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Obstetrics & Gynecology 2001;98:289-294
© 2001 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Umbilical Cord Plasma Interleukin-6 and Fetal Growth Restriction in Preeclampsia: A Prospective Study in Norway

Rønnaug A. Ødegård, MD, Lars J. Vatten, MD, PhD, Stein Tore Nilsen, MD, PhD, Kjell Å. Salvesen, MD, PhD, Hege Vefring, MS and Rigmor Austgulen, MD, PhD

From the Institute of Cancer Research and Molecular Biology, the Institute of Community Medicine and General Practice, Norwegian University of Science and Technology, Trondheim; the National Center for Fetal Medicine, University Hospital of Trondheim, Trondheim; and the Departments of Obstetrics and Gynecology, and Clinical Chemistry, Rogaland Central Hospital, Stavanger, Norway.

Address reprint requests to: Rønnaug A. Ødegård, MD, Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, University Medical Center, N-7489 Trondheim, Norway; E-mail: ronnaug. odegard{at}medisin.ntnu.no.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To study the association between umbilical plasma levels of interleukin-6 (IL-6) in relation to fetal growth in subgroups of preeclampsia, and in control pregnancies.

METHODS: Umbilical cord plasma was collected from 12,804 consecutive births. A total of 271 singleton cases of preeclampsia were identified, and classified as mild or severe, and as disease with early or late onset. As controls, 611 singleton pregnancies without preeclampsia were selected, and the ratio between observed and expected birth weight was used as a measure of fetal growth. In the analysis, we also included maternal smoking during pregnancy. Umbilical cord plasma IL-6 concentration was measured with an IL-6 bioassay. Comparing controls with subgroups of preeclampsia (severe and early onset), this study had a statistical power of 90% to detect a difference in cord IL-6 of 10 pg/mL.

RESULTS: In severe preeclampsia, cord plasma IL-6 concentration was lower than among controls (P < .001), and there was a sharp decrease in cord plasma IL-6 with decreasing birth weight ratio (P trend <.001). By further dividing the preeclampsia group into early or late onset, the strong association between low IL-6 levels and low birth weight ratio appeared to be present mainly in early-onset disease. These results were not confounded by maternal smoking.

CONCLUSION: Restricted fetal growth related to preeclampsia is associated with reduced umbilical cord plasma IL-6 concentration in cases with early-onset disease. In these cases, fetal growth restriction could be mediated by impaired trophoblast function.

A number of cytokines have key roles in normal placental and fetal growth.1–4 Interleukin-6 (IL-6) is a potent mitogen that is secreted by the trophoblast during normal pregnancy,5 and in vitro observations suggest that IL-6 stimulates growth, invasion, and differentiation of the trophoblast.6 Interleukin-6 contributes to the regulation of placental hormone production,7–9 and appears to be involved in angiogenesis.10,11 Previously, a few small studies have reported reduced IL-6 levels in amniotic fluid (AF)12 and umbilical cord blood13 associated with fetal growth restriction (FGR), and these findings support the hypothesis that IL-6 may be related to fetal growth at the fetomaternal interface.

Preeclampsia is a heterogeneous syndrome that is strongly associated with FGR in severe14 and early-onset disease.15,16 Fetal growth restriction in preeclampsia is attributed to reduced placental blood flow with subsequent impaired fetomaternal exchange of substrates, and the process may be initiated by unsuccessful transformation of uteroplacental spiral arteries.17 However, different patterns of adaptation to reduced placental blood flow may take place.18,19 The frequently observed increased development of placental terminal villi has been interpreted as an attempt to increase the placental surface area in order to enhance substrate transfer.18 In other cases of restricted fetal growth, placental compensation may be absent, and severe impairment of trophoblast has been described.20 Typically, these cases are characterized by early delivery.18

In the present study we have analyzed the association between IL-6 levels in umbilical cord plasma and fetal growth in preeclampsia (subgrouped according to clinical severity and gestational age at disease onset) and controls in a population of nearly 13,000 consecutive births. Because maternal smoking increases the risk of FGR, and shares some uteroplacental characteristics with preeclampsia,21 we also included maternal smoking in the analysis.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Umbilical cord blood samples were collected in a prospective study of pregnancy outcome that took place from January 1993 to December 1995 at Rogaland Central Hospital in Stavanger, Norway. The birthing clinic at this hospital serves exclusively a region of approximately 239,000 inhabitants, and there were 12,804 deliveries during the study. The Norwegian Medical Birth Registry records information on all deliveries that take place in Norway,22 and we searched the records to identify potential cases of preeclampsia and to select population controls, as described previously.15,23

