Compensated IUGR had in addition a middle cerebral artery RI below the 5th centile for gestational age reflecting arterial redistribution.

• Critical status IUGR: absent (AEDF) or reversed end diastolic flow (RAEDF) in the umbilical artery and/or severe venous Doppler anomalies: high suspicion of acidosis.

Methods

Distribution of Mod-MPI in each of the IUGR grades

0.4

0.5

0.6

0.7

0.8

MP

I

Uncompensated Compensated Critical

MPI and IUGR

• Question 3: Is the MPI a prognostic indicator?

MPI and IUGR

Pregnancy and Perinatal OutcomesIUGR

ControlsUncompensated Compensated Critical

Number (n) 43 19 10 14

Gest age –mean

(delivery)

39w4d (38w3d-

40w3d)

37w1d (36w-

37w5d)

35w6d (34w3d-

36w3d)

30w2d (29w5d-

32w1d)

Median MPI 0.37 (0.36-0.38) 0.52 (0.50-0.54) 0.63 (0.6-0.65) 0.7 (0.7-0.73)

Mode of Delivery –

C/S (%)

6 35 68 100

Birth Weight (g) 3110 (2960-

3476)

2156 (1890-2314) 1910 (1623-2118) 920 (850-1103)

5-min APGAR <6 - 5 6 11

Perinatal Deaths - - 1 4

HIE - - 2 3

Neonatal Resuscit - 5 5 11

Cord pH <7.15 - 1 3 10

IVH - - - 2

BPD - - - 2

Adverse outcome 0% 26% 60% 79%

Adverse Perinatal Outcome

• Severity of growth restriction

• Prematurity

• Cardiac dysfunction (hypoxaemia/acidaemia)

• Logistic regression analysis: MPI remained significant predictor for APO –adjusting GA, EFW, UA RI, DV, AFI and E/A ratio:

• Adjusted OR 95% CI:2.60 (1.15-5.83), p-0.02

Adverse Perinatal Outcome

MPI and E/A ratio as markers of adverse outcome0

.00

0.2

50

.50

0.7

51

.00

Se

nsi

tivity

0.00 0.25 0.50 0.75 1.001-Specificity

MPI AUC: 0.939 E/A Ratio AUC: 0.761

Reference

ROC curve: comparing Mod-MPI and DV PIV in prediction of perinatal mortality , both being

significant predictors.

MPI in IUGR

• A cut-off Mod-MPI value of 0.54 : sensitivity of 87% (CI:66-97%), specificity of 75%(CI:55-91%) and a likelihood ratio (LR) of 3.47 for an adverse outcome.

• A cut-off Mod-MPI value of 0.67 conferred a sensitivity of 100% (CI:54-100%), specificity of 81%(CI:65-92%) and LR of 5.28 for perinatal death.

• No abnormal outcomes occurred in controls

MPI in IUGR

Bhorat I, Bagratee J, Pillay M, Reddy T. Prenatal Diagnosis: 2015:35(3); 266-273

Conclusion:

• 1. Link between severity of MPI and adverse outcomes in IUGR.

• 2. Cut-off MPI values for adverse outcomes and perinatal death have been suggested.

• 3. MPI – allows tracking of cardiovascular deterioration between hypoxia and acidosis.

Conclusion

PET and MPI

• To determine whether fetuses in severe early onset pre-eclampsia (EO-PET) have cardiac dysfunction

• Does MPI deteriorate across stages of increasing placental vascular resistance in PET

• Whether this dysfunction influences perinatal outcome.

PET and MPI

PET and MPI

• Question 1: Is MPI altered in severe EO –PET?

PET and MPI

ResultsResults

Demographic and Sonographic Data and Cardiac Doppler Data

Control Group PET (Study) Group p-value

Maternal age (years) 28.91 (3.80) 28 95 (3.70) 0.523

Gest age (w) (IQR) 30 (30.57-31.28) 29.98 (30.43-32) 0.454

EWF (g) at assessment 1629 (1597 - 1713) 1214 (913 - 1354) 0.0001

AFI (cm) 12.83 (1.11) 11.46 (3.29) 0.0697

E/A ratio 0.79 (0.02) 0.66 (0.03) <0.0001

Median MOD-MPI (IQR) 0.38 (0.38-0.39) 0.62 (0.54-0.67) <0.001

ICT (ms) 28 (27-29) 35 (34-38) <0.001

IRT (ms) 39 (38-39) 58 (56-64) <0.001

ET (ms) 172 (171-172) 152 (150-156) <0.001

PET and MPI

• Question 2: Does MPI alter with deteriorating placental vascular resistance in PET?

