Postpartum antihypertensive treatment - is there a correlation to placental lesions?

doi:10.21203/rs.3.rs-2746229/v1

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Postpartum antihypertensive treatment - is there a correlation to placental lesions?

https://doi.org/10.21203/rs.3.rs-2746229/v1

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published 30 Oct, 2023

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Objective: We aimed to examine the association of clinical risk factors and placental lesions, in gestations complicated with preeclampsia, with the need for antihypertensive treatment in the early postpartum period.

Methods: The computerized files and placental reports of all singleton deliveries at 24.0 - 42.0 weeks complicated by preeclampsia were reviewed between January 2013 and October 2020. Obstetric characteristics and placental lesions were compared between patients who required antihypertensive treatment in the early postpartum period and those who did not (control group). Placentas were classified into maternal and fetal malperfusion lesions and inflammatory responses.

Results: As compared to controls (n=200), the anti-hypertensive treatment group (n=95) was characterized by increased rates of preterm birth, preeclampsia with severe features, and cesarean delivery (p<0.001 for all). More placental hematomas (p=0.01 and placental maternal vascular lesions (p=0.03) were observed in the antihypertensive treatment group as compared to controls. In a logistic regression analysis, gestational age (OR 0.86, 95% CI 0.79-0.93, p=0.001) and preeclampsia with severe features (OR 8.89, 95% CI 3.18-14.93 p<0.001) were found to be independentlyassociated with the need for postpartum antihypertensive treatment.

Conclusion: Placental vascular lesions are more common in preeclamptic patients who need postpartum antihypertensive treatment, yet only early onset of preeclampsia with severe features was found to be independently associated with antihypertensive treatment in the early postpartum period.

Preeclampsia

Hypertension

Placenta

Placental lesions

Anti-Hypertensive Treatment

Postpartum Hypertension

Preeclampsia is a multisystem pregnancy complication with heterogenous presentation and different underlying phenotypes [1–2]. The pathogenesis of the disease involves maternal vascular endothelial injury with resultant reduced placental oxygenation [3]. The decrease in placental oxygenation could be attributed to maternal vasculopathy (as in chronic hypertension, renal disease, or collagen disease) [4], abnormal placental mass (multiple gestations, diabetes mellitus, hydatidiform mole) [5], and defective penetration of trophoblastic cells into the vascular endothelial cells in the early stages of pregnancy are associated with disorders of deep placentation [6].

Placental involvement in the development of preeclampsia is supported by many studies [5, 7], and the correlation between placental histopathology and preeclampsia has been studied thoroughly. Most frequently, placental histopathology lesions observed in preeclampsia are those related to maternal vascular malperfusion lesions, such as increased syncytial knots, multiple infarcts, increased fibrin deposition, and atherosis of the decidual vessels [4]. Notably, placental findings were correlated with the different clinical presentations and severity of the disease [8–10].

Postpartum hypertension is observed in about 20% of patients with preeclampsia. The clinical management of postpartum hypertension focuses primarily on blood pressure control via use of antihypertensive medications. Antihypertensive treatment is required usually when blood pressure (BP) is ≥ 150/100 mmHg [11–13]. Only few studied the correlation between clinical risk factors and the need for treatment in the postpartum period in patients with preeclampsia [14–16]. We aimed to fill this gap and investigated possible association between clinical risk factors and placental histopathology lesions with the need for antihypertensive treatment in the early postpartum period, defined by us as anti-hypertensive treatment started prior to discharge from the hospital and was recommended to be continued after discharge, in preeclamptic women.

The medical records and placental pathological reports of all patients diagnosed with preeclampsia and delivered in a single university hospital from January 2013 to October 2020 were reviewed. Eligible cases for the study were identified from our computerized data system. Based on departmental protocol, placentas are sent for histopathology evaluation in any case of pregnancy complications, such as preeclampsia, fetal growth restriction, placental abruption, and preterm births.

