1. Prenatal Ultrasound & Early Detection of FASD
CIFASD Winter 2011 Meeting
Andrew D. Hull, M.D.
UCSD

2. Rationale for Study
Most FASD cases identified late because of failure to meet milestones
Early detection of FASD allows early intervention
Earlier interventions – more effective
Prenatal detection would allow earliest interventions possible

3. Specific Aim 1
To examine the utility of specific ultrasound measurements of fetal brain in the detection of fetuses who will go on to demonstrate features of FASD.
To correlate these ultrasound measures with postnatal assessment of growth and structural features as assessed by a standardized dysmorphological examination.
To correlate these ultrasound measures with altered neurobehavioral assessment at 6 & 12 months.
To assess the dose response relationship between these ultrasound measures and the timing and quantity of alcohol ingested prenatally.
To determine the best cut points and gestational age timing for ultrasound measures that produce the most sensitive and specific set of markers predicting above and the set with the highest positive predictive value.

4. Specific Aim 2
To assess the role of second and third trimester ultrasound assessment of biophysical profile (BPP) and startle response in the detection of fetuses who will go on to demonstrate features of FASD.
1. To correlate BPP and startle responses with postnatal assessment of growth and
structural features as assessed by a standardized dysmorphological examination
2. To correlate BPP and startle responses with altered neurobehavioral assessment at
6 & 12 months
3. To assess the dose response relationship between BPP and startle responses and
the timing and quantity of alcohol ingested prenatally
4. To determine the best cut points and gestational age timing for BPP and startle
responses that produce the most sensitive and specific set of markers predicting A -
To correlate BPP and startle responses with the ultrasound measures of brain growth in Specific Aim 1

5. Sonography Routine serial ultrasound exams
Studies at ~24 & ~34 wks compared
Routine biometry
Specific brain measurements

6. Transverse Cerebellar Diameter (TCD)
Brain Measurements
Occipital Frontal
Diameter (OFD)
Transverse Cerebellar Diameter (TCD)

7. Caval Calvarial Distance (CCD) Frontothalamic Distance (FTD)
Brain measurements
Caval Calvarial Distance (CCD)
Frontothalamic Distance (FTD)

8. Orbital Measurements Outer Orbital Diameter (OOD)
Intra Orbital Diameter (IOD)
Orbital Diameter (OD)
OOD OD
IOD
OOD

9. Pilot Data: 2nd Trimester Somatic measures*
* = P < 0.05

10. Pilot Data: 2nd Trimester Brain Measures* *
* = P < 0.05

11. Pilot Data: 3nd Trimester Somatic Measures*
* = P < 0.05

12. Pilot Data: 3rd Trimester Brain Measures*
* = P < 0.05 *

13. Pilot Data Findings Alcohol exposed fetuses have:
Reduced frontothalamic distance in both 2nd and 3rd trimesters
Reduced caval calvarial distance in 2nd trimester
Reduced BPD and orbital diameter in 3rd trimester

14. Update – Ongoing Project
845 Ultrasounds performed
Data Collection Ongoing
Patients continue to be recruited at 2 sites
310 second trimester subjects available for analysis (157 exposed 153 unexposed)
245 third trimester subjects available for analysis (129 exposed 116 unexposed)

15. Effect of Alcohol Exposure on Somatic Measures
<18
18-24
24-30
30+
BPD
0.115
0.870
0.151
0.934 HC
0.409
0.800
0.883
0.341 AC
0.940
0.699
0.928
0.799 FL
0.277
0.021
0.720
0.076 TL
0.832
0.878
0.974 HL
0.703
0.837
0.944
0.317
Foot
0.891
0.429
0.230
0.374

16. Effect of Alcohol Exposure on Brain Measures
<18
18-24
24-30
30+
TCD
0.036
0.829
0.751
0.831
OFD
0.787
0.177
0.495
0.084
CCD
0.344
0.641
0.690
0.477
FTD
0.567
0.148
0.281
0.785
OOD
0.329
0.907
0.614
0.299
IOD
0.157
0.841
0.294
0.562 OD
0.633
0.062
0.206

