Effects of Hypertensive Disorders of Pregnancy On The Mortality and Complications in Very Low Birth Weight Neonates

doi:10.21203/rs.3.rs-742435/v1

Download PDF

Research Article

Effects of Hypertensive Disorders of Pregnancy On The Mortality and Complications in Very Low Birth Weight Neonates

https://doi.org/10.21203/rs.3.rs-742435/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Purpose

This study was designed to investigate the effects of hypertensive disorders of pregnancy (HDP) on the mortality and complications in very low birth weight neonates.

Methods

Premature infants at a gestational age of < 37 weeks with a birth weight of < 1,500g were included in this retrospective analysis. Gestational age-matched pregnant women with normal blood pressure giving birth to a very low birth weight neonate served as normal control. HDP neonates were divided into three subgroups based on the disease severity, including gestational hypertension, pre-eclampsia and eclampsia. Then we compared the incidence of complications among three subgroups. We also analyzed the relationship between the subgroups and the neonatal prognosis.

Results

The incidence of fetal distress, small for gestational age (SGA), mechanical ventilation, neonatal respiratory distress syndrome (RDS), neonatal necrotizing enterocolitis (NEC, ≥ 2 stage), and mortality in HDP group were significantly higher than those of the control. The 1 min Apgar score in HDP group was significantly lower than that of the normal control (P < 0.05). There were significant differences in fetal distress, 1 min Apgar score, mechanical ventilation, RDS and NEC (≥ 2 stage) among HDP, pre-eclampsia and eclampsia subgroups (P < 0.05). Multivariate regression analysis indicated that pre-eclampsia was an independent risk factor for SGA (OR = 4.123, 95%CI: 2.783–6.109) and NEC (OR = 2.493, 95%CI: 1.161–5.351). Eclampsia was a risk factor for SGA (OR = 3.804, 95%CI: 1.239–11.681) and NEC (OR = 7.264, 95%CI: 1.771–29.797).

Conclusions

HDP may affect the prognosis of very low birth weight neonates. Pre-eclampsia and eclampsia were risk factors for SGA and NEC.

Obstetrics & Gynecology

hypertensive disorders of pregnancy

hypertension

pre-eclampsia

eclampsia

very low birth weight neonate

complications

Hypertensive disorders of pregnancy (HDP) is a group of pregnancy-induced idiopathic diseases coexiting with pregnancy and blood pressure increase. Patients with HDP usually show hypertension complicated with proteinuria or pathologic changes in other organs or systems at a gestational age of 20 weeks [1]. The prevalence of HDP is in a range of 3%-5% among pregnant women worldwide, while in developing countries, it is up to 15% causing a mortality of 5 ~ 15% [2, 3]. To date, HDP is responsible for the death of 100,000 pregnant women annually, and at the same time, it is also one of the major factors for preterm birth, which affects the health conditions of pregnant women and neonates [4].

The pathophysiological changes of HDP are featured by systemic vasospasm of small vessels, vascular endothelial cell injury and local tissue ischemia. These lead to ischemia in the organs among pregnant and postnatal women, which subsequently affect the organ function and even onset of eclampsia in some cases with severe conditions [5]. HDP is associated with fetal growth delay, abruptio placentae, fetal distress in uterus, neonatal asphyxia, stillbirth or dead-birth [6]. It has been proposed that intrauterine hypoxia caused by HDP can lead to redistribution of fetal blood flow, in order to ensure the blood supply in important organs through reducing the blood flow of secondary organs. On this basis, it may trigger the onset of short- and long-term complications in neonates such as neonatal necrotizing enterocolitis [7].

HDP treatment raises a sharp conflict between the mother and the fetus. At present, the only effective way is to terminate the pregnancy, which usually leads to premature delivery. Neonatal complications and mortality are highly relied on gestational weeks and post-birth body weight. Premature termination of pregnancy will be life-threatening for premature babies, however, prolonging the gestational week will expose the pregnant women under the risks of serious complications or even death [8, 9]. In clinical practice, it is still a challenge to deal with the maternal organ injuries and the fetal immaturity. In this study, we retrospectively analyzed the neonatal complications and mortality among HDP cases.

