Objective
The Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT) compared induction of labor and expectant management in suspected intrauterine growth restriction (IUGR) at term. In this subanalysis, we report neonatal morbidity between the policies based on the Morbidity Assessment Index for Newborns (MAIN).
Study Design
We used data from the DIGITAT. For each neonate, we calculated the MAIN score, a validated outcome scale.
Results
There were no differences in mean MAIN scores or in MAIN morbidity categories. We found that neonatal admissions are lower after 38 weeks’ gestational age compared with 36 and 37 weeks in both groups.
Conclusion
The incidence of neonatal morbidity in IUGR at term is comparable and relatively mild either after induction or after an expectant policy. However, neonatal admissions are lower after 38 weeks of pregnancy, so if induction to preempt possible stillbirth is considered, it is reasonable to delay until 38 weeks, provided watchful monitoring.
Intrauterine growth restriction (IUGR) is defined as an estimated fetal weight or an abdominal circumference below the 10th centile for gestational age. Postnatally, children with a birthweight below the 10th centile are classified as small for gestational age (SGA). The latter condition is identified only after birth. However, IUGR and SGA are associated with perinatal morbidity and mortality, even at term. There is no consensus on the management of pregnancies complicated by IUGR.
We recently performed the Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT) to investigate whether induction of labor for pregnancies with suspected IUGR beyond 36 weeks’ gestation reduced neonatal morbidity and mortality compared with an expectant approach with fetal and maternal surveillance. Unlike many retrospective studies on growth restriction, our study did not look retrospectively at children being born SGA but followed up children prospectively with suspected IUGR at term.
The study showed comparable primary fetal outcomes (a composite of perinatal death, 5 minute Apgar score below 7, umbilical arterial pH below 7.05, or admission to neonatal intensive care unit [NICU]) as well as comparable rates of operative deliveries. Although the total number of children admitted to the intensive care unit did not differ between the groups, more children in the induction group were admitted to an intermediate level of care than in the expectant group (48% vs 36%; difference, 12%; 95% confidence interval [CI], 5–20%).
Complications of late prematurity might explain this because children in the induction group were born on average 10 days earlier than in the expectant group, (266 days vs 277 days; difference, –9.9 days; 95% CI, –11 to –9). However, the difference may simply reflect policies for admission to intermediate levels of care related to prematurity rather than clinically relevant morbidity.
It is important to resolve these 2 competing explanations because in the expectant group, more children were severely growth restricted, defined as a birthweight below the third percentile (13% vs 31%: difference, –18%; 95% CI, –24% to –12%) and therefore had a possible higher risk of neonatal morbidity. To study the net influence of the 2 policies on neonatal morbidity in detail, the Morbidity Assessment Index for Newborns (MAIN) score, a validated outcome measure for neonatal morbidity, was calculated and compared.
Materials and Methods
This is a secondary analysis of the DIGITAT. The original trial was approved by the University of Leiden Institutional Review Board (P04.210). Written informed consent was obtained from all participants before randomization.
The study population consisted of children born to mothers who participated in the DIGITAT. Between November 2004 and November 2008, pregnant women with a singleton fetus in cephalic presentation and suspected IUGR between 36 +0 and 41 +0 weeks were recruited. Suspected IUGR was defined as a fetal abdominal circumference or an estimated fetal weight below the 10th percentile or deceleration of the fetal abdominal circumference in the third trimester.
Exclusion criteria were previous cesarean section, diabetes mellitus, or gestational diabetes requiring insulin therapy, renal failure, human immunodeficiency virus seropositivity, prelabor rupture of membranes, severe preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), or a fetus with aneuploidy or congenital abnormalities suspected on ultrasound. Fetuses with decreased or absent movements, and those with abnormal heart rate tracings, were also excluded.
Consenting women were randomly allocated to either induction or expectant monitoring. Participants allocated to the expectant monitoring group were monitored until the onset of spontaneous labor with daily fetal movement counts and twice-weekly heart rate tracings, ultrasound examination, maternal blood pressure measurement, assessment of proteinuria, laboratory tests of liver and kidney function, and full blood count. Women were monitored as either an outpatient or an inpatient, according to local protocol. In the expectant monitoring group, induction of labor or planned cesarean section was performed for obstetrical indications, such as suboptimal fetal heart rate tracings, prolonged rupture of membranes, or postmaturity between T plus 7 and T plus 14 days, at the obstetrician’s discretion.
Morbidity was calculated using the MAIN score. This score was developed to provide a numeric index of early neonatal outcomes of prenatal care and adverse prenatal exposures in babies delivered beyond 28 weeks of gestation. It is a sensitive and discriminative outcome measure for obstetric clinical trials and is particularly suited for studies with outcomes other than extreme preterm delivery. The data items, such as Apgar scores at 5 and 10 minutes, cord blood pH, hyperbilirubinemia, hypoglycemia, intraventricular hemorrhage, and the need for intubation, can all be obtained from the hospital discharge summaries. The final score is divided into 4 morbidity categories: below 150 (no/minimal morbidity), 151-500 (mild morbidity), 501-800 (moderate morbidity), and more than 800 (severe morbidity).
A MAIN score greater than zero is considered as a positive MAIN score. For children admitted to the NICU or intermediate level care, items for the MAIN score were obtained from the discharge summaries. For those discharged home immediately after birth or admitted only to the maternal ward, no separate discharge summaries are written, so for them 5 and 10 minute Apgar scores and arterial umbilical artery pH only were used, assuming that the other items, if not reported, were normal.
