A Clinical Trial of Oral Hydration Therapy for the Management of Very Preterm Nonsevere Preeclampsia

INTRODUCTION

Preeclampsia is a devastating human-specific disorder of pregnancy. Preterm preeclampsia comprises a significant group of women with a financial and emotional burden on the community in terms of pregnancy wastage, neonatal intensive care, and long-term effects of preterm birth and IUGR associated with preeclampsia.

Hypertensive disorders in pregnancy are the second most common direct cause of maternal mortality worldwide – comprising 14% of all causes. In South Asia, 10.3% of all deaths are on account of hypertension.¹

Of the estimated 2.6 million stillbirths annually, approximately 16% occur in pregnancies complicated by hypertensive disorders in pregnancy. Neonatal morbidities occur 10–20 times more often than neonatal deaths. About 1 in 250 primigravidae give birth prior to 34 weeks due to preeclampsia.²

OBJECTIVES OF THE STUDY

To determine the effectiveness of oral hydration therapy compared with controls in decreasing mean arterial pressure and extending the duration of pregnancy in very preterm nonsevere preeclampsia.

MATERIALS AND METHODS

RESULTS

Phases of enrolment for intervention and follow-up of cases in the study are described in Figure 1.

The daily urine output of patients was more than 2.5 liters.

Baseline characteristics of cases are mentioned in Table 1.

When the groups were matched by gestational age, the maximum number of participants were in the 26–29-week 6-day category in the oral hydration group, making 55% of the total 20 participants. The control group had a maximum number of participants of all groups, including 12 in the 26–29-week 6-day category and 11 in the 30–33-weeks 6-day category.

Of the total 50 patients, 4 patients were referred as hypertensive disorders in pregnancy. About 27 were detected as hypertensive during regular ANC visits. Others were diagnosed after admission.

The majority of the patients in each group did not have any significant past history. Some known hypertensive patients were also included in the study, who had superimposed nonsevere preeclampsia. Three patients were diabetics, two among them were in oral hydration group.

There was no statistical difference between cases and controls in terms of serum sodium and serum potassium between patients at recruitment and on 5th day after initiation of treatment (p = 0.392; p = 0.772). These results show that hydration therapy does not produce electrolyte imbalance.

It was observed that diastolic BP significantly reduced in oral hydration group after 5 days of starting treatment. There was no significant difference in mean BP 5 days after starting treatment in the oral hydration group (Table 2). There was no significant difference between systolic blood pressure (SBP), diastolic blood pressure (DBP) and MAP at the termination of pregnancy in both groups.

Severe preeclampsia, hemolysis, elevated liver enzymes, low platelet count (HELLP), partial HELLP, imminent eclampsia, eclampsia, and oligohydramnios were considered as PIH-related indications. Fetal compromise, Post datism, PROM, PPROM, previous LSCS,Spontaneous onset of labor were considered non-PIH-related indications for termination of pregnancy.

Indications for termination of pregnancy included 70% due to non-pregnancy-induced hypertension (PIH)-related indications in oral hydration therapy. Among controls, 44% were terminated due to non-PIH indications and 56% due to PIH-related indications.

About 60% of participants in oral hydration and 52% in the control group had good outcomes, and a maximum number of maternal complications like severe preeclampsia, imminent eclampsia, eclampsia, HELLP, partial HELLP, and CVT were seen in the control group.

There was a significant difference between oral hydration group and controls in terms of birth weight of babies with p-value of 0.011. The mean birth weight of the oral hydration group was 2.5 kg, and that of the control group was 2 kg.

About 60% (12) of participants in oral hydration and 52% (13) in control group had good outcomes of the mother just post delivery.

Good outcomes included those cases who had mild preeclampsia or their BP became normal after delivery. Bad outcomes were those patients who developed severe preeclampsia, imminent eclampsia, eclampsia, CVT, HELLP, partial HELLP, or died.

There was no significant difference between the groups in terms of fetal outcomes statistically, but the maximum proportion of babies (16%) had died in the control group compared with 10% in oral hydration group.

There was a significant difference between oral hydration group and control in terms of the prolongation of pregnancy. Mean prolongation of pregnancy in oral hydration group was 38.6 days and in the control group was 26.7 days (p = 0.037).