17. Measures of Fetal Behavior
Biophysical Profile
Spontaneous “startles”
Evoked startles
Fetal Heart Rate Changes following VAS

18. Biophysical Profile (BPP)
Component
Notes
Score
Fetal Movement
> 3 body or limb movements
0/2
Fetal Tone
One active flexion/extension of limb or opening and closing of hand
Fetal Breathing Movements
> 1 episode (incl hiccups)
Amniotic Fluid Volume
2x2 cm pocket

19. Alcohol and BPP No studies addressing effects in humans
If give Moms at 37 weeks a couple of glasses of wine and measure BPP - breathing movements cease but other movement unchanged
In sheep chronically fed alcohol – the suppressive effect on breathing disappears with multiple exposures

20. BPP - Update

21. BPP - Update

22. BPP - Update No apparent effect on time to obtain BPP
No apparent effect on overall BPP score
Need to look at individual components – particularly fetal breathing

23. Natural History of Startles
Spontaneous
Start at 8 weeks
Decrease in frequency with increasing gestational age
Evoked
Can evoke a response from 24 weeks

24. Alcohol and Startles Spontaneous Evoked
Alcohol seems to increase number of spontaneous startles at all gestational ages
Evoked
Alcohol seems to reduce likelihood for an evoked startle

25. Startle Responses
Protocol – observe fetus during routine imaging at <14, & >26 weeks
Record spontaneous startles (30 min)
Generalized sudden movement starting in limbs lasting 1 second
After observation period wait for 2 minutes of inactivity then:
Attempt evoked startle (after 14 wks only) 2 sec VAS – if startle response within 4.5 sec +ve, if not -ve

26. Spontaneous Startles
<24 wks
>24 wks (m 31)
>24 wks (m 35)

27. Evoked Startles
<24 wks
>24 wks (m 31)
>24 wks (m 35)

28. Startles - Update Frequency of spontaneous startles fall over GA
More spontaneous startles in exposed group than unexposed
Number of subjects that show evoked startles rise then fall across GA
Exposed group less likely to show evoked startles at all GA

29. FHR following VAS Measure FHR at baseline 2 sec VAS
Measure FHR 5 sec after end of VAS

30. Change from Baseline in FHR following VAS

31. Specific Aim 1 – Lots to Do
To examine the utility of specific ultrasound measurements of fetal brain in the detection of fetuses who will go on to demonstrate features of FASD.
To correlate these ultrasound measures with postnatal assessment of growth and structural features as assessed by a standardized dysmorphological examination IN PROCESS
To correlate these ultrasound measures with altered neurobehavioral assessment at 6 & 12 months. IN PROCESS
To assess the dose response relationship between these ultrasound measures and the timing and quantity of alcohol ingested prenatally. IN PROCESS
To determine the best cut points and gestational age timing for ultrasound measures that produce the most sensitive and specific set of markers predicting above and the set with the highest positive predictive value. IN PROCESS

32. Specific Aim 2 – Lots to do
To assess the role of second and third trimester ultrasound assessment of biophysical profile (BPP) and startle response in the detection of fetuses who will go on to demonstrate features of FASD.
1. To correlate BPP and startle responses with postnatal assessment of growth and
structural features as assessed by a standardized dysmorphological examination IN PROCESS
2. To correlate BPP and startle responses with altered neurobehavioral assessment at
6 & 12 months IN PROCESS
3. To assess the dose response relationship between BPP and startle responses and
the timing and quantity of alcohol ingested prenatally IN PROCESS
4. To determine the best cut points and gestational age timing for BPP and startle
responses that produce the most sensitive and specific set of markers predicting A -
To correlate BPP and startle responses with the ultrasound measures of brain growth in Specific Aim 1 IN PROCESS

33. Targets Recruitment will continue through 2011
Babies born through 2012
Follow up for dysmorphology exams through 2012
Follow up for neurobehavioral testing through 2013
Combine pilot and current datasets

34. Thank You