We initially identified approximately 1300 cases with clinical information possibly indicative of preeclampsia, and verified and supplemented this information with details from hospital records. We identified 307 singleton pregnant women who fulfilled the diagnostic criteria for preeclampsia (see below); umbilical cord blood was available from 271. One case was excluded because of culture-proven neonatal sepsis. The definition of preeclampsia has been reported previously24; that is, persistent diastolic blood pressure (BP) of at least 90 mmHg had to develop after 20 weeks’ gestation, and diastolic BP had to increase by at least 25 mmHg. In addition, proteinuria had to be present, and cutoff was defined as 0.3 mg/L (semiquantitative dipstick 1+) in at least one urine sample after 20 weeks’ gestation without simultaneous urinary infection. Preeclampsia was classified as severe (n = 70) if diastolic BP increased to at least 110 mmHg, along with proteinuria 3+ on dipstick, or at least 500 mg/24 hours. Cases with eclampsia and suspected hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome were regarded interchangeable with severe preeclampsia, whereas all other cases of preeclampsia were classified as mild (n = 200). We used delivery before or at 34 weeks’ gestation as a proxy for early-onset disease,25 and classified 34 patients as having early-onset preeclampsia and 236 as having late-onset preeclampsia. For comparison, the medical birth registry selected two separate groups of women without preeclampsia who gave birth at the hospital during the same period as described previously.15,23 One group consisted of the first women who gave birth after the women with preeclampsia. The other group was randomly selected by computer among all other births at the hospital but frequency matched by mother’s age to avoid confounding between effect of preeclampsia and maternal age. Using each control group separately in the analyses yielded almost identical results, and we decided to pool the two groups to increase statistical precision. The results presented are based on the pooled analyses. We obtained cord blood from 611 control women, and one was excluded because of culture-proven neonatal sepsis.

Information on maternal smoking was obtained at about 18 weeks’ gestation, and was available for 259 of the women with preeclampsia and in 570 controls. Because few women reported smoking more than ten cigarettes per day, the participants were dichotomized as smokers or nonsmokers. All other baseline data were obtained at the first maternal visit at about 12 weeks of pregnancy, and the infant data were collected from hospital records after discharge from the hospital. Blood samples were collected passively from the placental side of the umbilical cord after delivery. All blood samples were collected in syringes containing heparin, and chilled to 4C up to 60 hours before being centrifuged at 3000 rpm for 15 minutes. Plasma was stored at -80C until analysis.

As a measure of fetal growth we used the ratio between observed and expected birth weight (birth weight ratio),26 and the ratio was adjusted for sex and gestational age at birth. Weight curves estimated from ultrasonographic measurements in a population of healthy pregnant Swedish women were used to determine the expected birth weights.27 Gestational age at birth was calculated from routine ultrasonographic measurements at 18 weeks’ gestation. Small-for-gestational age (SGA) was defined as birth weight two standard deviations (SD) or more below the expected birth weight, which corresponds to more than 24% lower birth weight than expected (birth weight ratio less than 0.76),27 or to approximately 840 g reduction of birth weight for a term infant. This cutoff for SGA corresponds approximately to the 2.3 percentile. Table 1Go lists some characteristics of the groups.


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  		Table 1. Descriptive Data in Preeclampsia and in Controls
 