Subjects

Premature infants at a gestational age of < 37 weeks with a birth weight of < 1,500 g, hospitalized in Neonatal Department of Fujian Maternal and Child Health Hospital from January 2016 to January 2021, were included in this retrospective analysis. Those with combined chromosomal abnormalities, severe congenital malformations and/or genetic metabolic diseases were excluded from this study. HDP was defined as presence of gestational hypertension, pre-eclampsia, as well as eclampsia. Gestational age-matched pregnant women with normal blood pressure giving birth to a very low birth weight neonate served as normal control.

Subgroup analysis

In this section, the patients were divided into three subgroups based on the disease severity, including gestational hypertension, pre-eclampsia and eclampsia. Then we compared the incidence of complications and mortality among these subgroups.

Data collection

A self-designed questionnaire was utilized in this study including: (i) maternal information: parity, number of fetus, blood pressure, utilization of antihypertensive drugs, other pregnancy complications, prenatal hormone usage, delivery mode, as well as postpartum complications; (ii) neonatal information: gestational age, sex, birth weight, small for gestational age (SGA) infant, birth asphyxia, mechanical ventilation, neonatal respiratory distress syndrome (RDS), neonatal necrotizing enterocolitis (NEC), neonatal bronchopulmonary dysplasia, and intraventricular hemorrhage; (iii) neonatal death: death due to poor or even no responses to hospital rescue, critical illness, or financial difficulties and other reasons. A comparison was performed to these information between two groups.

Statistical analysis

SPSS 20.0 software was used for data analysis. The measurement data that were normally distributed were expressed as mean ± standard deviation. Inter-group differences were compared by two independent samples t-test or one-way variance analysis. The counting data were described by frequency and rate, and the difference between groups was compared by Chi square test. Logistic regression analysis and step-by-step method were used for the multivariate analysis. A P value of less than 0.05 was statistically significant.

Comparison of general information

In HDP group, a total of 308 very low birth weight infants were included. Among these cases, 27 (8.8%) with a gestational age of < 28 weeks, 183 (59.4%) with a gestational age of 28–32 weeks, and 98 (31.8%) with a gestational age of 32–37 weeks. For the body weight, 57 cases (18.5%) showed a body weight of less than 1,000 g, and 251 cases (81.5%) showed a body weight of 1,000 g-1,500 g. In the control group, 30 cases (9.7%) were less than 1,000 g and 278 cases (90.3%) were in a range of 1,000 g and 1,500 g. There were statistical differences in the body weight and the prevalence of premature rupture of membrane between the two groups (P < 0.05). The mother age and cesarean section rate in the HDP group were significantly higher those of the normal control (P < 0.05, Table 1).

Table 1

Comparison of peripartum data in the very low birth weight infants
Variables	HDP patients (n = 308)	Non-HDP patients (n = 308)	t/χ²	P value
Male	148 (48%)	151 (49%)	0.058	0.809
Gestational age	30.8 ± 2.2	30.7 ± 2.1	0.781	0.435
Birth weight	1185.5 ± 217.2	1286.7 ± 177.2	6.331	0.000
Maternal age	31.5 ± 5.8	29.7 ± 4.6	4.389	0.000
In vitro fertilization-embryo transfer	41 (13.3%)	50 (16.2%)	1.044	0.307
Primiparity	99 (32.1%)	105 (34.1%)	0.264	0.607
Singleton pregnancy	210 (68.2%)	191 (62.0%)	2.579	0.108
Prenatal hormone	279 (90.6%)	283 (91.9%)	0.325	0.569
Infants delivered by DM mother	79 (25.6%)	72 (23.4%)	0.430	0.512
Premature rupture of fetal membrane	43 (14.0%)	128 (41.6%)	58.487	0.000
Caesarean section	241 (78.2%)	161 (52.3%)	45.827	0.000
Placental abruption	44 (14.3%)	53 (17.2%)	0.991	0.319
Placenta previa	8 (2.6%)	14 (4.5%)	1.697	0.193
HDP, hypertensive disorders of pregnancy; DM, diabetes mellitus.