Included in the study were singleton deliveries at 24–42 weeks of gestation, complicated by preeclampsia in which placental histological was performed. Preeclampsia was defined according to the current American College of Obstetricians and Gynecologists criteria [11]. Preeclampsia with severe features was diagnosed when systolic BP was ≥ 160 mm Hg and/or diastolic BP was ≥ 110 mm Hg (with or without proteinuria) and one or more signs and symptoms of significant end-organ dysfunction [12]. In any case of preeclampsia with severe features, patients were treated with magnesium sulfate and antihypertensive medications as appropriate. Patients who required initiation of antihypertensive therapy during the intrapartum period and continued with the treatment during the postpartum period were included in the study.

We excluded from the study pregnancies with lack of prenatal care, multiple gestations, and patients with chronic hypertension, defined as women with antenatal elevated hypertension prior or hypertension prior to 20 weeks of gestation and were under antihypertensive treatment during pregnancy.

Patients with systolic BP of 150 to 159 mmHg and/or diastolic BP of 100 to 109 mmHg in the early postpartum period (during their hospitalization after birth) were treated with antihypertensive medications. The treatment of choice was Labetalol, starting with a dose of 200 mg twice a day, and up to 2400 mg over 24 hours either twice a day or three times a day. In cases of persistently elevated BP, additional drugs were given such as angiotensin-converting enzyme (ACE) inhibitors as Enalapril starting with a dose of 5mg once a day and up to 10mg twice a day and /or extended-release nifedipine as Nifedilong 30 mg once a day and up to 60 mg a day.

For the purpose of the study, maternal characteristics, obstetric outcomes, and placental pathology reports were compared between patients who required antihypertensive treatment (anti-hypertensive treatment group) during the postpartum period and patients who did not need any medications for their BP (control group).

Data collection

The following data were collected from patients' medical files: age, gravidity, parity, body mass index (BMI kg/m²), diabetes mellitus (pre-gestational or gestational), history of previous preeclampsia, pre-pregnancy diagnosis of thrombophilia (defined as any thrombophilia, inherited or acquired), smoking, and in-vitro fertilization. Gestational age at delivery was noted, as was the mode of delivery (cesarean delivery (CD) vs. vaginal delivery), and the presence of preeclampsia with or without severe features. Daily BP measurements and the need for antihypertensive medications were recorded in the early postpartum period.

Following birth, neonates were examined by trained pediatricians. Birth weight percentiles were recorded using the updated local growth charts [17]. Small for gestational age (SGA) was defined as actual birthweight ≤ 10th percentile. The following data were collected from neonatal records: five-minute Apgar scores, cord blood pH, neonatal intensive care unit (NICU) admissions, sepsis, blood transfusion, need for phototherapy, respiratory distress syndrome, mechanical ventilation or support, necrotizing enterocolitis, intraventricular hemorrhage, hypoxic-ischemic encephalopathy, seizures, and death. Composite adverse neonatal outcome was defined as one or more neonatal complications.

Placental examination

As part of our departmental protocol, the placentas of all deliveries complicated by preeclampsia were sent for histopathological evaluation. Placental pathology examinations were performed by a single pathologist (author L.S), using our standard protocol. Placental lesions were classified according to the criteria adopted by the Society for Pediatric Pathology [4, 10], as was previously reported by us [18].

Briefly, after removing the membranes and cord, the placentas were weighed, and the percentile was determined according to placental weight charts [19]. Placental lesions were categorized into: a. maternal vascular malperfusion lesions (placental hemorrhages, vascular and villous changes); b. Fetal vascular malperfusion lesions (vascular and villous changes); c. Inflammatory lesions (chorioamnionitis and villitis of unknown etiology)

Statistical analysis

Data were analyzed with Epi Info 7.0 (Center for Disease Control and Prevention, Atlanta, GA). Continuous variables were calculated as mean ± SD or median and range and compared with Student's t-test or Mann Whitney as appropriate. Categorical variables were calculated as number (%) and compared with chi-square test or by Fisher exact test, as appropriate. A P-value of less than 0.05 was considered statistically significant.

