The ELGAN Study

The Extremely Low Gestational Age Newborns (ELGAN) Study was designed to identify characteristics and exposures that increase the risk of structural and functional neurologic disorders in extremely low-gestational-age infants. During the years 2002 through 2004, women who delivered <28th postmenstrual week at 14 participating institutions in 11 cities in 5 states were asked to enroll in the study. The enrollment and consent processes were approved by the institutional review boards of the participating institutions.

Mothers were approached for consent either upon antenatal admission or shortly after delivery, depending on clinical circumstance and institutional preference. In all, 1249 mothers of 1506 infants consented. Approximately 260 women were either missed or did not consent to participate. Of the 1205 infants who survived to age 2 years, 1056 (88%) had a neurologic examination at approximately 24 months corrected age. Fully 877 children had complete information on variables of interest and are the subjects of our analyses.

Demographic and pregnancy variables

After delivery, a trained research nurse interviewed each mother in her native language about her sociodemographic, anthropometric, reproductive, and medical history (eg, conditions and medications) using a structured data collection form. The mother’s report of her own characteristics and exposures during pregnancy, as well as the sequence of events leading to delivery were taken as valid, even when her medical record provided discrepant information. Women who acknowledged consuming a medication were questioned as to whether the medication was taken under the direction of a physician; these responses were tabulated.

Shortly after the mother’s discharge, the research nurse reviewed the maternal chart using a second structured data collection form. The medical record was relied on for establishing the validity of events whose occurrence followed maternal admission to hospital.

The clinical circumstances that led to preterm delivery were operationally defined using data from the maternal interview and data abstracted from the medical record. Each mother/infant pair was assigned to the category that described the primary reason for preterm delivery.

Gestational age estimates were based on a hierarchy of the quality of available information. Most desirable were estimates based on the dates of embryo retrieval, intrauterine insemination, or fetal ultrasound <14th week (62%). When these were not available, reliance was placed sequentially on a fetal ultrasound at ≥14 weeks (29%), last menstrual period without fetal ultrasound (7%), and gestational age recorded in the log of the neonatal intensive care unit (1%).

To describe fetal growth, we used the birthweight Z-score, defined as the number of SD the infant’s birthweight was above or below the median weight of infants at the same gestational age in a standard dataset.

Placenta variables

Placentas were handled in a sterile manner from time of collection to biopsy. Of the samples, 82% were obtained within 1 hour of delivery. The microbiologic procedures are described in detail elsewhere. Briefly, the frozen samples were allowed to thaw at room temperature and a portion approximately 1 cm ² was removed and weighed. Then it was diluted 1:10 with sterile phosphate-buffered saline and homogenized, and aliquots were plated on selective and nonselective media, including prereduced brucella-base agar with 5% sheep blood enriched with hemin and vitamin K ₁ , tryptic soy agar with 5% sheep blood, chocolate agar, and A-7 agar. After incubation, the various colony types were enumerated, isolated, and identified by established criteria.

In keeping with the guidelines of the 1991 College of American Pathologists Conference, representative sections were taken from all abnormal areas as well as routine sections of the umbilical cord and a membrane roll, and full-thickness sections from the center and a paracentral zone of the placental disc. After training to minimize observer variability, study pathologists examined the slides for histologic characteristics listed on a standardized data form they helped create. Placental inflammation consisted of any of the following: inflammation of the chorionic plate of grade 3 (neutrophils up to amnionic epithelium) or stage 3 (>20 neutrophils/20×), moderate/severe chorioamnionitis (numerous large or confluent foci of neutrophils), and inflammation of umbilical cord (neutrophils in perivascular Wharton jelly). Infarcts were searched for, while syncytial knots in the chorionic villi were scored as increased or not.

Protocol cranial ultrasound scans

Routine scans were performed by technicians at all study hospitals using digitized high-frequency transducers (7.5 and 10 MHz). Ultrasound scans included the 6 standard quasicoronal views and 5 sagittal views using the anterior fontanel as the sonographic window. The 3 sets of protocol scans were defined by the postnatal day on which they were obtained (1: days 1-4; 2: days 5-14; 3: day 15-week 40). After creation of a manual and data collection form, efforts to minimize observer variability included conference calls to discuss aspects of images prone to different interpretations. Templates of multiple levels of ventriculomegaly were included in the manual. All ultrasound scans were read by 2 independent readers, each at a separate institution, who were not provided clinical information. The images, usually as electronic images on a CD imbedded in the software eFilm Workstation (Merge Healthcare/Merge eMed, Milwaukee, WI), were sent to a sonologist at another ELGAN Study institution for a second reading. The eFilm program allowed the second reader to see what the first reader saw, and provided options to zoom and alter gains. When the 2 readers differed in their recognition of moderate/severe ventriculomegaly or an echolucent (hypoechoic) lesion, the films were sent to a third (tie-breaking) reader who did not know what the earlier readers reported.