Comparison of major complications and mortality between the groups

The incidence of fetal distress, SGA, mechanical ventilation, RDS, NEC (≥ 2stage) and mortality in HDP group were significantly higher than those of the control (P < 0.05). In addition, the 1 min Apgar score in the HDP group was significantly lower than that of the control (P < 0.05, Table 2).

Table 2

Comparison of major complications and mortality between the very low birth weight infants
Variables	HDP patients (n = 308)	Non-HDP patients (n = 308)	t/χ²	P value
Fetal distress	127 (41.2%)	74 (24%)	20.744	0.000
Apgar score at 1 min	8.3 ± 2.2	8.9 ± 1.8	-3.212	0.001
SGA	152 (49.4%)	81 (26.3%)	28.161	0.000
Mechanical ventilation	73 (23.7%)	51 (16.6%)	4.887	0.027
RDS	97 (31.5%)	68 (22.1%)	6.962	0.008
Sepsis	66 (21.4%)	49 (15.9%)	3.090	0.079
BPD	31 (10.1%)	32 (10.4%)	0.894	1.000
ROP	38 (12.4%)	26 (8.4%)	2.511	0.113
NEC, ≥2stage	24 (7.8%)	11 (3.6%)	5.119	0.024
IVH	78 (25.3%)	86 (27.9%)	1.536	0.215
PVH	4 (1.3%)	3 (0.97%)	0.000	1.000
PPHN	0 (0%)	1 (0.3%)	/	1.000
Cholestasis	17 (5.5%)	11 (3.6%)	1.347	0.246
Death or predicted death	47 (15.3%)	28 (9.1%)	5.481	0.019
SGA, small for gestational age; RDS, respiratory distress syndrome; BPD, bronchopulmonary dysplasia; ROP, retinopathy of prematurity; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; PPHN, Persistent pulmonary hypertension in the newborn

Comparison of major complications and mortality among the subgroups

There were significant differences in the fetal distress, 1 min Apgar score, ventilation, RDS and NEC (≥ 2 stage) (P < 0.05). The incidence of complications in the eclampsia and pre-eclampsia subgroups was significantly higher than that of the gestational hypertension group, especially the eclampsia subgroup (P < 0.01). The incidence of SGA in the eclampsia subgroup was lower than that of the pre-eclampsia subgroup. There were no statistical differences in the mortality and suspected mortality among these subgroups (P > 0.05, Table 3).

Table 3

Comparison of major complications and mortality between the very low birth weight infants with different severity of HDP
Variables	Gestational hypertension (n = 72)	Pre-eclampsia (n = 222)	Eclampsia (n = 14)	F/χ²	P value
Fetal distress	11 (15.3%)	109 (49.1%)	7 (50%)	26.130	0.000
Apgar score at 1 min	8.4 ± 2.0	8.4 ± 2.1	6.4 ± 3.1	5.694	0.004
SGA	16 (22.2%)	128 (57.7%)	8 (57.1%)	27.668	0.000
Mechanical ventilation	20 (27.8%)	46 (20.7%)	7 (50%)	7.107	0.029
RDS	15 (20.8%)	74 (33.3%)	8 (57.1%)	8.410	0.015
NEC, ≥ 2 stage	2 (2.8%)	19 (8.6%)	3 (21.4%)	6.324	0.042
Death	10 (13.8%)	33 (14.8%)	4 (28.6%)	2.050	0.359
SGA, small for gestational age; RDS, respiratory distress syndrome; NEC, neonatal necrotizing enterocolitis; HDP, hypertensive disease of pregnancy.

Multivariate regression analysis on the premature infant morality and major complications

In this section, multivariate regression analysis was performed after adjusting the gestational age, postbirth weight, sex, delivery mode, placental abruption, placenta praevia, prenatal hormone, gestational diabetes mellitus, neonatal asphyxia and maternal age. Our data showed that pre-eclampsia was a risk factor for SGA (OR = 4.123, 95%CI: 2.783–6.109) and NEC (OR = 2.493, 95%CI: 1.161–5.351) among the very low birth weight infants. Eclampsia was a risk factor for SGA (OR = 3.804, 95%CI: 1.239–11.681) and NEC (OR = 7.264, 95%CI: 1.771–29.797) among the very low birth weight infants (Table 4).

