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

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

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 1 - 3 above and the set with the highest positive predictive value.

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

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

BPP - Update

BPP - Update

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

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

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

Startle Responses Protocol – observe fetus during routine imaging at <14, 18-26 & >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

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

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

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

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

Change from Baseline in FHR following VAS

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 1 - 3 above and the set with the highest positive predictive value. IN PROCESS

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

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

Thank You