A multivariate forward logistic regression analysis was performed to identify independent risk factors for antihypertensive treatment during the postpartum period. The following independent variables were included: maternal age, nulliparity, preeclampsia with severe features, previous preeclampsia, placental marginal or retroplacental hematoma, and placental maternal vascular lesions.

During the study period, 295 singleton deliveries were eligible for the study. Among them, 95 (32%) necessitated antihypertensive treatment in the early postnatal period (anti-hypertensive treatment group), and 200 (68%) did not need antihypertensive medications and served as controls.

Patient's characteristics are presented in Table 1. There were no between-groups differences in maternal age, BMI (kg/m²), nulliparity, conception via in vitro fertilization, and co-morbidities. As expected from the study design, the median systolic and diastolic BP were significantly higher in the anti-hypertensive treatment group as compared to the control group.

Table 1

Demographic characteristics of the studied groups
	Anti hypertensive treatment group n = 95	Control group n = 200	P
Age, (years)	32.5 ± 6.8	31.3 ± 6.6	0.14
Assisted reproduction	12/83 (14.4%)	27/181 (14.9%)	0.92
BMI (kg/m²)	28.1 ± 8.8	25.9 ± 6.2	0.08
Gravidity	2.5 ± 1.9	2.0 ± 1.3	0.03
Parity	0.9 ± 1.3	0.6 ± 1.0	0.04
Nulliparous	50 (52.6%)	122 (61.0%)	0.17
DM	17 (17.8%)	42 (21.0%)	0.49
Chronic hypertension *	11 (11.5%)	16 (8.0%)	0.31
Smokers	10 (10.5%)	19 (9.5%)	0.78
Thrombophilia	1 (1.0%)	2 (1.0%)	> 0.99
Previous PE	15 (15.7%)	19 (9.5%)	0.11
Data presented as mean ± SD or n (%) as appropriate. SD: standard deviation, n: number, BMI – body mass index, pre-gestational, DM – diabetes mellitus, pre-gestational or gestational DM, PE – preeclampsia. Chronic hypertensive patients included were not on anti-hypertensive medications.

As compared to controls, the anti-hypertensive treatment group was characterized by lower gestational age at delivery, 35.1 ± 3.9 weeks vs. 37.1 ± 2 weeks, respectively, p < 0.001, higher rates of PTL (delivery < 37 weeks), preeclampsia with severe features and CD, (p < 0.001 for all). Mean neonatal birthweight was lower in the anti-hypertensive treatment group as compared to controls 2233 ± 941grams vs. 2658 ± 779 grams, p < 0.001, with a higher rate of composite adverse neonatal outcome 30.2% vs. 14.3%, (p = 0.002), (Table 2).

Table 2

Obstetric and neonatal outcome
	Anti hypertensive treatment group n = 95	Control group n = 200	P
Gestational age, (weeks)	35.1 ± 3.9	37.1 ± 2.8	< 0.001
Premature delivery	59 (62.1%)	70 (35.0%)	< 0.001
PE with severe features	86 (90.5%)	114 (57.0%)	< 0.001
CD	79 (83.1%)	129 (64.5%)	0.001
Birth weight, (grams)	2233 ± 941	2658 ± 779	< 0.001
SGA	27 (28.4%)	51 (25.5%)	0.59
Five-minute Apgar score < 7	5 (5.2%)	1 (0.5%)	0.01
Cord pH < 7.1	7 (7.5%)	12 (6.0%)	0.62
Adverse composite neonatal index	26 (30.2%)	27 (14.3%)	0.002
Postpartum daily systolic BP, median (range)	156 (133–190)	138 (111–157)	< 0.001
Postpartum daily diastolic BP, median (range)	94 (75–110)	83 (64–99)	< 0.001
Data presented as mean ± SD or n (%) as appropriate. SD: standard deviation, n: number; Premature delivery < 37 weeks, PE – preeclampsia, CD- cesarean delivery, SGA – small for gestational age, BP – blood pressure. Adverse composite neonatal index was defined as at least one of the following: phototherapy, respiratory distress, sepsis, blood transfusion, cerebral complications, necrotizing enterocolitis (NEC), Neonatal Intensive Care Unit (NICU) admission or neonatal death

