The Journal of Maternal-Fetal & Neonatal Medicine
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Perinatal risk factors and mode of delivery associated with mortality in very low birth weight infants Serife Esra Cetinkaya, Emel Okulu, Feride Soylemez, İlke Mungan Akin, Seda Sahin, Tugba Akyel, Serdar Alan, Begum Atasay, Saadet Arsan & Acar Koc To cite this article: Serife Esra Cetinkaya, Emel Okulu, Feride Soylemez, İlke Mungan Akin, Seda Sahin, Tugba Akyel, Serdar Alan, Begum Atasay, Saadet Arsan & Acar Koc (2015) Perinatal risk factors and mode of delivery associated with mortality in very low birth weight infants, The Journal of Maternal-Fetal & Neonatal Medicine, 28:11, 1318-1323, DOI: 10.3109/14767058.2014.953476 To link to this article: http://dx.doi.org/10.3109/14767058.2014.953476
Accepted author version posted online: 21 Aug 2014. Published online: 10 Sep 2014. Submit your article to this journal
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Date: 11 November 2015, At: 05:26
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2015; 28(11): 1318–1323 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.953476
ORIGINAL ARTICLE
Perinatal risk factors and mode of delivery associated with mortality in very low birth weight infants _ Mungan Akin2, Seda Sahin1, Tugba Akyel1, Serdar Alan2, Serife Esra Cetinkaya1, Emel Okulu2, Feride Soylemez3, Ilke 2 2 3 Begum Atasay , Saadet Arsan , and Acar Koc Department of Obstetrics and Gynecology, 2Division of Neonatology, Department of Pediatrics, and 3Division of Perinatology, Department of Obstetrics and Gynecology, Ankara University School of Medicine, Ankara, Turkey
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1
Abstract
Keywords
Objective: To investigate the association of perinatal risk factors including delivery mode with mortality in very low birthweight (VLBW) in a tertiary hospital setting. Methods: Medical records of 241 live-born VLBW infants (1500 g) were retrospectively reviewed. Details of maternal, obstetrical, perinatal risk factors and their associations with infant mortality were evaluated. Results: The overall infant mortality rate was 23.2%. Mortality was significantly higher for infants born at 27 gestational weeks and with a birthweight of 750 g (p ¼ 0.000 and p ¼ 0.000, respectively), showing a steep decrease thereafter. On ROC analysis, a cut off of 26.5 weeks was determined for mortality with a sensitivity of 57.1% and a specificity of 90.3% (area under the curve ¼ 0.792, 95% CI: 0.719–0.866). On multivariate regression analysis, gestational week at birth, birthweight, antenatal steroid treatment and pathologic Doppler ultrasound findings were found as independent risk factors for mortality. Conclusions: Gestational week at birth, birthweight and antenatal steroid treatment remain the most important perinatal risk factors for infant mortality in VLBW infants. Mode of delivery does not seem to be associated with mortality when adjusted for other perinatal risk factors.
Infant mortality, mode of delivery, perinatal risk factors, very low birthweight infants
Introduction Despite improvements in neonatal care and availability of intrauterine transfer to level III units in the past two decades, prematurity is still the major cause of neonatal morbidity and mortality, with serious economic and psychosocial implications [1–3]. The improvements in perinatal and neonatal care have led to an increase in cesarean rates to decrease mortality and morbidity for very low birthweight (VLBW) infants [4–6]. However, increasing cesarean rates also add to maternal morbidity significantly. Still, the optimal obstetric management and the impact of delivery mode on the survival of VLBW infants remain controversial. Data regarding the mode of delivery for the VLBW infant are conflicting not only for vertex [4,7–12] but also for breech presentations; whilst some studies have shown that cesarean section may have a beneficial effect for breech presenting infants [7,8,13], others have not [14,15]. A recent study comparing neonatal and maternal outcome by mode of delivery in VLBW singleton infants reported no neonatal benefit, but higher maternal morbidity with cesarean delivery [16]. Address for correspondence: Serife Esra Cetinkaya, MD, Department of Obstetrics and Gynecology, Ankara University School of Medicine, Ankara, Turkey. Tel: + 90 (312) 595 62 88. Fax: + 90 (312) 320 35 53. E-mail: [email protected]
History Received 2 June 2014 Revised 21 July 2014 Accepted 7 August 2014 Published online 10 September 2014
Studies focusing on the effect of labor on outcomes by delivery mode have also conflicting results [17,18]. It has also been reported that cesarean section was associated with improved survival in small for gestational age (SGA) infants but not in appropriate for gestational age infants [19]. It is, thus, important to consider all possible obstetrical risk factors including mode of delivery in order to improve neonatal outcome. This would without doubt be best determined by randomized controlled prospective studies, but this has been proven to be quite difficult because of recruitment difficulties [6]. In this retrospective cohort study, we aimed to investigate the association of perinatal risk factors including mode of delivery with mortality for VLBW infants in a tertiary hospital setting.