Table 4

Multi-variate regression analysis of major complications and mortality between the very low birth weight infants with different severity of HDP
Group	Fetal distress	Prenatal asphyxia	SGA	Mechanical ventilation	RDS	NEC, ≥ 2 stage	Death or predicted death
Gestational hypertension
Corrected OR value	0.500	1.581	0.797	1.214	0.490	0.720	0.902
95% CI	0.220–1.134	0.809–3.089	0.432–1.471	0.602–2.449	0.240 − 0.099	0.156–3.318	0.384–2.122
P value	0.097	0.181	0.468	0.588	0.055	0.673	0.814
Pre-eclampsia
Corrected OR value	0.729	0.863	4.123	0.890	1.454	2.493	1.170
95% CI	0.432–1.230	0.492–1.516	2.783–6.109	0.487–1.626	0.879–2.406	1.161–5.351	0.580–2.360
P value	0.236	0.609	0.000	0.704	0.145	0.019	0.661
Eclampsia
Corrected OR value	1.410	2.192	3.804	1.472	2.578	7.264	1.497
95% CI	0.306–6.489	0.655–7.340	1.239–11.681	0.426–5.093	0.769–8.468	1.771–29.797	0.370–6.063
P value	0.659	0.203	0.020	0.541	0.125	0.006	0.572
SGA, small for gestational age; RDS, respiratory distress syndrome; NEC, neonatal necrotizing enterocolitis

The incidence of HDP is high and presenting an increasing trend year by year with the increase in the number of elderly parturient women worldwide. Accordingly, the prevalence of HDP-related complications also shows gradual increase. [2, 3]. To date, there is a close relationship between the incidence and mortality of high-risk pregnant women and premature infants and national economy level and social health status. It also reflects the overall medical conditions of the nation, especially the level of perinatal medical development [4, 10]. To improve the prognosis of pregnant women and premature infants, the clinicians should pay more attention to the prevention and management of HDP, as well as the short- and long-term complications of premature infants.

This study was the first systematic study focused on the effects of HDP on the short-term prognosis of neonates with a birth weight of less than 1,500 g. In this study, we found that the HDP was associated with increased incidence of fatal distress, neonatal asphyxia, SGA, mechanical ventilation, hyaline membrane disease, NEC and mortality. Among these factors, eclampsia and preeclampsia were the independent risk factors for SGA and NEC.

Compared with the control group, the birth weight was lower in HDP group, while the incidence of SGA is higher in the HDP group (P < 0.05). After adjusting gestational age and gender, multivariate regression analysis was performed, which showed that preeclampsia and eclampsia were the independent risk factors for SGA. According to the previous description [5, 11, 12], HDP patients presented invasion of incomplete trophoblast into the uterine artery, coexistence of decidua vessels and intravascular trophoblast, as well as the extensive changes in the uterine spiral arteries such as vascular endothelial injury, insufficient protoplasm in vessel wall, endometrial cell proliferation and lipid accumulation, which finally lead to pathogenesis of atherosclerosis. Atherosclerosis was the cause of the stenosis and atresia of uterine spiral artery, which may result in decreased perfusion of placenta blood flow and inadequate supply of fetal nutrition. Subsequently, it would cause intrauterine growth retardation, fetal growth delay, and SGA. In addition, our data showed that there was a positive correlation between severity of HDP and the prevalence of SGA. The incidence of SGA infants in the pregnant women with preeclampsia and eclampsia was significantly higher than that of the gestational hypertension. These suggested that the degree of placental dysfunction showed a positive relation with HDP severity [13].