Placental histopathological lesions are presented in Table 3. As compared to the control group the antihypertensive treatment group was characterized by lower placental weight (p = 0.03) higher rate of placental hematomas and more maternal vascular lesions (p = 0.01, p = 0.03, respectively). There was no between-group difference in other placental lesions such as fetal vascular malperfusion lesions, chorioamnionitis, or villitis of unknown etiology.

Table 3

Placental lesions of the studied groups
	Anti hypertensive treatment group n = 95	Control group n = 200	P
Placental weight, (grams)	410 ± 167	449 ± 148	0.03
Maternal vascular malperfusion (MVM) lesions
Composite MVM lesions	74 (77.8%)	134 (67.0%)	0.05
Marginal / retroplacental hematoma	18 (18.9%)	18 (9.0%)	0.01
Vascular lesions	30 (31.5%)	41 (20.5%)	0.03
Villous changes	57 (60.0%)	106 (53.0%)	0.25
Fetal vascular malperfusion (FVM) lesions
Composite FVM lesions	12 (12.6%)	34 (17.0%)	0.33
Vascular lesions	8 (8.4%)	23 (11.5%)	0.42
Villous changes	6 (6.3%)	17 (8.5%)	0.51
Inflammatory lesions
VUE	8 (8.4%)	23 (11.5%)	0.42
Chorioamnionitis	9 (9.4%)	30 (15.0%)	0.19
Data presented as mean ± SD or n (%) as appropriate. SD: standard deviation, n: number VUE – villitis of unknown etiology, Chorioamnionitis – maternal and / or fetal inflammatory responses. Maternal vascular changes included - acute atherosis and mural hypertrophy; Villous changes - increased syncytial knots, villous agglutination, increased intervillous fibrin deposition, distal villous hypoplasia, and parenchymal infarcts; Fetal vascular lesions included - thrombosis of the chorionic plate and stem villous vessels; Villous changes - villous stromal-vascular karyorrhexis and avascular villi

To identify independent risk factors for antihypertensive treatment during the postpartum period, a logistic regression analysis was performed, revealing that only gestational age (OR 0.86, 95% CI 0.79–0.93, p < 0.001) and preeclampsia with severe features (OR 8.89, 95% CI 3.18–14.93 p < 0.001) were found to be independently associated with antihypertensive treatment in the postpartum period (Table 4).

Table 4

Logistic regression model for the need of postpartum hypertensive treatment
	OR	95% CI		P
	OR	Lower	Upper	P
Maternal age, years	1.03	0.99	1.07	0.11
Nulliparity	0.95	0.51	1.77	0.89
Gestational age, weeks	0.86	0.79	0.93	< 0.001
PE with severe features	6.89	3.18	14.93	< 0.001
Previous PE	1.83	0.74	4.53	0.18
Placental maternal malperfusion lesions	1.08	0.57	2.06	0.79
PE- preeclampsia OR: odds ratio, C.I: confidence interval

The present study demonstrates that placental hematomas and maternal vascular lesions were more common among women who were treated with antihypertensive treatment in the post-partum period. However, only gestational age at delivery and the presence of preeclampsia with severe features were found to be independently associated with the need for antihypertensive treatment in the postpartum period.

Women with preeclampsia during labor usually lower their BP in the early postpartum period, typically 48 h after delivery. Yet, it might peak again later, even after discharge from the hospital. The incidence of postpartum hypertensive treatment during the postpartum period ranges between 33–51% [11]. Clearly, identifying those who might need antihypertensive medications is of major importance in order to prevent associated possible maternal morbidities such as stroke, pulmonary edema, or renal failure.