Materials and methods Medical records of all live-born VLBW infants (1500 g) born at the Department of Obstetrics and Gynecology of Ankara University School of Medicine between January 2008 and December 2012 were retrospectively analyzed. Infants with structural and/or genetic anomalies were excluded from analysis. Details of history, clinical and obstetrical maternal data including labor and delivery and neonatal outcome data
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DOI: 10.3109/14767058.2014.953476
derived from the records of the neonatal intensive care unit were evaluated. Maternal age, parity and illness (chronic hypertension, preeclampsia/eclampsia and diabetes), preterm premature rupture of membranes (pPROM), preterm labor, antenatal steroids, tocolytic treatment, antenatal magnesium use, clinical chorioamnionitis, placental abruption, placenta previa, Doppler ultrasound (US) findings, non-reassuring/pathologic cardiotocography, gestational age at birth, mode of delivery, gender, birth weight, SGA infant, multiple pregnancy, fetal presentation, indications and the presence of active or latent labor prior to cesarean section were examined as perinatal variables. Chronic hypertension was defined as the presence of elevated blood pressure (140/90 mmHg) before pregnancy or before the 20th week of gestation. Preeclampsia was defined as hypertension presenting beyond 20 weeks of gestation with 4300 mg protein in a 24-h urine collection or 430 mg/mmol in a spot urine sample. Eclampsia was defined as the occurrence of seizures in a pregnant woman with preeclampsia [20]. Women were diagnosed as having gestational diabetes according to the criteria of National Diabetic Data Group [21]. pPROM was defined as membrane rupture more than six hours before the onset of regular uterine contractions before the 37th gestational week. Preterm labor was considered when uterine contractions occurred together with cervical dilation and effacement before the 37th gestational week. Antenatal steroid treatment was classified in four groups; no antenatal steroids, partial (if delivery occurred less than 24 h after the last dose), complete (if delivery occurred between 24 h and seven days after the last dose) and prolonged (if delivery occurred 47 d after the last dose). The diagnosis of clinical chorioamnionitis was based on a maternal temperature of 438 C with or without uterine tenderness and/or foul vaginal discharge with no other cause of fever. Cervical insufficiency was defined as painless cervical dilation in the second trimester, in the absence of contractions, labor or other pathology such as bleeding or membrane rupture. Gestational age was expressed in terms of completed weeks and was based on the last menstrual period and/or early prenatal US examination. SGA was defined as birth weight less than the 10th percentile for gestational age according to the growth charts of Lubchenco et al. [22]. Active labor at cesarean section was defined as the presence of at least four contractions in 20 min and cervical dilatation of 2 cm in primigravidae and 3cm in parous women. The primary outcome variable was mortality, defined as infant death prior to hospital discharge. Statistical analysis was done with the Statistical Package for Social Sciences (SPSS version 15.0 for Windows, Chicago, IL). Groups were compared using the independent-samples Student’s t-test, Mann–Whitney, Chi-squared tests, two-way ANOVA and Kruskal–Wallis tests where appropriate. Pearson correlation analysis was used for the correlation between mortality and gestational week at birth/ birthweight. ROC analysis was used to determine the cut off gestational week at birth for infant mortality. The highest value of the area under the curve (AUC) was determined. Univariate and multivariate logistic regression models were
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used to determine the independent risk factors associated with infant mortality. Variables with a p value of 50.20 in the univariate analysis were included in the multivariate analysis. p50.05 was considered as statistically significant.
Results During the study period, 9103 babies were born, of which 1196 (13.14%) were preterm (537 gestational weeks) and 251 (2.76%) were VLBW infants. Ten infants (4%) were excluded because of structural/genetic anomalies, and the final study population comprised 241 live born VLBW infants. The median gestational age at birth was 29.3 weeks (21–37 weeks), and the median birthweight was 1100 g (400–1500 g); 23.2% (n ¼ 56) of the infants were born at 27 gestational weeks, 36.5% (n ¼ 88) at 27–30 gestational weeks and 40.2% (n ¼ 97) at 30 gestational weeks. The cesarean section rate was 79.3% (n ¼ 191), and the vaginal birth rate was 20.7% (n ¼ 50). Maternal age, parity, percentage of women with previous vaginal birth and infant gender were similar among the groups of infant mortality (i.e. infants who died prior to hospital discharge and survivors). Gestational age at birth and birthweight were significantly lower in the mortality group (median 26.2 versus 30 weeks, p ¼ 0.000 and 730 versus 1200 g, p ¼ 0.000). Time to birth from antenatal corticosteroid therapy was significantly shorter in the mortality group than the survivors (median 48 versus 96 h, p ¼ 0.026). The rate of clinical chorioamnionitis and cervical insufficiency were significantly higher in the mortality group (12.5% versus 4.3%, p ¼ 0.05 and 12.5% versus 3.8%, p ¼ 0.023, respectively). Pathologic/non-reassuring cardiotocography was more frequent in the group of survivors (38.4% versus 23.2%, p ¼ 0.037). The rates of the remaining risk factors (percentage of SGA infants, pathologic Doppler findings, multiple pregnancy, vertex or breech presentation, preterm labor, pPROM, labor at cesarean section, preeclampsia/eclampsia and chronic maternal diseases) were similar among the groups. The overall mortality rate was 23.2%; mortality rate was 17.3% for infants born by cesarean section and 46% for infants born vaginally (p ¼ 0.000; Table 1). Indications for cesarean section were: pathologic/non-reassuring cardiotocography (44.2%), twin-malpresentation (16.3%), severe preeclampsia/ HELLP syndrome (10.5%), triplets (5.8%), placenta previa (4.7%), prior cesarean section (3.2%), placental abruption (2.6%) and others (12.7%) (anhydramnios, IUGR and singleton malpresentation). Mortality showed a moderate and inverse correlation with gestational age and birthweight (Pearson r ¼ 0.450 and r ¼ 0.576, respectively). Mortality was significantly higher for infants born at 27 gestational weeks and for infants with a birthweight of 750 g, showing a steep decrease thereafter. ROC analysis confirmed this cut off; a cut off of 26.5 weeks was determined with a sensitivity of 57.1% and a specificity of 90.3% (AUC ¼ 0.792, 95% CI: 0.719–0.866; Figure 1). Infants who received no antenatal steroids, and those with partial antenatal steroid treatment had a higher mortality rate than infants with complete or prolonged antenatal steroid treatment (p ¼ 0.006). Mortality was similar in infants with
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J Matern Fetal Neonatal Med, 2015; 28(11): 1318–1323
Table 1. Mortality rates according to perinatal risk factors.