The incidence of NEC in the HDP group was significantly higher than that in the control group. After adjusting the gestational age and gender, multivariate regression analysis was conducted, which indicated that preeclampsia and eclampsia were the independent risk factors for NEC. Similarly, Yang C et al [14] reported that HDP was closely associated with the increased risk of neonatal NEC. Lee et al indicated that placental blood supply insufficiency induced by HDP would trigger intrauterine hypoxia, which may result in redistribution of fetal blood flow to ensure the supply of important organs through reducing the blood flow of secondary organs. Therefore, the blood supply to the fetal brain, liver and other vital organs is preferentially guaranteed, while the blood supply to the intestinal tract and other secondary organs is insufficient. It may affect intestinal development, especially the establishment of intestinal immune barriers. Consequently, the neonates delivered by HDP pregnant women show a high probability of being infected by NEC. It is found in this study that the incidence rate of NEC has a positive relation with HDP. The incidence rate of newborn NEC is the highest in pregnancies with eclampsia followed by preeclampsia and gestational hypertension. On this basis, we speculated that the injury of the intestinal tract and other target organs showed a positive correlation with HDP severity.

The incidence of neonatal asphyxia, mechanical ventilation, RDS, and mortality in the HDP group was significantly higher than that of control group. However, after adjusting the gestational age, birth weight and maternal factors in the perinatal period, multivariate regression analysis was performed, which demonstrated no significant effects on these conditions. For the reasons, it may be associated with the attention of HDP in clinical practice, especially the pregnant women of the pre-eclampsia. The physicians would recommend pregnant and fetal monitoring and interference actively in order to prevent the progression of pre-eclampsia [15, 16]. Our data indicated that the majority of cases (90%) underwent hormonal therapy to ensure the pulmonary development, which could sharply reduce the possibility of RDS induced by preterm delivery. In addition, the incidence of cesarean section in the HDP group was significantly higher than that of control group. This implied that effective monitoring and interferences were given to the pregnant women together with a detailed delivery schedule. For those with aberrant indications of HDP, immediate termination of pregnancy was given through cesarean section, which then reduced the possibilities of risks to the pregnant women and fetus after ongoing pregnancy. This provides helpful information for the management of HDP for the staff in the perinatal centers.

There are some limitations in this study. First, the sample size is adequate to some extent, but it yields some limitations due to a single-centered retrospective property. Second, in this study, we did not include the treatment information of the HDP patients into analysis. The neonatal prognosis may be affected by different treatment regimens, which is not considered in our analysis.

In summary, there are really some effects of HDP on the neonatal complications and mortality although there are some limitations. Nowadays, more and more attention has been paid to the effects of HDP on the neonatal prognosis. Our data provided helpful information on the early-stage prognosis of HDP premature birth, which contributed to the management and prognostic evaluation of HDP in clinical practice.

Funding

This study was supported by the Young Talent Program of Fujian Health Bureau [No. 2019-1-16, granted to Baoquan Zhang], and Sailing Project of Fujian Medical University [No. 2020QH1194, granted to Baoquan Zhang], and the Social Developmental Induction Program of Fujian Province [No. 2019Y0058, granted to Changyi Yang].

Conflicts of interest

The authors declare that they have no conflict of interest.

Availability of data and material

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

Not applicable.

Authors' contributions

Conceptualization: BQ Zhang; Methodology: BQ Zhang, XJ Chen; Formal analysis and investigation: HY Shi, WL Xiu, Y Dai; Writing - original draft preparation: BQ Zhang; Writing - review and editing: CY Yang; Funding acquisition: BQ Zhang, CY Yang.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Ethical Committee of Fujian Maternal and Child Health Hospital (No.: 2017-502).

Consent to participate

Each subject signed the informed consent.

Consent for publication

Written informed consent was obtained from the participants for publication of this article and any accompanying tables.

Acknowledgments

Not applicable.