DISCUSSION

Imbalance between angiogenic and antiangiogenic factors causes preeclampsia. Antiangiogenic factor, soluble fms-like tyrosine kinase1 (sFlt-1) induces preeclampsia-like phenotype in experimental models, and circulates at high levels in preeclampsia.³ Extracorporeal removal of circulating sFlt-1 by dextran-sulfate apheresis reduces proteinuria and stabilizes blood pressure without apparent adverse effects on the fetus and mother.⁴

Samartha Ram et al. concluded that oral hydration therapy with urine output 3962 ± 989 mL/24 hrs helps to prolong very preterm preeclamptic pregnancies to term with good perinatal outcome. Continuation of pregnancy in cases was 7.51 ± 5.22 weeks, and in controls, it was 1.38 ± 1.18 weeks (p = 0.000). Significant decrease in RDS, NICU admission days (p = 0.000, 0.001), and increase in birth weights and take-home babies (p = 0.000, 0.041) were observed in cases. The limitation of the study was blood, and urine sflt level was not measured in the study.⁵ Hereby referred to as reference study/index study.

The current study was done in a tertiary care institute, which caters to a large number of deliveries with a high prevalence of preeclampsia with significant morbidity and noticeable mortality. Going by large numbers, as there is no proven method to prolong pregnancy and perinatal outcomes, we decided to try a different method and compare it to currently followed treatment at our institute, in terms of maternal and neonatal outcomes.

A wide range of unproven interventions are available to treat or prevent preeclampsia. But, there is a need for low-cost, simple, easy, and practicable interventions. In this study, we have compared controls with one such modality, i.e., oral hydration therapy, which is an intervention with the least-possible cost. With this, we wanted to test the hypothesis that oral hydration therapy may significantly reduce clinical symptoms and may also help to continue pregnancies to viability, as enhanced renal excretion of sFlt1 is possible.

There was also a significant difference between prolongation of pregnancy between oral hydration therapy group and controls (p = 0.037) (Table 3).

In oral hydration group, of the two neonatal deaths, one could be attributed to hypoglycemia as the mother was diabetic. In the control group, 4 babies died due to LBW leading to sepsis and/or respiratory distress. Thus, though there was a difference clinically, there was no statistical difference on analysis (Table 4).

Current study showed that oral hydration therapy significantly decreased diastolic blood pressure when compared with controls after 5 days of intervention, i.e., the group consuming antihypertensives only (p = 0.02) as seen in Table 5.

There was no statistical difference between cases and controls in terms of serum sodium and serum potassium between patients at recruitment and on the 5th day after initiation of oral hydration therapy (p = 0.392, p = 0.772). Even in the reference study, there was no statistically significant difference in serum sodium and potassium levels between cases and controls (p = 0.072, p = 0.201). These results show that hydration therapy does not cause electrolyte imbalance.

When termination of pregnancy was considered, in this study, 30% were terminated due to PIH-related indications in oral hydration therapy. Among controls, 56% were terminated due to PIH indications. Whereas in reference study, 75% of the controls were terminated due to PIH-related indications and only 5% of subjects on oral hydration therapy were terminated due to PIH-related indications (Table 6).

In this study, there was a significant difference between oral hydration group and controls in terms of birth weight of babies as in Table 7.

LIMITATIONS OF THE STUDY

• Urine output per day was maintained to be more than 2500 mL but the average urine output of all the days was not calculated.

• sflt levels in blood and/or urine could not be calculated as the facility is not available in this institution.

• Blinding was not possible as one arm of the study included drinking water in large amounts, which could not be blinded.

ETHICAL APPROVAL

All procedures performed in studies involving human participants were in accordance with ethical standards of the Institutional and/or National Research Committee and with the 1964 Helsinki declaration and its later amendments or comparable with ethical standards.

ORCID

Sucheta Suresh https://orcid.org/0000-0003-2156-7834

REFERENCES

1. Say L, Chou D, Gemmill A, et al. Global causes of maternal death: A WHO systematic analysis. Lancet Glob Health 2014; 2(6):e323–e333. DOI: 10.1016/S2214-109X(14)70227-X.

2. von Dadelszen P, Magee LA. Preventing deaths due to hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol 2016;36:83–102. DOI: 10.1016/j.bpobgyn.2016.05.005.

3. Yadav S, Singh Y, Natu SM, et al. Serum levels of soluble Fms like tyrosine kinase-1 (sFlt-1) in normotensive and preeclamptic pregnancy. Int J Med Res Rev 2013;1(3):114–119. DOI: 10.17511/ijmrr.2013.i03.07.

4. Thadhani R, Hagmann H, Schaarschmidt W, et al. Removal of soluble Fms-like tyrosine kinase-1 by dextran sulfate apheresis in preeclampsia. J Am Soc Nephrol 2016;27(3):903–913. DOI: 10.1681/ASN.2015020157.

5. Samartha Ram H, Sai Samyukta I, Nagasree V. Oral hydration therapy for the management of very preterm preeclampsia. IOSR J Dental Med Sci 2016;15(11):35–41. DOI: 10.9790/0853-1511083541.