Table 1. Continued
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Mortality % (n) (n ¼ 56) Delivery mode Cesarean section Vaginal birth Parity Nulliparous Multiparous Previous cesarean section Previous vaginal birth No Yes Gender Female Male Gestational age at birth, weeks 27 27–30 430 Birthweight, grams 750 750–1000 41000 SGA Yes No Pathologic Doppler Yes No Multiple pregnancy Yes No Presentation Vertex Breech Antenatal corticosteroid therapy None 524 h 24 h–7 d 47 d Antenatal Mg therapy Yes No Preterm labor Yes No pPROM Yes No Clinical chorioamnionitis Yes No Tocolysis Yes No Cervical insufficiency Yes No Labor at cesarean section None Active Latent Non-reassuring/pathologic cardiotocography Yes No Placental abruption Yes No
Mortality % (n) (n ¼ 56)
p
17.3 (33) 46 (23)
0.000
24.2 (39) 25.5 (12) 15.2 (5)
0.488
22.7 (44) 25.5 (12)
0.678
20.6 (26) 26.1 (30)
0.317
57.1 (32) 17 (15) 9.3 (9)
0.000
79.5 (31) 28.1 (16) 6.2 (9)
0.000
25.5 (14) 22.6 (42)
0.658
36.8 (7) 22.1 (49)
0.160
23.5 (24) 23 (32)
0.927
23.7 (42) 20 (11)
0.565
35.7 33.3 17.4 9.8
(20) (10) (15) (4)
0.006*
26.8 (11) 22.8 (44)
0.580
26.1 (36) 19.2 (19)
0.215
23 (17) 23.3 (38)
0.954
46.7 (7) 21.7 (49)
0.051
30.1 (22) 20 (32)
0.089
50 (7) 21.7 (49)
0.023
18.2 (18) 27.8 (5) 12.9 (9)
0.299
15.5 (13) 27.4 (43)
0.037
50 (4) 22.7 (52)
0.092
Chronic hypertension Yes No Preeclampsia Yes No Eclampsia Yes No Hypertensive disorders in pregnancy Yes No Diabetes Yes No
p
22.2 (2) 23.7 (54)
1.000
17.7 (11) 25 (44)
0.244
28.6 (2) 23 (53)
0.665
18.5 (12) 25.3 (44)
0.268
14.3 (1) 23.5 (54)
1.000
*Post hoc analysis; None versus524 h, p ¼ 0.825; none versus 24 h–7 d, p ¼ 0.014; none versus47 d, p ¼ 0.03;524 h versus47 d, p ¼ 0.014; 524 h versus 24 h–7 d, p ¼ 0.068; 24 h–7 d versus47 d, p ¼ 0.256. SGA: small for gestational age; pPROM: preterm premature rupture of membranes. p50.05 statistically significant.
Figure 1. ROC analysis for mortality according to gestational week.
(continued )
complete or prolonged antenatal steroid treatment (p ¼ 0.256). Infants who were born from mothers with clinical chorioamnionitis showed significantly higher mortality rates (46.7% versus 21.7%, p ¼ 0.05). Infants who were born from mothers with cervical insufficiency also had higher mortality rates (50% versus 21.7%, p ¼ 0.023). Mortality was significantly lower in infants with non-reassuring/pathologic cardiotocography (15.5% versus 27.4%, p ¼ 0.037). On subanalysis, infants with non-reassuring/pathologic cardiotocography had a significantly higher gestational age at birth compared with infants with a normal FHR pattern (30.8 ± 2.3 gestational weeks versus 28.3 ± 2.8 gestational weeks,
Perinatal risk factors and mortality in VLBW infants
DOI: 10.3109/14767058.2014.953476
Table 2. Candidate independendent risk factors for infant mortality in very low birthweight infants on univariate analysis.
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Vaginal delivery Gestational week at birth 27–30 430 Birthweight (g) 750–1000 41000 Pathologic Doppler Antenatal steroids 24 h–7 d 47 d Clinical chorioamnionitis Tocolysis Cervical insufficiency Pathologic cardiotocography Placental abruption
OR (95% CI)
p
4.079 (2.085–7.977)
0.000
0.154 (0.072–0.332) 0.077 (0.032–0.182)
0.000
degrees of freedom Chi-square test with a significance level (alpha) of 0.05 for antenatal steroid treatment. A sample size of 241 achieved 31% power to detect an effect size (W) of 0.0943 using one degree of freedom Chi-square test with a significance level (alpha) of 0.05 for pathologic Doppler findings.
0.101 (0.038–0.265) 0.017 (0.006–0.048) 2.060 (0.769–5.513)
0.000
Discussion
0.160 0.006 0.015 0.006 0.051 0.089 0.023 0.037 0.092
In this study, gestational week at birth, birthweight, absent or partial antenatal steroid treatment (none or 524 h) and pathologic Doppler US findings were found to be the independent perinatal risk factors for infant mortality. Although significantly related to mortality on univariate analysis, mode of delivery did not seem to affect infant mortality when controlled for other perinatal risk factors on multivariate analysis. Our findings support the studies where no advantage of delivery via cesarean section on neonatal survival was reported [11,12,14,23]. Malloy et al. examined neonatal mortality in 1765 VLBW inborn infants (51500 g) admitted to seven neonatal intensive care centers. They suggested that, after accounting for certain maternal and fetal factors such as gestational age, preeclampsia, breech presentation, presence or absence of labor and for center effects, cesarean delivery was not associated with a lower risk of mortality [14]. Riskin et al. and Wylie et al. reported of no survival advantage from cesarean section in vertex presenting VLBW infants in their population based studies [11,23]. In a more recent singlecentered study, Durie et al. also found that neonatal outcome was not affected by delivery mode in vertex presenting singleton VLBW infants [12]. On the contrary, Lee and Gould reported of a survival benefit for cesarean section, especially for lower weight categories in their very large populationbased cohort study [9]. In retrospective analyses of medical interventions where the outcomes are not known well and, thus, are not evidence based, selection bias is an important confounding factor. This is especially true for selecting the mode of delivery in VLBW infants; this decision is based somewhat ‘‘arbitrarily’’ on the choice of the clinician and parents in regard to the expectations of viability for the newborn. Indeed, in our study, for most infants born vaginally, vaginal delivery was either preferred because of low expectations of survival for these fetuses or patients were admitted at an advanced stage of labor and had a precipitous vaginal delivery. These factors may explain the higher mortality rate for vaginal delivery on univariate analysis; nevertheless, on multivariate analysis taking into account other possible confounders, mode of delivery did not seem to be an independent risk factor for mortality for these VLBW infants. It is, of course, difficult to draw solid conclusions from these types of studies and well-designed prospective studies are needed. As it was a retrospective analysis, it has biases and confounders, which we could not control. However, only six randomized trials including only 122 women exist to date and four trials including 116 women were analyzed in a very recent meta-analysis, in which the need for further studies and recruitment difficulties were mentioned [24]. We aimed to investigate the association of all possible perinatal risk factors with mortality in VLBW infants and
0.380 0.195 3.161 1.725 3.612 0.485 3.404
(0.174–0.830) (0.061–0.625) (1.092–9.147) (0.917–3.248) (1.209–10.791) (0.244–0.965) (0.823–14.082)
p50.05 statistically significant.
