1. The study of the association between environmental exposure and preterm birth: design and methodological aspects
Patrizia Schifano and Xavier Basagana
“Challenges for epidemiology in the context of the National Health Service” Rome October 2012

2. Preterm Birth
Preterm birth is reported to be the main cause of perinatal mortality in the US and in Europe
5-7 % of total birth in Europe
10-12% of total birth in the US
The etiology of preterm birth is not well known:
probably a mix of genetic, environmental and socio-economic factors
Also a small reduction in the duration of pregnancy has resulted to be associated with adverse health outcomes in neonatal and later life

3. Who is preterm?
Preterm births are classified in early and late preterm, according to gestational age
Singleton late preterm births (34-36 weeks) comprise the largest proportion (74%) of singleton preterm births and the fastest-growing segment.

4. Preterm birth and health outcomes
The severity of heath conditions decrease with gestational age, but also late preterm infants have a higher incidence of morbidity and mortality when compared with term infants
Brain injury, neuro-developmental disorders, broncopulmonary displasia and growth impairment are the main group of causes associated with preterm birth

5. Preterm births and environmental exposure
Several specific mechanisms are suspected to underlie adverse birth outcomes among mothers exposed to environmental hazards
Recently there is a growing interest in studying the potential effect of air temperature and air pollutants.
2011, Environmental Research
Few studies have examined the relationship between ambient temperature and birth outcomes directly
Very heterogeneus studies by study design, definition of birth outcomes, exposure windows and statistical methods
Further research is needed

6. Methodological critical aspects
Sample Size
Small expected effect
Measure of gestational age
Window of exposure
It is not clear which is the most vulnerable period during pregnancy; this changes according to the exposure and the outcome considered
Adjustment for seasonality
Births have their on seasonality; this has to be taken into account in the study of the effect of temperature
Confounders and effect modifiers of the association
Week of gestation
Maternal characteristic
Other meteorological exposure

7. Confounding by gestational age in time series
A Time series approach is well suited for the study of most environmental exposures and preterm birth
Individual-level risk factors that do not vary across time cannot act as confounder
Potential for confounding by gestational age and individual risk factors in time series studies of pregnancy outcomes
Darrow et al, Epidemiology, 2009

8. Confounding by gestational age in time series
Gestational age is a strong predictor of imminent birth
Gestational age distribution might vary seasonally in the pregnancy risk set, acting as a confounder of the preterm-temperature relationship
Risk factors invariant at the individual level may vary seasonally when aggregated into pregnancy risk-set, and act as confounders of the studied relationship
Methods that account for gestational age are reccomanded

9. What is relevant to know for public health
Is there an effect of heat on preterm probability?
2. By how much does heat shorten average gestational age?
3. During which gestational weeks can heat induce
labor?
Rome study
Barcelona study
Rome study
Is the heat-preterm birth relationship relevant for public health?

10. The Study of Rome
Objective: to evaluate the effect of maternal short-term exposure to heat on the probability of pre-term delivery
Study population: cohort of births occurred in Rome between 2001 and 2010, from April to October
Inclusion Criteria
Single birth between the 22° and 36° week of gestation
Natural delivery
Other delivery tipology with spontaneous onset of labour
Mother resident in Rome and who gave birth in city hospitals
Gestational age: date of birth - date of last menstrual period
78633 births
4314 preterm births (5.5%)

11. Statistical analysis Exposure: Daily maximum apparent temperature
Seasonality of births
Lag structure
Shape
Percent change in the mean daily number of preterm birth per 1°C increase in maximum apparent temperature
Model: Poisson generalized additive model
Outcome variable: daily number of preterm births
Offeset: daily number of ongoing gestation in utero at risk for preterm birth
Adjusted for: seasonal trend, long term trend, day of the week, holidays, air polluttants: PM10; NO2, O3

12. Results:
Lag distribution of maximum apparent temperature effect on preterm births
lag 0-3
lag 0-7

13. Results:
Whole Year
April - October
Linear relationship

14. Results:
%Change in pre-term births between 22° and 36° week per 1°C increase in MAT (best model according to AIC)
lag 0-3
lag 0-7
IC95% 0.73 – 2.79
IC95% 0.32 – 2.69
No confounding by air pollutants
Effect of Ozone in an indipendent model

15. Results:
Sensitivity analysis of births between 22nd and 32th week (484 cases)
Any significant effect
no effect
lack of power
Sensitivity analysis on cesarean deliveries (elective and emergency)
Any significant effect

16. The study of Barcelona Cohort of 7,585 pregnant women.
Dadvand et al. Climate extremes and the length of gestation. EHP 2011;119:
Cohort of 7,585 pregnant women.
Similar inclusion criteria than in Rome.
Gestational age: Objective measure (ultrasound exam).
Statistical analysis:
Linear regression of gestational age.
Exposure: binary indicator for extreme heat
based on 99th percentile of heat index.
lags 0-6 examined.
2-Stage model to control for time trends.

17. The study of Barcelona Rationale for the analysis:
Extreme heat could induce labor.
This could happen at any gestational age.
After a extreme heat event we should observe lower lengths of gestation.

18. The study of Barcelona
Main result: The day after a extreme heat event there is a 5 day reduction in average length of gestation.
Concerns:
This provides an answer to Question 2.
It does not directly address effect on pre-term births.
More powerful than binary response.
Average change may not be the appropriate metric.
Changes can be more noticeable in the left tail.
Gestational age not normally distributed.

19. Recap 3 relevant scientific questions.
2 different types of analysis, each one addressing a different question.
Both techniques have some advantages and some drawbacks.
Power & efficiency
Interpretation, clinical relevance
Distributional properties
Choice of cut-off …

20. Way forward Flexible Bayes regression
Flexible method for density regression, which allow the entire density to change flexibly with predictors.
From: Dunson DB. Flexible Bayes regression of epidemiologic data. In: The Oxford Handbook of Applied Bayesian Analysis

21. Flexible Bayes Regression
E.g. Approximate the distribution by a mixture of four Normals (4 latent classes): full term births, late preterm births, early preterm births, and late term births.
Mixture model:

22. Flexible Bayes Regression
Example: distribution of gestational length as a function of DDE.
Thicker left tail at high values of DDE.

23. Flexible Bayes Regression
From this analysis we can get other outputs.
E.g. to answer question 2:

24. Flexible Bayes Regression
E.g. to answer questions 1 and 3:
use various thresholds for defining preterm birth

25. Flexible Bayes Regression
Advantages:
Single analysis to answer all questions (e.g. multiple thresholds for preterm).
It does not discard information → Efficiency gains.
Especially important since one may have limited data in the tails, where the main interest is.
Bayesian approach of dealing with sparsity
→ borrowing information.
Across values of gestational age
Across values of the exposure.
Leads to smooth and realistic estimates.

26. Future challenges and collaborations
Collaboration between DEP and CREAL
To design a more powerful and efficient study:
Multicentric
Italian cohort (multicity cohort, 6 cities)
Spanish cohort (multicity cohort, 2 cities)
Applying the proposed methodology
Answer to question 1 to 3
Study potential effect modifiers of the analysed association
Effect of ozone and other polluttant on preterm birth
Interaction between temperature and ozone