Ghulmiyyah L, Sibai B (2012) Maternal mortality from preeclampsia/eclampsia. Semin Perinatol 36:56–59. https://doi.org/10.1053/j.semperi.2011.09.011
Souza JP, Gülmezoglu AM, Vogel J et al (2013) Moving beyond essential interventions for reduction of maternal mortality (the WHO Multicountry Survey on Maternal and Newborn Health): a cross-sectional study. Lancet 381:1747–1755. https://doi.org/10.1016/s0140-6736(13)60686-8
Chappell LC, Brocklehurst P, Green ME et al (2019) Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial. Lancet 394:1181–1190. https://doi.org/10.1016/s0140-6736(19)31963-4
Tong J, Niu Y, Chen ZJ, Zhang C (2020) Comparison of the transcriptional profile in the decidua of early-onset and late-onset pre-eclampsia. J Obstet Gynaecol Res 46:1055–1066. https://doi.org/10.1111/jog.14257
Phipps E, Prasanna D, Brima W, Jim B (2016) Preeclampsia: Updates in Pathogenesis, Definitions, and Guidelines. Clin J Am Soc Nephrol 11:1102–1113. https://doi.org/10.2215/cjn.12081115
Wadhwani P, Saha PK, Kalra JK, Gainder S, Sundaram V (2020) A study to compare maternal and perinatal outcome in early vs. late onset preeclampsia. Obstet Gynecol Sci 63:270–277. https://doi.org/10.5468/ogs.2020.63.3.270
A JYL, B KHP BAK, A HRY, B EYJ, B SHC (2017) Maternal and Placental Risk Factors for Developing Necrotizing Enterocolitis in Very Preterm Infants. Pediatrics Neonatology 58:57–62
Telang MA, Bhutkar SP, Hirwani RR (2013) Analysis of patents on preeclampsia detection and diagnosis: a perspective. Placenta 34:2–8. https://doi.org/10.1016/j.placenta.2012.10.017
Simenc GB, Ambrozic J, Prokselj K, Tul N, Cvijic M, Mirkovic T, Lackner HK, Lucovnik M (2018) Optic nerve ultrasound for fluid status assessment in patients with severe preeclampsia. Radiol Oncol 52:377–382. https://doi.org/10.2478/raon-2018-0047
Kahsay HB, Gashe FE, Ayele WM (2018) Risk factors for hypertensive disorders of pregnancy among mothers in Tigray region, Ethiopia: matched case-control study. BMC Pregnancy Childbirth 18:482. https://doi.org/10.1186/s12884-018-2106-5
Wang A, Holston AM, Yu KF, Zhang J, Toporsian M, Karumanchi SA, Levine RJ (2012) Circulating anti-angiogenic factors during hypertensive pregnancy and increased risk of respiratory distress syndrome in preterm neonates. J Matern Fetal Neonatal Med 25:1447–1452. https://doi.org/10.3109/14767058.2011.640368
San Juan-Reyes S, Gómez-Oliván LM, Islas-Flores H, Dublán-García O (2020) Oxidative stress in pregnancy complicated by preeclampsia. Arch Biochem Biophys 681:108255. https://doi.org/10.1016/j.abb.2020.108255
Nelson DB, Ziadie MS, McIntire DD, Rogers BB, Leveno KJ (2014) Placental pathology suggesting that preeclampsia is more than one disease. Am J Obstet Gynecol 210:66.e61-67. https://doi.org/10.1016/j.ajog.2013.09.010
Yang CC, Tang PL, Liu PY, Huang WC, Chen YY, Wang HP, Chang JT, Lin LT (2018) Maternal pregnancy-induced hypertension increases subsequent neonatal necrotizing enterocolitis risk: A nationwide population-based retrospective cohort study in Taiwan. Medicine 97:e11739. https://doi.org/10.1097/md.0000000000011739
Witcher PM, Chez BF, Baird SM (2015) Multisystem Effects of Hypertensive Disorders of Pregnancy: A Comprehensive Review. J Perinat Neonatal Nurs 29:229–239. https://doi.org/10.1097/jpn.0000000000000114
Garovic VD, August P (2013) Preeclampsia and the future risk of hypertension: the pregnant evidence. Curr Hypertens Rep 15:114–121. https://doi.org/10.1007/s11906-013-0329-4

Download PDF

Version 1

posted

You are reading this latest preprint version

Effects of Hypertensive Disorders of Pregnancy On The Mortality and Complications in Very Low Birth Weight Neonates

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusions

Introduction

Materials And Methods

Subjects

Subgroup analysis

Data collection

Statistical analysis

Results

Comparison of general information

Comparison of major complications and mortality between the groups

Comparison of major complications and mortality among the subgroups

Multivariate regression analysis on the premature infant morality and major complications

Discussion

Declarations

References

Status:

Version 1