Table 3. Risk factors for infant mortality in very low birthweight infants on multivariate logistic regression analysis.
Gestational week at birth 27–30 430 Pathologic Doppler Antenatal steroids None 524 h Tocolysis
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OR (95% CI)
p
0.116 (0.044–0.305) 0.043 (0.014–0.133) 11.685 (2.876–47.480)
0.000 0.000 0.001
3.658 (1.376–9.724) 5.036 (1.541–16.458) 2.250 (0.912–5.551)
0.009 0.007 0.078
p50.05 statistically significant.
respectively, p ¼ 0.000). On univariate analysis, antenatal steroid treatment, gestational week at birth, birthweight, mode of delivery, cervical insufficiency, tocolysis, pathologic Doppler findings, placental abruption, non-reassuring/pathologic cardiotocography and chorioamnionitis were found as candidate independent variables for infant mortality and were included in the multivariate analysis (Table 2). As birthweight and gestational week at birth were related to each other, only gestational week at birth was included. Results of the multivariate analysis are listed in Table 3. Increasing gestational week at birth was found protective for infant mortality. The absence of or partial antenatal steroid treatment and pathologic Doppler were found as independent variables for mortality. Tocolysis remained in the model as a contributing factor, but did not reach statistical significance (p ¼ 0.078). Power analysis was performed for gestational week at birth, birthweight, mode of delivery and antenatal steroid treatment. A sample size of 241 achieved 100% power to detect an effect size (W) of 0.4490 using a two degrees of freedom Chi-Square Test with a significance level (alpha) of 0.05 for gestational week at birth; 100% power to detect an effect size (W) of 0.6229 using a two degrees of freedom Chisquare test with a significance level (alpha) of 0.05 for birthweight; 98% power to detect an effect size (W) of 0.2758 using two degrees of freedom Chi-square test with a significance level (alpha) of 0.05 for mode of delivery; 86% power to detect an effect size (W) of 0.2276 using three
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therefore did not exclude possible confounders such as multiple pregnancy and breech presentation. We found no association between multiple pregnancy, breech presentation and mortality, supporting findings of a study with a similar design [25]. In our study, we found that both complete and prolonged antenatal steroid treatment were protective against infant mortality. Antenatal steroids have been shown to reduce neonatal mortality, respiratory distress syndrome, IVH and NEC before 34 weeks of gestation. The optimal interval after antenatal steroid treatment to delivery has been reported to be more than 24 h and less than seven days [26], and that this beneficial effect diminishes 14 d after administration [27]. In a recent meta-analysis, repeat doses of antenatal steroids were found to be associated with less respiratory distress and fewer serious health problems in the first few weeks after birth, with a reduction in fetal size at birth. However, in the long term, there was neither benefit nor harm [28]. At present, the administration of multiple courses of steroids is controversial and more than a single additional rescue course is not recommended, as there are concerns regarding the risk of multiple steroid courses on fetal growth [29]. Interestingly, pathologic/non-reassuring cardiotocography was associated with lower infant mortality; on sub analysis, we saw that these infants had a mean gestational age at birth around 31 weeks, which was significantly higher than infants with a normal FHR pattern (30.8 ± 2.3 gestational weeks versus 28.3 ± 2.8 gestational weeks, respectively, p ¼ 0.000). Thus, the effect of gestational age at birth, which was found as a major risk factor for mortality, probably had an important contribution to this finding. Moreover, ‘‘non-reassuring’’ fetal heart rate pattern is in fact a subjective clinical judgment, with a high interobserver and intraobserver variability in interpretation. Indeed, on the final multivariate regression analysis, pathologic/non-reassuring cardiotocography was not found as an independent factor for infant mortality. Our study population was relatively small and may not be generalizable to larger populations. Nevertheless, obstetrical and neonatal management were all performed in a rather uniform way in a single tertiary center and reliability of clinical data was high, which may be a possible limitation of population based studies depending on birth certificates. We were also able to extract data and to evaluate important risk factors such as time to birth from antenatal steroid treatment, pathologic/nonreassuring cardiotocography, pathologic Doppler findings, clinical chorioamnionitis and cervical insufficiency. In conclusion, the results of our study support findings of previous studies; gestational week at birth, birth weight and antenatal steroid treatment (none or 524 h) remain the most important risk factors for mortality in VLBW infants despite improvements in neonatal care. Mode of delivery does not seem to affect infant mortality and, additionally, although our sample size was underpowered for pathologic Doppler findings, it may be associated with infant mortality in this group of newborns and should be studied in larger well designed studies.
Declaration of interest The authors report no declarations of interests.
