“Balance, Fit”, intrauterine life and

lifelong diseasePreliminary analyses in the National

Collaborative Perinatal Project

Levels of intervention

◦ Tertiary: Aimed at reducing the chronic effects of established disease.

◦ Secondary: Aimed at curing disease.

◦ Primary: Preventing disease.

Public health and intervention

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◦ Peri disease factors

◦ Young adult factors

◦ Childhood factors

◦ Genetic factors

The causal pie in adult disease

Ecologic

◦ High cardiovascular death rates in 1950 correlated with high infant mortality in the early 1900’s.

In an area of high infant mortality, “survivors” were still comparatively stressed.

Retrospective cohorts

◦ Nurses Health study, etc.

◦ Common feature- BW used as a surrogate for adequacy of the intrauterine environment

Fetal origins of adult disease

Heart attack

Stroke

Hypertension

Diabetes

Obesity, syndrome X

Breast cancer

Osteoporosis

Diseases with “fetal origins” (associated with BW)

Does size matter?

◦ 2500 g BW 16g heart

◦ 3000 g 22 g heart

(37.5% more heart)

Possible mechanisms

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“Small is bad”?

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Small or “relatively small”?

The thrifty phenotype?

Fetal origins and diabetes

29621 singleton liveborn infants

Standard placental measures◦ Shape

◦ Larger and smaller diameters

◦ Thickness

◦ Distance from cord insertion to the nearest disk edge

◦ Umbilical cord length

◦ Placental weight

Outcome variable: BW

The data set

Disk shape

Larger and smaller diameters

Distance from cord insertion to disk edge

Cord length

Disk thickness

Placental weight

The “predictor” variables

Birth weight

BMI at ages 4 and 7 years

The outcome

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Umbilical cord length

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3 disk dimensions

Normal- 500 g

Abnormal 1st-2nd trimester, 500 g

Abnormal from 1st-2nd trimester, 250 g

Abnormal 3rd trimester, 400 g

Time-stamping abnormal growth

Linear terms

◦ Higher order terms

◦ Interactions

Local solutions (MARS 2.0)

Regression Analysis Plan

Indirect/Direct effects on BW

Indirect/Direct effects on PW

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Direct and Indirect Effects

Pick 10 different random seeds

Get at least 9 different patterns of significant higher order terms and/or interactions

Inspection of distributions suggests differences lie with outlier partitioning

“significant” terms generally negative, indicating floor/ceiling effects

Problems with standard regression

And so to MARS 2.0

Intrauterine “Balance” and childhood outcomes

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Placental weight and birth weight

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No evidence for placental “senescence”

“Post maturity syndrome”

“Fetal intolerance to labor”

Interpretations

Fetal-placental weight ratio◦ How many grams of baby supported by each gram of

placental

◦ ~7:1 at term

◦ Too low placental dysfunction

◦ Too high↓ placental reserves

Ponderal index◦ Fatness ratio (weight*100/length^3)

◦ Third trimester weight gain

New terms

Fetoplacental weight ratio

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PW and BW Effects

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PW and BW Effects continued

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Does bad “intrauterine balance” affect childhood growth?

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Interpretability of LR

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Interpretation: the cord length-age 7 BMI association is independent of PW

Age 7 BMI and cord length

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Cord length BW Age 7 BMI

Cord length Age 7 BMI= only at extreme cord lengths

Age 7 BMI, cord length, adj for BW

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◦ N= 36

◦ N~ 1000

◦ N~ 25,000

FPR knots used to categorize data

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N=240

N~ 23,000

N~ 3,000

FPR knots used to categorize data

Recode BW into groups

◦ <2500 g: “Intrauterine growth restriction” Suggests chronic intrauterine deprivation

◦ >4000 g: Macrosomia Diabetic type metabolic pathology

◦ “Normal”

Can placental growth classify pathologic fetal growth that continues into childhood?

TreeNet, RF and Age 4 and 7 BMI

Set penalties for misclassification

Score data

Incorrectly scored children are either bigger or smaller than expected given their placental dimensions◦ They don’t “fit” their placentas

Does “lack of fit” mark children’s growth trajectory?

Score data

Class N Cases N Mis-Classed

% Error Cost

0 2,023 175 8.65 175

1 17,946 17,946 100.00 179,460

2 1,093 61 5.58 61

TreeNet classification:Misclassification for Learn Data

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TN BWT grp- Predgrp= “Wrong”

Observed Predicted

<2500 2500-4000 >4000

<2500 10.8 11.1 11.4

2500-4000 10.0 11.4 12.0

>4000 10.9 11.4 11.8

Do “kids who don’t fit” differ from those who do? (Age 4 BMI)

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TN and RF scoring

The placenta’s purpose is to “make a baby”

Values of placental dimensions where the placenta is bigger but the baby is not “unbalanced”

“Unbalanced” babies may be physiologically vulnerable and may have different childhood growth trajectories

Intrauterine “Balance”

Your placenta provides all oxygen and nutrients and genetics aside is the principal determiner of fetal growth

If you are bigger or smaller than your placenta predicts, you don’t “fit”

Children who don’t “fit” may be physiologically vulnerable and have different childhood development trajectories

Intrauterine “fit”

MARS and RandomForest allow complementary and unique insights into how placental growth is translated into fetal growth

Placental measures can be used to characterize the fetal environment, with physiologic and time-order inferences that may be important to “fetal origins” research

Summary