Pregnancy and postpartum dynamics revealed by millions of lab tests

Pregnancy and delivery involve dynamic alterations in many physiological systems. However, the physiological dynamics during pregnancy and after delivery have not been systematically analyzed at high temporal resolution in a large human population. Here we present the dynamics of 76 lab tests based on a cross-sectional analysis of roughly 41 million measurements from over 300,000 pregnancies. We analyzed each test at weekly intervals from 20 weeks preconception to 80 weeks postpartum, providing detailed temporal profiles. About half of the tests take three months to a year to return to baseline during postpartum, highlighting the physiologic load of childbirth. The precision of the data revealed the effects of preconception supplements, overshoots after delivery, and intricate temporal responses to changes in blood volume and renal filtration rate. Pregnancy complications – gestational diabetes, pre-eclampsia, and postpartum hemorrhage – showed distinct dynamical changes. These results provide a comprehensive dynamic portrait of the systems physiology of pregnancy.

Methods
Study Population

The study population consisted of individuals from the Clalit healthcare database, Israel's largest health maintenance organization (HMO). We considered all pregnancies of females aged 20 to 35 between 2003 and 2020. Information about pregnancies before 2003 is not available. We estimated the fraction of first pregnancies for the years 2010-2020 to reduce the influence of first pregnancies before 2003 which we cannot account for. For more information, see “stats.csv”.

Data Collection

Medical records were pseudonymized by hashing of personal identifiers and randomization of dates by a random number of weeks uniformly sampled between 0 and 13 weeks for each patient and adding it to all dates in the patient diagnoses, laboratory, and medication records. This randomization does not affect timing relative to delivery. 

We examined the timeframe of 60 weeks before delivery to 80 weeks after delivery for all documented labours within our study population. 0 is denoted as the week of delivery. We identified deliveries by ICD9 code V27 and confirmed a childbirth record for the individual. We excluded preterm deliveries (≤37 gestational weeks, ICD9 code 644) stillbirths, and labors with more than one newborn. Nonetheless, 12% of deliveries were at the ≤37 gestational weeks and missing the 644 code.

To mitigate ascertainment bias of the test results, for each test, we removed data from individuals with chronic disease that affected the test if the onset of the disease was up to 6 months after the test. We also removed data from individuals who purchased drugs that affected the tests in the 6 months before the tests. Chronic diseases are defined as non-pediatric ICD9 codes with a Kaplan−Meyer survival drop of >10% over 5 years and are assigned above a minimal average drop of 1/3 per y. Drugs that affect a test were defined as drugs with significant effect on the test (false discovery rate < 0.01). This step allowed us to focus on a relatively healthy subset of the pregnant population, reducing the confounding effects associated with specific health conditions listed above or medication usage.

To exclude the potential effect of follow-up pregnancies in the 80 weeks following delivery, we excluded lab values from individuals with another delivery within 40 weeks following the measurement.

For each pregnancy, we gathered all available test values including standard blood count, kidney and liver function tests, blood coagulation tests, lipid panel, inflammation markers, and hormones. We then discretized test values into time points relative to the time of birth in weekly intervals for each test. In addition to test values, we also extracted data on patients including age (at measurement, mean, and interquartile range) and BMI (the most proximal BMI measurement in medical records outside pregnancy, mean and interquartile range, if available).

Privacy concerns

Retrospective test results were aggregated and only statistical information was kept. Our ethical agreement with Clalit does not require informed consent for the publication of this aggregated data. Weekly intervals with a single measurement per test were removed. Mean values were kept for weekly intervals (per test) with 10 measurements or less and other values (percentiles, standard deviation) were removed, ensuring individual measurements cannot be interpreted from the aggregated data.