J Matern Fetal Neonatal Med, 2015; 28(11): 1318–1323
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ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20
Perinatal risk factors and mode of delivery associated with mortality in very low birth weight infants Serife Esra Cetinkaya, Emel Okulu, Feride Soylemez, İlke Mungan Akin, Seda Sahin, Tugba Akyel, Serdar Alan, Begum Atasay, Saadet Arsan & Acar Koc To cite this article: Serife Esra Cetinkaya, Emel Okulu, Feride Soylemez, İlke Mungan Akin, Seda Sahin, Tugba Akyel, Serdar Alan, Begum Atasay, Saadet Arsan & Acar Koc (2015) Perinatal risk factors and mode of delivery associated with mortality in very low birth weight infants, The Journal of Maternal-Fetal & Neonatal Medicine, 28:11, 1318-1323, DOI: 10.3109/14767058.2014.953476 To link to this article: http://dx.doi.org/10.3109/14767058.2014.953476
Accepted author version posted online: 21 Aug 2014. Published online: 10 Sep 2014. Submit your article to this journal
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Date: 11 November 2015, At: 05:26
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2015; 28(11): 1318–1323 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.953476
ORIGINAL ARTICLE
Perinatal risk factors and mode of delivery associated with mortality in very low birth weight infants _ Mungan Akin2, Seda Sahin1, Tugba Akyel1, Serdar Alan2, Serife Esra Cetinkaya1, Emel Okulu2, Feride Soylemez3, Ilke 2 2 3 Begum Atasay , Saadet Arsan , and Acar Koc Department of Obstetrics and Gynecology, 2Division of Neonatology, Department of Pediatrics, and 3Division of Perinatology, Department of Obstetrics and Gynecology, Ankara University School of Medicine, Ankara, Turkey
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Abstract
Keywords
Objective: To investigate the association of perinatal risk factors including delivery mode with mortality in very low birthweight (VLBW) in a tertiary hospital setting. Methods: Medical records of 241 live-born VLBW infants (1500 g) were retrospectively reviewed. Details of maternal, obstetrical, perinatal risk factors and their associations with infant mortality were evaluated. Results: The overall infant mortality rate was 23.2%. Mortality was significantly higher for infants born at 27 gestational weeks and with a birthweight of 750 g (p ¼ 0.000 and p ¼ 0.000, respectively), showing a steep decrease thereafter. On ROC analysis, a cut off of 26.5 weeks was determined for mortality with a sensitivity of 57.1% and a specificity of 90.3% (area under the curve ¼ 0.792, 95% CI: 0.719–0.866). On multivariate regression analysis, gestational week at birth, birthweight, antenatal steroid treatment and pathologic Doppler ultrasound findings were found as independent risk factors for mortality. Conclusions: Gestational week at birth, birthweight and antenatal steroid treatment remain the most important perinatal risk factors for infant mortality in VLBW infants. Mode of delivery does not seem to be associated with mortality when adjusted for other perinatal risk factors.
Infant mortality, mode of delivery, perinatal risk factors, very low birthweight infants
Introduction Despite improvements in neonatal care and availability of intrauterine transfer to level III units in the past two decades, prematurity is still the major cause of neonatal morbidity and mortality, with serious economic and psychosocial implications [1–3]. The improvements in perinatal and neonatal care have led to an increase in cesarean rates to decrease mortality and morbidity for very low birthweight (VLBW) infants [4–6]. However, increasing cesarean rates also add to maternal morbidity significantly. Still, the optimal obstetric management and the impact of delivery mode on the survival of VLBW infants remain controversial. Data regarding the mode of delivery for the VLBW infant are conflicting not only for vertex [4,7–12] but also for breech presentations; whilst some studies have shown that cesarean section may have a beneficial effect for breech presenting infants [7,8,13], others have not [14,15]. A recent study comparing neonatal and maternal outcome by mode of delivery in VLBW singleton infants reported no neonatal benefit, but higher maternal morbidity with cesarean delivery [16]. Address for correspondence: Serife Esra Cetinkaya, MD, Department of Obstetrics and Gynecology, Ankara University School of Medicine, Ankara, Turkey. Tel: + 90 (312) 595 62 88. Fax: + 90 (312) 320 35 53. E-mail: [email protected]
History Received 2 June 2014 Revised 21 July 2014 Accepted 7 August 2014 Published online 10 September 2014
Studies focusing on the effect of labor on outcomes by delivery mode have also conflicting results [17,18]. It has also been reported that cesarean section was associated with improved survival in small for gestational age (SGA) infants but not in appropriate for gestational age infants [19]. It is, thus, important to consider all possible obstetrical risk factors including mode of delivery in order to improve neonatal outcome. This would without doubt be best determined by randomized controlled prospective studies, but this has been proven to be quite difficult because of recruitment difficulties [6]. In this retrospective cohort study, we aimed to investigate the association of perinatal risk factors including mode of delivery with mortality for VLBW infants in a tertiary hospital setting.