Data were analyzed according to intention to treat. Continuous variables were compared using a Student t test or Fisher exact test when data were normally distributed or the nonparametric Mann-Whitney U test for skewed data. The χ 2 test was used for categorical variables. Treatment effects were presented as difference in percentages with 95% CIs. P values less than .05 were considered to indicate statistical significance. If more than 5% of observations were missing, this was indicated in the footnote of the table. The scores for the induction and expectant groups were compared for all babies and stratified by gestational age at time of randomization and for the different admission types.
We studied the effect of gestational age at randomization on different outcome parameters, such as mean MAIN score, severe MAIN score, and composite adverse neonatal outcome. This was done using generalized additive logistic regression models in which the effect of gestational age is estimated with a smoothed curve. We tested for differences between the 2 groups using likelihood ratio tests.
Results
In the DIGITAT trial, 321 women were randomized for induction and 329 for an expectant management policy ( Figure 1 ). The MAIN score was assessed in 308 induction group babies and in 315 expectant management group babies. Baseline characteristics and main trial results are displayed in Table 1 . There were no differences between the randomized groups in maternal comorbidities such as preeclampsia or gestational hypertension, heart and vascular disorders, or autoimmune disease (data not shown).
| Characteristic | Induction of labor (n = 321) | Expectant monitoring (n = 329) | Difference in percentage or mean (95% CI) |
|---|---|---|---|
| Nulliparous | 182 (56.7) | 201 (61.1) | −4.4 (−12.0 to 3.2) |
| Maternal age, y | 26.9 (23.3–31.2) | 27.4 (23.3–31.4) | −0.04 (−8.6 to 7.8) |
| BMI at study entry a | 21.9 (19.7–25.5) | 22.2 (19.7–25.6) | −0.1 (−1.0 to 0.7) |
| Maternal smoking b | 138 (46.9) | 127 (40.8) | −6.1 (−1.8 to 14) |
| Gestational age at randomization, d | 264 (258–269) | 264 (258–268) | −0.7 (−2.1 to 0.7) |
| White c | 254 (83.6) | 253 (81.1) | −2.5 (−3.6 to 8.5) |
| Education | |||
| Lower professional school | 168 (52.3) | 170 (51.7) | 0.6 (−7.0 to 8.4) |
| Medium professional school | 26 (8.1) | 37 (11.2) | −3.1 (−7.7 to 1.4) |
| Unknown | 127 (39.6) | 122 (37.1) | −2.5 (−5.0 to 10.0) |
| Inclusion criteria | |||
| Fetal abdominal circumference less than the 10th percentile | 262 (81.6) | 270 (82.1) | −0.5 (−6.4 to 5.5) |
| Estimated fetal weight less than the 10th percentile | 296 (92.2) | 308 (93.6) | −1.4 (−5.4 to 2.5) |
| Flattening of fetal abdominal circumference curve | 83 (25.9) | 84 (25.5) | −0.4 (−6.4 to 7.0) |
| Onset of labor | |||
| Spontaneous | 12 (3.7) | 151 (46.0) | −42.3 (−48.1 to −36.5) |
| Induction | 306 (95.6) | 166 (50.6) | 45.0 (39.2–50.9) |
| Elective cesarean section | 2 (0.6) | 11 (3.3) | −2.7 −4.9 to −0.6) |
| Mode of delivery | |||
| Spontaneous | 249 (77.6) | 257 (78.1) | 0.5 (−6.9 to 5.8) |
| Vaginal instrumental | 27 (8.4) | 27 (8.2) | 0.2 (−4.0 to 4.4) |
| Cesarean section | 45 (14.0) | 45 (13.7) | 0.3 (−5.0 to 5.6) |
| Time between randomization and onset of labor, d | 0.9 (0.7–1.7) | 10.4 (5.6–16.0) | −9.6 (−10.8 to −8.5) d |
| Gestational age at birth, d | 266 (261–271) | 277 (269–283) | −9.9 (−11.3 to −8.6) d |
| Birthweight, g | 2420 (2220–2660) | 2550 (2255–2850) | −130 (−188 to −71) d |
| Birthweight by percentile | |||
| Less than third percentile | 40 (12.5) | 100 (30.6) | −18.1 (−24.3 to −12.0) d |
| Third to fifth percentile | 82 (25.5) | 79 (24.2) | 1.3 (−5.3 to 8.0) |
| Fifth to 10th percentile | 88 (27.5) | 62 (18.9) | 8.5 (−2.0 to 14.9) |
| 10th to 25th percentile | 88 (27.4) | 66 (20.2) | 7.2 (0.7−13.8) |
| Greater than 25th percentile | 23 (7.2) | 20 (6.1) | −1.1 (−2.8 to 4.9) |
| Composite adverse neonatal outcome | 17 (5.3) | 20 (6.1) | −0.8 (−4.3 to 2.8) |
| Neonatal admission | |||
| Intensive care | 9 (2.8) | 13 (4.0) | −1.2 (−4 to 1.6) |
| Intermediate care | 155 (48.3) | 118 (35.9) | 12.4 (4.9–20.0) e |
| Maternal ward | 89 (27.8) | 116 (35.7) | −7.9 (−15 to −0.7) e |
| No admission | 67 (20.9) | 78 (24.0) | −3.1 (9.5–3.4) |
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