In the current study, among patients with preeclampsia during labor, 32% required antihypertensive treatment in the early postpartum period-before discharge from the hospital [ 20–21]. In concordance with a previous report [14], we observed several clinical features that are mostly associated with the need for treatment. Additionally, lower placental weights and an increased rate of placental lesions, which are known to be the hallmark of preeclampsia, as placental hematoma and vascular maternal malperfusion lesions, were also associated with the treatment group. The main placental lesions observed were acute atherosis and mural hypertrophy of decidual vessels, which share morphological features with early atherosclerotic lesions that eventually lead to decreased uteroplacental blood flow. Nevertheless, after performing logistic regression analysis, we could identify risk factors that were independently associated with the need for treatment: gestational age at delivery with OR 0.86, CI95% 0.79–0.93, p < 0.001 and preeclampsia with severe features with OR 6.89, 95%CI, 3.18–14.93, p < 0.001. Notably, the difference observed in neonatal birth-weights between the groups probably results from the earlier gestational age at delivery among the anti-hypertensive group.

These findings point toward the association observed between early-onset preeclampsia (with severe features), atherosclerosis, and long-term maternal morbidity [22]. A subset of patients diagnosed with early severe preeclampsia are those that probably will need antihypertensive treatment. These patients might suffer from an asymptomatic cardiovascular impairment, aortic stiffens, and increased risk of long-term consequences such as chronic hypertension, ischemic heart disease, heart failure, and end-stage renal disease [23]. Notably, the American Heart Association now recommends that a pregnancy history be part of the evaluation of cardiovascular risk, further establishing the opportunity for prediction and prevention of long-term maternal risks associated with preeclampsia and pregnancy complications [24].

The present study is unique in several aspects. This is the first study aimed to correlate the need for antihypertensive treatment to placental histology characteristics. All placentas were evaluated by a single pathologist (author L.S) according to the criteria adopted by the Society for Pediatric Pathology, and the corresponding placental findings were detected. The pathologist was blinded to the need for antihypertensive treatment.

This study is not without limitations. First, due to its retrospective design. Unintended selection bias may occur by sending placentas for histopathology evaluation, mostly from preeclampsia with severe features. Second, gestational matched controls were not used in the current study. Third, maternal cardiovascular evaluation and long-term follow-up were unavailable. Therefore, patients with increased BP after discharge from the hospital were not included.

In conclusion, several clinical risk factors and placental vascular malperfusion lesions are common in preeclamptic patients who need antihypertensive treatment. Yet, only early gestational age at delivery and preeclampsia with severe features are independently associated with the need for hypertensive medications in the postpartum period. Larger studies are needed to identify the subgroup of patients who will benefit from rigorous follow-up and early treatment.

Funding- This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest- The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethics approval- Approval for the study was obtained from the local ethics committee (# 0122-20-WOMC). In all cases, the placentas were sent to histopathology for evaluation, in accordance with our departmental policy that routinely performs placental analyses in complicated pregnancies.

Consent to participate- The study was a retrospective study. The institutional ethics committee exempted the authors from obtaining individual informed consent.

Consent to publication- Not applicable

Availability of data and material- Data is available on request due to privacy/ethical restrictions.

Code availability- Not applicable

Authors' contribution

Z Fridman Kogan - project development, data collection, first draft of manuscript writing;

S Nahum Fridland- data collection;

H Ganer Herman- data analysis and manuscript editing;

H Miremberg - data collection;

M Bustan - data collection;

L Schreiber - project development;

M Kovo- project development and manuscript editing

Authors statements:

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Authors have no relevant financial or non-financial interests to disclose.

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You are reading this latest preprint version

Postpartum antihypertensive treatment - is there a correlation to placental lesions?

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Journal Publication

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Abstract

Introduction

Materials and methods

Data collection

Placental examination

Statistical analysis

Results

Discussion

Declarations

References

Status:

Journal Publication

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