Materials and methods Medical records of all live-born VLBW infants (1500 g) born at the Department of Obstetrics and Gynecology of Ankara University School of Medicine between January 2008 and December 2012 were retrospectively analyzed. Infants with structural and/or genetic anomalies were excluded from analysis. Details of history, clinical and obstetrical maternal data including labor and delivery and neonatal outcome data
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DOI: 10.3109/14767058.2014.953476
derived from the records of the neonatal intensive care unit were evaluated. Maternal age, parity and illness (chronic hypertension, preeclampsia/eclampsia and diabetes), preterm premature rupture of membranes (pPROM), preterm labor, antenatal steroids, tocolytic treatment, antenatal magnesium use, clinical chorioamnionitis, placental abruption, placenta previa, Doppler ultrasound (US) findings, non-reassuring/pathologic cardiotocography, gestational age at birth, mode of delivery, gender, birth weight, SGA infant, multiple pregnancy, fetal presentation, indications and the presence of active or latent labor prior to cesarean section were examined as perinatal variables. Chronic hypertension was defined as the presence of elevated blood pressure (140/90 mmHg) before pregnancy or before the 20th week of gestation. Preeclampsia was defined as hypertension presenting beyond 20 weeks of gestation with 4300 mg protein in a 24-h urine collection or 430 mg/mmol in a spot urine sample. Eclampsia was defined as the occurrence of seizures in a pregnant woman with preeclampsia [20]. Women were diagnosed as having gestational diabetes according to the criteria of National Diabetic Data Group [21]. pPROM was defined as membrane rupture more than six hours before the onset of regular uterine contractions before the 37th gestational week. Preterm labor was considered when uterine contractions occurred together with cervical dilation and effacement before the 37th gestational week. Antenatal steroid treatment was classified in four groups; no antenatal steroids, partial (if delivery occurred less than 24 h after the last dose), complete (if delivery occurred between 24 h and seven days after the last dose) and prolonged (if delivery occurred 47 d after the last dose). The diagnosis of clinical chorioamnionitis was based on a maternal temperature of 438 C with or without uterine tenderness and/or foul vaginal discharge with no other cause of fever. Cervical insufficiency was defined as painless cervical dilation in the second trimester, in the absence of contractions, labor or other pathology such as bleeding or membrane rupture. Gestational age was expressed in terms of completed weeks and was based on the last menstrual period and/or early prenatal US examination. SGA was defined as birth weight less than the 10th percentile for gestational age according to the growth charts of Lubchenco et al. [22]. Active labor at cesarean section was defined as the presence of at least four contractions in 20 min and cervical dilatation of 2 cm in primigravidae and 3cm in parous women. The primary outcome variable was mortality, defined as infant death prior to hospital discharge. Statistical analysis was done with the Statistical Package for Social Sciences (SPSS version 15.0 for Windows, Chicago, IL). Groups were compared using the independent-samples Student’s t-test, Mann–Whitney, Chi-squared tests, two-way ANOVA and Kruskal–Wallis tests where appropriate. Pearson correlation analysis was used for the correlation between mortality and gestational week at birth/ birthweight. ROC analysis was used to determine the cut off gestational week at birth for infant mortality. The highest value of the area under the curve (AUC) was determined. Univariate and multivariate logistic regression models were
Perinatal risk factors and mortality in VLBW infants
1319
used to determine the independent risk factors associated with infant mortality. Variables with a p value of 50.20 in the univariate analysis were included in the multivariate analysis. p50.05 was considered as statistically significant.
Results During the study period, 9103 babies were born, of which 1196 (13.14%) were preterm (537 gestational weeks) and 251 (2.76%) were VLBW infants. Ten infants (4%) were excluded because of structural/genetic anomalies, and the final study population comprised 241 live born VLBW infants. The median gestational age at birth was 29.3 weeks (21–37 weeks), and the median birthweight was 1100 g (400–1500 g); 23.2% (n ¼ 56) of the infants were born at 27 gestational weeks, 36.5% (n ¼ 88) at 27–30 gestational weeks and 40.2% (n ¼ 97) at 30 gestational weeks. The cesarean section rate was 79.3% (n ¼ 191), and the vaginal birth rate was 20.7% (n ¼ 50). Maternal age, parity, percentage of women with previous vaginal birth and infant gender were similar among the groups of infant mortality (i.e. infants who died prior to hospital discharge and survivors). Gestational age at birth and birthweight were significantly lower in the mortality group (median 26.2 versus 30 weeks, p ¼ 0.000 and 730 versus 1200 g, p ¼ 0.000). Time to birth from antenatal corticosteroid therapy was significantly shorter in the mortality group than the survivors (median 48 versus 96 h, p ¼ 0.026). The rate of clinical chorioamnionitis and cervical insufficiency were significantly higher in the mortality group (12.5% versus 4.3%, p ¼ 0.05 and 12.5% versus 3.8%, p ¼ 0.023, respectively). Pathologic/non-reassuring cardiotocography was more frequent in the group of survivors (38.4% versus 23.2%, p ¼ 0.037). The rates of the remaining risk factors (percentage of SGA infants, pathologic Doppler findings, multiple pregnancy, vertex or breech presentation, preterm labor, pPROM, labor at cesarean section, preeclampsia/eclampsia and chronic maternal diseases) were similar among the groups. The overall mortality rate was 23.2%; mortality rate was 17.3% for infants born by cesarean section and 46% for infants born vaginally (p ¼ 0.000; Table 1). Indications for cesarean section were: pathologic/non-reassuring cardiotocography (44.2%), twin-malpresentation (16.3%), severe preeclampsia/ HELLP syndrome (10.5%), triplets (5.8%), placenta previa (4.7%), prior cesarean section (3.2%), placental abruption (2.6%) and others (12.7%) (anhydramnios, IUGR and singleton malpresentation). Mortality showed a moderate and inverse correlation with gestational age and birthweight (Pearson r ¼ 0.450 and r ¼ 0.576, respectively). Mortality was significantly higher for infants born at 27 gestational weeks and for infants with a birthweight of 750 g, showing a steep decrease thereafter. ROC analysis confirmed this cut off; a cut off of 26.5 weeks was determined with a sensitivity of 57.1% and a specificity of 90.3% (AUC ¼ 0.792, 95% CI: 0.719–0.866; Figure 1). Infants who received no antenatal steroids, and those with partial antenatal steroid treatment had a higher mortality rate than infants with complete or prolonged antenatal steroid treatment (p ¼ 0.006). Mortality was similar in infants with
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J Matern Fetal Neonatal Med, 2015; 28(11): 1318–1323
Table 1. Mortality rates according to perinatal risk factors.