Interleukin-6 bioactivity was measured by the hybridoma cell line B 13.29 clone 9, which depends on IL-6 for growth,28 and we followed the procedures for colorimetric assay described by Tada et al.29 Briefly, diluted plasma samples were added to B 13.29 and growth was measured after 64 hours by using MTT. Human recombinant IL-6 (Genzyme, Cambridge, MA) was used as a reference standard, and the results were expressed in pg/mL. Each sample was analyzed in duplicate with four dilutions from 1:20 to 1:160 and the assay was run in eight sequences. The detection limit of the assay was 4.9 pg/mL, and IL-6 was detected in umbilical cord plasma from 80% of infants exposed to preeclampsia and in 89% of control infants. All samples below the detection limit were given the value 0. The intra-assay variation was on average less than 7%, and the inter-assay variation 25%. Because a high intra-assay variation was expected, all subjects were analyzed in the order they were included in the study, and samples from three cases and six controls were interspersed on each microtiter plate. Therefore, a relatively high interassay variation would influence the results only in a random fashion, and differences between groups would be underestimated. We examined if the time between blood collection and freezing influenced IL-6 levels, and an interval of 60 hours did not influence the results. We also analyzed whether factors that may inhibit IL-6 activity were present, and found low levels of inhibiting activity in samples with both high and low IL-6 levels, in preeclampsia and control samples (data not shown). Monoclonal anti-IL-6 (R&D Systems, Minneapolis, MN) inhibited the activity of IL-6.

Interleukin-6 had a skewed distribution, and was therefore expressed as the median value [pg/mL (inter-quartile range)]. Mann–Whitney U test and Student t test were used to compare continuous variables between groups, and differences between proportions were assessed by {chi}2 tests. The standardized birth weight (birth weight ratio) was divided into four clinical categories: less than 0.76 corresponds to a strict definition (-2 SD) of SGA, and 0.76–0.89 is a broad category of relatively small infants. The category 0.90–1.09 includes infants with appropriate weight for their gestation, and the category greater than 1.09 includes large infants. Within the groups, we tested for trend of IL-6 (presented as P trend) across ordinal categories of birth weight ratio by Kruskal–Wallis H test, and repeated the test after stratifying the groups according to maternal smoking. At each category of standardized birth weight, we compared cord plasma IL-6 concentrations among groups by Mann–Whitney U tests. Comparing controls with subgroups of preeclampsia (severe and early onset), this study had a statistical power of 90% to detect a difference in cord IL-6 of 10 pg/mL. All statistical analyses were calculated using the Statistical Package for the Social Science (SPSS) 10.05 (SPSS, Inc., Chicago, IL).


   RESULTS
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Overall, the concentration of IL-6 in cord plasma did not differ between the preeclampsia group and controls (Table 1Go). In severe, in contrast to mild, preeclampsia (Table 2Go), cord plasma IL-6 concentration was, however, lower than among controls (10 compared with 16 pg/mL, P < .001). In severe preeclampsia, a sharp decrease was observed in cord plasma IL-6 concentration with decreasing birth weight ratio (P trend < .001). Among controls, there was only a slight decrease in cord plasma IL-6 with decreasing birth weight ratio, and in mild preeclampsia, cord plasma IL-6 did not differ from control levels at any category of birth weight ratio (Table 2Go).


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  		Table 2. Umbilical Cord Plasma Interleukin-6, by Levels of Birth Weight Ratio, in Mild or Severe Preeclampsia, and in Controls
 
By further dividing the preeclampsia group into early or late onset (Table 3Go), the results suggest that the strong association between low IL-6 levels and low birth weight ratio was present mainly in early-onset disease. Only eight infants in early preeclampsia had appropriate weight for their gestation, and among these infants, cord plasma IL-6 mainly concentration was lower than among controls (3 compared with 16 pg/mL). One third of the early-onset group was clinically classified as having mild preeclampsia (Table 4Go), but for early-onset disease, cord plasma IL-6 did not differ between mild and severe preeclampsia (2 and 0 pg/mL, respectively).


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  		Table 3. Umbilical Cord Plasma Interleukin-6, by Level of Birth Weight Ratio, in Early and Late Onset Preeclampsia, and in Controls
 

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  		Table 4. Cord Plasma IL-6 Levels in Subgroups of Preeclampsia
 
In late-onset preeclampsia (Table 3Go), cord plasma IL-6 concentration was no different from control levels at any category of birth weight ratio. Forty-six cases of late onset were classified as severe (Table 4Go), but in late-onset disease, cord plasma IL-6 concentration did not differ between mild and severe disease (13 and 18 pg/mL respectively, P = .1). Thus, the strong association between low IL-6 and low birth weight ratio appeared to be present only in early-onset preeclampsia.