CP diagnosis

To standardize neurological examinations at all sites, a stand-alone, multimedia-training video/CD-ROM was developed, based on elements of a standard neurological examination. The video/CD-ROM program had audiovisual teaching sequences, voiceover commentary, graphics, and text to organize the training and amplify key teaching points. The training video provided instruction in the proper method of performing each item of the examination and illustrated all possible findings. Additionally, the CD contained 6 sets of 20 video clips for interobserver testing purposes. Repeated testing resulted in 96% agreement with the gold-standard pediatric neurologist assessment.

A diagnostic algorithm that assigned children to CP subtypes demonstrated how an experienced pediatric neurologist might go about making a CP diagnosis in a young child.

Data analysis

We evaluated the hypothesis that very preterm newborns whose mother consumed an NSAID or acetaminophen during pregnancy were not at increased or decreased risk of white matter lesions recognized on neonatal cranial ultrasound scans or of a CP subtype at age 2 years. Although aspirin is an NSAID, we evaluated aspirin separately from other NSAIDs.

We did not know the specific indication for each medication consumed although we collected information regarding disorders of pregnancy that might have prompted their use. Our including antibiotics among the drugs consumed allows us to explore the contribution of confounding by indication. In essence, if consumption of an NSAID was merely a marker of antenatal inflammation, and not in itself a brain-damaging exposure, then the risks of brain damage following NSAID exposure could be compared to the risks of brain damage following antibiotic consumption.

Similarly, we included acetaminophen among the drugs of interest because it provides symptomatic relief comparable to that provided by NSAIDs, but unlike NSAIDs, acetaminophen has no known antiinflammatory capabilities. Consequently, comparing the risks of brain damage following NSAID consumption to the risks following acetaminophen consumption allows an assessment of the potential contribution of diminishing inflammation.

In this sample, multifetal gestations did not have a higher risk of any CP diagnosis. Data were therefore analyzed with the infant, rather than the mother, as the unit of analysis. Thus, a mother of twins was counted twice, once for each newborn. Additional analyses to determine the effect of including multiple infants from the same mother on variance estimates did not significantly influence our findings.

We created Tables 1 through 5 to help identify potential confounders. For example, were women who consumed a medication more likely to have an inflamed placenta than women who did not? Similarly, were the newborns who developed ventriculomegaly more likely to have an inflamed placenta than infants who did not? We calculated the probabilities (Fisher exact test) that column percents on the same line in adjacent columns occurred randomly.

TABLE 2

Delivery characteristics among prenatal medication consumers

Delivery characteristic	Antibiotic		Aspirin		NSAID		Acetaminophen		Row N
	Yes	No	Yes	No	Yes	No	Yes	No
Delivery indication
Preterm labor	47	45	53	45	39	46	46	44	396
pPROM	19	22	14	22	23	21	21	21	185
Preeclampsia	13	14	6	14	11	14	15	13	120
Abruption	10	12	6	11	13	11	10	12	97
Cervical insufficiency	8	4	14	4	6	5	4	6	43
Fetal indication	3	4	6	4	8	4	4	4	36
Gestational age 23-24 wk	23	19	29	20	25	20	23	17	178
Gestational age 25-26 wk	41	47	43	46	47	45	43	48	399
Birthweight Z-score <−2 a	5	6	0	6	5	6	5	6	45
Placenta bacteriology
Aerobe	31	31	35	31	30	31	30	32	271
Anaerobe	26	30	37	28	22	29	29	29	251
Mycoplasma	14	8	0	11	16	10	11	9	89
Placenta histology
Any inflammation a , b	42	38	59	38	41	39	39	40	344
Infarct	16	19	16	18	27	17	20	16	155
Increase syncytial knots	22	21	22	21	19	21	20	22	182
Column N	262	615	49	828	64	813	442	435	877

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