Table 1. Continued
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Mortality % (n) (n ¼ 56) Delivery mode Cesarean section Vaginal birth Parity Nulliparous Multiparous Previous cesarean section Previous vaginal birth No Yes Gender Female Male Gestational age at birth, weeks 27 27–30 430 Birthweight, grams 750 750–1000 41000 SGA Yes No Pathologic Doppler Yes No Multiple pregnancy Yes No Presentation Vertex Breech Antenatal corticosteroid therapy None 524 h 24 h–7 d 47 d Antenatal Mg therapy Yes No Preterm labor Yes No pPROM Yes No Clinical chorioamnionitis Yes No Tocolysis Yes No Cervical insufficiency Yes No Labor at cesarean section None Active Latent Non-reassuring/pathologic cardiotocography Yes No Placental abruption Yes No
Mortality % (n) (n ¼ 56)
p
17.3 (33) 46 (23)
0.000
24.2 (39) 25.5 (12) 15.2 (5)
0.488
22.7 (44) 25.5 (12)
0.678
20.6 (26) 26.1 (30)
0.317
57.1 (32) 17 (15) 9.3 (9)
0.000
79.5 (31) 28.1 (16) 6.2 (9)
0.000
25.5 (14) 22.6 (42)
0.658
36.8 (7) 22.1 (49)
0.160
23.5 (24) 23 (32)
0.927
23.7 (42) 20 (11)
0.565
35.7 33.3 17.4 9.8
(20) (10) (15) (4)
0.006*
26.8 (11) 22.8 (44)
0.580
26.1 (36) 19.2 (19)
0.215
23 (17) 23.3 (38)
0.954
46.7 (7) 21.7 (49)
0.051
30.1 (22) 20 (32)
0.089
50 (7) 21.7 (49)
0.023
18.2 (18) 27.8 (5) 12.9 (9)
0.299
15.5 (13) 27.4 (43)
0.037
50 (4) 22.7 (52)
0.092
Chronic hypertension Yes No Preeclampsia Yes No Eclampsia Yes No Hypertensive disorders in pregnancy Yes No Diabetes Yes No
p
22.2 (2) 23.7 (54)
1.000
17.7 (11) 25 (44)
0.244
28.6 (2) 23 (53)
0.665
18.5 (12) 25.3 (44)
0.268
14.3 (1) 23.5 (54)
1.000
*Post hoc analysis; None versus524 h, p ¼ 0.825; none versus 24 h–7 d, p ¼ 0.014; none versus47 d, p ¼ 0.03;524 h versus47 d, p ¼ 0.014; 524 h versus 24 h–7 d, p ¼ 0.068; 24 h–7 d versus47 d, p ¼ 0.256. SGA: small for gestational age; pPROM: preterm premature rupture of membranes. p50.05 statistically significant.
Figure 1. ROC analysis for mortality according to gestational week.
(continued )
complete or prolonged antenatal steroid treatment (p ¼ 0.256). Infants who were born from mothers with clinical chorioamnionitis showed significantly higher mortality rates (46.7% versus 21.7%, p ¼ 0.05). Infants who were born from mothers with cervical insufficiency also had higher mortality rates (50% versus 21.7%, p ¼ 0.023). Mortality was significantly lower in infants with non-reassuring/pathologic cardiotocography (15.5% versus 27.4%, p ¼ 0.037). On subanalysis, infants with non-reassuring/pathologic cardiotocography had a significantly higher gestational age at birth compared with infants with a normal FHR pattern (30.8 ± 2.3 gestational weeks versus 28.3 ± 2.8 gestational weeks,
Perinatal risk factors and mortality in VLBW infants
DOI: 10.3109/14767058.2014.953476
Table 2. Candidate independendent risk factors for infant mortality in very low birthweight infants on univariate analysis.
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Vaginal delivery Gestational week at birth 27–30 430 Birthweight (g) 750–1000 41000 Pathologic Doppler Antenatal steroids 24 h–7 d 47 d Clinical chorioamnionitis Tocolysis Cervical insufficiency Pathologic cardiotocography Placental abruption
OR (95% CI)
p
4.079 (2.085–7.977)
0.000
0.154 (0.072–0.332) 0.077 (0.032–0.182)
0.000
degrees of freedom Chi-square test with a significance level (alpha) of 0.05 for antenatal steroid treatment. A sample size of 241 achieved 31% power to detect an effect size (W) of 0.0943 using one degree of freedom Chi-square test with a significance level (alpha) of 0.05 for pathologic Doppler findings.
0.101 (0.038–0.265) 0.017 (0.006–0.048) 2.060 (0.769–5.513)
0.000
Discussion
0.160 0.006 0.015 0.006 0.051 0.089 0.023 0.037 0.092
In this study, gestational week at birth, birthweight, absent or partial antenatal steroid treatment (none or 524 h) and pathologic Doppler US findings were found to be the independent perinatal risk factors for infant mortality. Although significantly related to mortality on univariate analysis, mode of delivery did not seem to affect infant mortality when controlled for other perinatal risk factors on multivariate analysis. Our findings support the studies where no advantage of delivery via cesarean section on neonatal survival was reported [11,12,14,23]. Malloy et al. examined neonatal mortality in 1765 VLBW inborn infants (51500 g) admitted to seven neonatal intensive care centers. They suggested that, after accounting for certain maternal and fetal factors such as gestational age, preeclampsia, breech presentation, presence or absence of labor and for center effects, cesarean delivery was not associated with a lower risk of mortality [14]. Riskin et al. and Wylie et al. reported of no survival advantage from cesarean section in vertex presenting VLBW infants in their population based studies [11,23]. In a more recent singlecentered study, Durie et al. also found that neonatal outcome was not affected by delivery mode in vertex presenting singleton VLBW infants [12]. On the contrary, Lee and Gould reported of a survival benefit for cesarean section, especially for lower weight categories in their very large populationbased cohort study [9]. In retrospective analyses of medical interventions where the outcomes are not known well and, thus, are not evidence based, selection bias is an important confounding factor. This is especially true for selecting the mode of delivery in VLBW infants; this decision is based somewhat ‘‘arbitrarily’’ on the choice of the clinician and parents in regard to the expectations of viability for the newborn. Indeed, in our study, for most infants born vaginally, vaginal delivery was either preferred because of low expectations of survival for these fetuses or patients were admitted at an advanced stage of labor and had a precipitous vaginal delivery. These factors may explain the higher mortality rate for vaginal delivery on univariate analysis; nevertheless, on multivariate analysis taking into account other possible confounders, mode of delivery did not seem to be an independent risk factor for mortality for these VLBW infants. It is, of course, difficult to draw solid conclusions from these types of studies and well-designed prospective studies are needed. As it was a retrospective analysis, it has biases and confounders, which we could not control. However, only six randomized trials including only 122 women exist to date and four trials including 116 women were analyzed in a very recent meta-analysis, in which the need for further studies and recruitment difficulties were mentioned [24]. We aimed to investigate the association of all possible perinatal risk factors with mortality in VLBW infants and
0.380 0.195 3.161 1.725 3.612 0.485 3.404
(0.174–0.830) (0.061–0.625) (1.092–9.147) (0.917–3.248) (1.209–10.791) (0.244–0.965) (0.823–14.082)
p50.05 statistically significant.