To assess the impact of maternal smoking on the relation between IL-6 and birth weight ratio, we stratified the preeclampsia group and the controls according to maternal smoking during pregnancpy. The results showed that the association between cord plasma IL-6 concentration and birth weight ratio was similar in smokers and nonsmokers, both within the preeclampsia group and among controls (data not shown).


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We observed a strong decrease in cord plasma IL-6 with decreasing birth weight in preeclampsia, and subgroup analysis showed that this association could be attributed to a particular effect in early-onset disease. The subgroup of early-onset preeclampsia included only 34 cases; however, its population base is an obvious advantage. Among controls, we found no clear association between birth weight ratio and cord plasma IL-6 levels. Previously, a study of FGR in preeclampsia found no association with cord blood IL-6 concentration,30 but failed to account for differences in gestational age between the groups. However, our results may correspond to those of a small study that reported low levels of cord blood IL-6 concentration in preeclampsia before 32 weeks’ gestation.31

To adjust for differences in gestational age, we calculated a standardized birth weight ratio (observed over expected birth weight) based on ultrasonographic measurements in a population of healthy pregnant women in Sweden.27 Despite adjustment for gestational age, we cannot exclude the possibility of residual confounding by gestational age related to our main finding.

Usually, IL-6 production increases in gestational tissues before labor,32 but it is not clear whether labor in itself increases cord blood IL-6 concentration.13,30 In our study, cesarean delivery was more frequent in early preeclampsia, therefore mode of delivery could have influenced our results. However, a previous study showed no difference in IL-6 between vaginal and cesarean deliveries,33 and in vitro studies have reported similar production of IL-6 in placental tissue explants in labor and in cesarean deliveries.32,34 Therefore, confounding by mode of delivery may not be a likely explanation for the association between low birth weight and low levels of cord plasma IL-6 concentration related to early preeclampsia. Furthermore, differences in prenatal steroid administration did not influence our results, because cord plasma IL-6 concentration was similar in those who received steroids and those who did not (data not shown).

Maternal smoking is known to reduce fetal growth,14,35 but we found no association between maternal smoking and cord plasma IL-6 concentration. Moreover, both in preeclampsia and among controls, maternal smoking had no effect on the association between cord plasma IL-6 concentration and birth weight. Therefore, the association between cord plasma IL-6 concentration and low birth weight in early preeclampsia is not likely to be confounded by maternal smoking.

Secretion of placental IL-6 appears to be relatively constant during pregnancy,5 and venous cord blood levels may be positively correlated with placental secretion.36 In this study, we used blood that was passively drawn from the umbilical cord. This blood is mainly venous, and cord plasma IL-6 levels may therefore indicate placental production of IL-6. A causal interpretation of our findings may therefore suggest that IL-6 plays a role in reducing fetal growth related to early preeclampsia.

Main placental functions take place in villous trophoblasts, including fetomaternal transfer of substrates and synthesis of proteins and steroid hormones.7,9 Placental IL-6 is synthesized mainly in villous trophoblasts,5 and appears to mediate several trophoblast functions by autocrine or paracrine mechanisms.7,8 The placental secretion of IL-6 is reduced in preeclampsia,37 indicating impaired trophoblast function and thereby severe placental insufficiency. Therefore, there may be a causal link between low cord plasma IL-6 concentration and low birth weight in early preeclampsia, and impairment of villous trophoblasts. Recent studies have suggested that the placental terminal villi are severely poorly developed in early restriction of fetal growth, both in the presence and absence of preeclampsia,17–19 showing reduced proliferation of villous trophoblast and accelerated aging of syncytiotrophoblasts.19

Fetal growth restriction in late-onset preeclampsia was not associated with a reduction in cord plasma IL-6 compared with control pregnancies. Thus, our results indicate that the underlying pathogenesis of FGR related to preeclampsia may depend on clinical subtype, and that in early-onset preeclampsia trophoblast impairment is more likely to be present than in preeclampsia with late onset.


   Footnotes
 
Rønnaug Ødegård is a research fellow supported by the Norwegian Research Council and the Norwegian University of Science and Technology.

We thank Anita Haugan for laboratorial help, and valuable contribution to the preparation of the paper.

PII S0029-7844(01)01396-5

Received December 4, 2000. Received in revised form March 9, 2001. Accepted March 14, 2001.


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