PET and MPI

Comparison of Mod-MPI values between the 4 levels of severity in Study (PET) Groups

0.5

0.5

50

.60

.65

0.7

MP

I

0.7<= UA <0.8 0.8<= UA <0.85 UA>= 0.85 AEDF

PET and MPI

• Question 3: Is the MPI a prognostic indicator of APO in severe EO-PET?

PET and MPI

Pregnancy and Perinatal Outcomes in the Control and Study Groups

Control

(normals)

Group 1

0.7<=UA <

0.8

Group 2

0.8<=UA

<0.85

Group 3

RI ≥0.85

Group 4

AEDF/REDF/

Abn DV PIV

N = 30 N = 9 N = 10 N = 5 N = 6

Median MPI0.38

(0.38-0.39)

0.54

(0.5-0.58)

0.62

(0.6-0.62)

0.65

(0.6-0.67)

0.68

(0.65-0.71)

Birth Weight (g)

mean

3085

(2989-3315)

1636

(1465- 1765)

1242

(1023-1356)

1196

(980-1236)

950

(855-1046)

Mean Gest age

(w) at delivery39.2 32w3d 31w3d 30w6d 30w2d

APGARS <6

(5min)

-3 5 3 5

Neonatal death-

- - 2 3

pH <7.15 - 1 2 2 4

HIE - - 2 1 1

IVH - - - - 1

BPD 1 -

Perinatal

complications- 33% 50% 60% 83%

Adverse Perinatal Outcome – PET

• Worsening placental vascular resistance

• Prematurity

• Cardiac dysfunction

• Logistic regression analysis MPI remained significant predictor after adjusting for gestational age and E/A ratio

• Adjusted OR 95% CI: 1.82 (1.06-3.11), p- value 0.03

Adverse Perinatal Outcome - PET

Significant relationship between the myocardial performance

index and adverse outcome (area under the curve of 0.95)

ROC: Significant relationship depicted between myocardial performance index and prediction of perinatal death (area

under the curve of 0.95)

MPI and PET

• For adverse perinatal outcome, a cut-off Mod-MPI value of >0.55 conferred a sensitivity of 100% (95% Confidence interval [CI] 82.3-100%), specificity of 82% (95% CI 51-96.5%) and a LR of 5.5.

• For perinatal death, a cut-off Mod-MPI value of 0.67 conferred a sensitivity of 100% (95% CI 52-100%), specificity of 84% (95% CI 62.5-94%) and an LR of 6.25.

• The E/A ratios were significantly decreased in the pre-eclampticgroup compared to controls (0.66 vs 0.79, p < 0.0001).No adverse outcomes were noted in the control group.

MPI and PET

MPI and Pre-eclampsia

• 1. Fetal cardiac function is significantly impaired in severe EO-PET

• 2. Tracking MPI measurements may allow the clinician to monitor myocardial performance of fetuses in severe EO-PET across deteriorating placental vascular resistances.

• 3.Specific cut-off Mod-MPI values for prediction of adverse perinatal outcome and perinatal death have been suggested.

MPI and Pre-eclampsia

Conclusions

1. Mod-MPI may be the only non-invasive technique in monitoring fetuses in gestational diabetes in order to detect a significantly abnormal metabolic milieu.

2. Monitoring tool for assessing deteriorating cardiovascular function in IUGR fetuses, and thereby guide the physician to optimal timing of delivery before overt acidosis, myocardial necrosis or perinatal death sets in.

3. Pre-eclampsia: evaluation of fetal cardiac function using the mod-MPI and E/A ratios together with the evaluation of umbilical artery Doppler flow could be included into an integrated monitoring model in the management of PET pregnancies

Conclusions

Conclusions

• These studies of fetal cardiac dysfunction in high risk obstetric conditions makes the argument for fetal cardiac function to being part of an integrated approach to establish fetal wellbeing in high risk obstetrics

Conclusions