Table 3. Risk factors for infant mortality in very low birthweight infants on multivariate logistic regression analysis.
Gestational week at birth 27–30 430 Pathologic Doppler Antenatal steroids None 524 h Tocolysis
1321
OR (95% CI)
p
0.116 (0.044–0.305) 0.043 (0.014–0.133) 11.685 (2.876–47.480)
0.000 0.000 0.001
3.658 (1.376–9.724) 5.036 (1.541–16.458) 2.250 (0.912–5.551)
0.009 0.007 0.078
p50.05 statistically significant.
respectively, p ¼ 0.000). On univariate analysis, antenatal steroid treatment, gestational week at birth, birthweight, mode of delivery, cervical insufficiency, tocolysis, pathologic Doppler findings, placental abruption, non-reassuring/pathologic cardiotocography and chorioamnionitis were found as candidate independent variables for infant mortality and were included in the multivariate analysis (Table 2). As birthweight and gestational week at birth were related to each other, only gestational week at birth was included. Results of the multivariate analysis are listed in Table 3. Increasing gestational week at birth was found protective for infant mortality. The absence of or partial antenatal steroid treatment and pathologic Doppler were found as independent variables for mortality. Tocolysis remained in the model as a contributing factor, but did not reach statistical significance (p ¼ 0.078). Power analysis was performed for gestational week at birth, birthweight, mode of delivery and antenatal steroid treatment. A sample size of 241 achieved 100% power to detect an effect size (W) of 0.4490 using a two degrees of freedom Chi-Square Test with a significance level (alpha) of 0.05 for gestational week at birth; 100% power to detect an effect size (W) of 0.6229 using a two degrees of freedom Chisquare test with a significance level (alpha) of 0.05 for birthweight; 98% power to detect an effect size (W) of 0.2758 using two degrees of freedom Chi-square test with a significance level (alpha) of 0.05 for mode of delivery; 86% power to detect an effect size (W) of 0.2276 using three
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therefore did not exclude possible confounders such as multiple pregnancy and breech presentation. We found no association between multiple pregnancy, breech presentation and mortality, supporting findings of a study with a similar design [25]. In our study, we found that both complete and prolonged antenatal steroid treatment were protective against infant mortality. Antenatal steroids have been shown to reduce neonatal mortality, respiratory distress syndrome, IVH and NEC before 34 weeks of gestation. The optimal interval after antenatal steroid treatment to delivery has been reported to be more than 24 h and less than seven days [26], and that this beneficial effect diminishes 14 d after administration [27]. In a recent meta-analysis, repeat doses of antenatal steroids were found to be associated with less respiratory distress and fewer serious health problems in the first few weeks after birth, with a reduction in fetal size at birth. However, in the long term, there was neither benefit nor harm [28]. At present, the administration of multiple courses of steroids is controversial and more than a single additional rescue course is not recommended, as there are concerns regarding the risk of multiple steroid courses on fetal growth [29]. Interestingly, pathologic/non-reassuring cardiotocography was associated with lower infant mortality; on sub analysis, we saw that these infants had a mean gestational age at birth around 31 weeks, which was significantly higher than infants with a normal FHR pattern (30.8 ± 2.3 gestational weeks versus 28.3 ± 2.8 gestational weeks, respectively, p ¼ 0.000). Thus, the effect of gestational age at birth, which was found as a major risk factor for mortality, probably had an important contribution to this finding. Moreover, ‘‘non-reassuring’’ fetal heart rate pattern is in fact a subjective clinical judgment, with a high interobserver and intraobserver variability in interpretation. Indeed, on the final multivariate regression analysis, pathologic/non-reassuring cardiotocography was not found as an independent factor for infant mortality. Our study population was relatively small and may not be generalizable to larger populations. Nevertheless, obstetrical and neonatal management were all performed in a rather uniform way in a single tertiary center and reliability of clinical data was high, which may be a possible limitation of population based studies depending on birth certificates. We were also able to extract data and to evaluate important risk factors such as time to birth from antenatal steroid treatment, pathologic/nonreassuring cardiotocography, pathologic Doppler findings, clinical chorioamnionitis and cervical insufficiency. In conclusion, the results of our study support findings of previous studies; gestational week at birth, birth weight and antenatal steroid treatment (none or 524 h) remain the most important risk factors for mortality in VLBW infants despite improvements in neonatal care. Mode of delivery does not seem to affect infant mortality and, additionally, although our sample size was underpowered for pathologic Doppler findings, it may be associated with infant mortality in this group of newborns and should be studied in larger well designed studies.
Declaration of interest The authors report no declarations of interests.
J Matern Fetal Neonatal Med, 2015; 28(11): 1318–1323
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