2016 年 4 巻 1 号 p. 24-29
Aim: Oligohydramnios contributes to a negative fetal prognosis. Management of oligohydramnios in obstetric clinical practice is important. We assessed the clinical efficacy of Gorei-San for the treatment of oligohydramnios.
Methods: Single deepest pocket (SDP) changes before and after treatment for oligohydramnios (SDP decrease to less than 3 cm) were examined. A total of 51 pregnant mothers who were experiencing oligohydramnios were enrolled in the study. The changes in SDP were compared between 27 women treated with Gorei-San (7.5 g/day) and 24 untreated women. The first measurements of SDP in both groups were obtained when the SDP had decreased to less than 3 cm (start point: SP), and the second measurements were obtained at the next regular examination (end point: EP).
Results: The average SDP significantly increased in women treated with Gorei-San from the SP (2.37±0.41 cm) (mean±SD) to the EP (3.15±0.62 cm) (mean±SD) (P<0.001). In contrast, there were no significant changes in the untreated women from the SP (2.5±0.15 cm) (median±quartile) (non-normally distributed) to the EP (2.63±0.68 cm) (mean±SD) (P=0.59).
Conclusions: Gorei-San was helpful in the treatment of oligohydramnios. Although further studies are needed to confirm our findings, we believe that this new application of Gorei-San for the treatment of oligohydramnios is a clinically applicable strategy.
Oligohydramnios contributes to a negative fetal prognosis.1) It has also been reported that the rates of cesarean deliveries and operative vaginal deliveries are higher in pregnant women with oligohydramnios.2) These factors then contribute to increased maternal and fetal risks. Therefore, management of oligohydramnios in obstetric clinical practice is important. However, to date, effective treatments for oligohydramnios have not yet been established.
Gorei-San/Wu-Ling-San is a blended traditional herbal oriental medicine used to promote water metabolism.3) Gorei-San/Wu-Ling-San, which is called Gorei-San in Japan also called Wu-Ling-San in China, modulates the distribution of water throughout the body.4) Gorei-San is widely used to treat edema, such as scrotum edema and cardiac edema, urine retention and difficult urination and has been used to promote blood circulation.5)
We previously reported that Gorei-San is effective in treating gestational edema.4) In cases of gestational edema, amniotic fluid decreases in the late trimester periods of pregnancy.6) We also previously reported that the administration of Gorei-San to pregnant women with pretibial edema can prevent subsequent reductions in amniotic fluid volume.6)
These results retrospectively suggested that Gorei-San may be effective in the treatment of oligohydramnios in the late trimester period. Therefore, this study aimed to assess prospectively the clinical efficacy of Gorei-San for the treatment of oligohydramnios.
Pregnant mothers who delivered between January 1, 2012 and December 31, 2013 and who experienced oligohydramnios at our hospital were enrolled in this study.
Miyamura previously demonstrated that a single deepest pocket (SDP) measurement of <3 cm is the most useful criterion for oligohydramnios in the prediction of fetal distress,7) therefore, oligohydramnios was defined as SDP of less than 3 cm in the present study.
A total of 51 subjects were enrolled, and the subjects were divided into two groups: those who opted for Gorei-San treatment and those who opted for follow-up without medication. SDP changes were compared between these groups. The placement of participants into the treatment or non-treatment group was based on the preference of the patient, and assignment was not random.
A total of 27 pregnant mothers whose SDP values had decreased to less than 3 cm (oligohydramnios) were treated with Gorei-San and were enrolled in the study as the treated group. These pregnant mothers did not receive any other treatment during pregnancy.
A total of 24 pregnant mothers whose SDP values had decreased to less than 3 cm and were follow-up without any treatment as a medication during pregnancy and were enrolled in the study as the untreated group (control subjects).
To measure the amniotic fluid volume of each subject, the SDP was measured with ultrasonic equipment.8) The first measurements of SDP in both groups were obtained when the SDP had decreased to less than 3 cm (before treatment in the treated group; start point), and the second measurements of both groups were obtained at the next regular examination (end point). Gorei-San treatment were continued until delivery. If SDP became equal or greater than 3 cm at endpoints, it defined cure. Authors and sonographers were not blinded to the use of Gorei-San at start and endpoints. However, these measurements were performed carefully not to introduce bias.
The exclusion criteria were as follows: multiple pregnancies, clear fetal deformities, the presence of fetal hydrops, and the presence of pregnancy induced hypertension (defined as one of the following findings after 20 weeks of gestation: albuminuria levels greater than 300 mg/day; diastolic blood pressure greater than 90 mmHg; or systolic blood pressure greater than 140 mmHg9)).
This study was approved by the Ethics Committee of Akiyama Memorial Hospital. All patients provided written informed consent.
Gorei-San treatmentThe ingredients of Gorei-San are presented in Table 1. The prescribed dose was 7.5 g/day.
| Common Name | Latin Name | Volume |
|---|---|---|
| Alisma Rhizome | Alismatis Rhizoma | 4.0 g |
| Atractylodes Lancea Rhizome | Atractylodis Lanceae Rhizoma | 3.0 g |
| Chuling | Polyporus | 3.0 g |
| Hoelen | Hoelen | 3.0 g |
| Cinnamon Bark | Cinnamomi Cortex | 1.5 g |
“TsumuraTJ-17: It contains 2 g of powdered extract medicine manufacturing with above-mentioned rate in 7.5 g”.
SPSS Statistical Software, version 14.0 for Windows (SPSS Inc., Chicago, IL, USA), was used for all statistical analyses. The distribution of each SDP in the treated and untreated groups were checked by the Jarque-Bera (JB) test, and the rejection risk (P) was calculated. If the P values were less than 0.05, the distribution was considered non-normal. The JB test revises P by Monte Carlo simulation when there is a few sample sizes. P=0.05 when there are many samples is equivalent to about P=0.12 in number of samples 20–30. Central values are shown as the median±quartile if a variable was non-normally distributed. Others are shown as the mean±standard deviation (SD).
Mann-Whitney U test were used to compare the subjects’ baseline characteristics. Wilcoxon signed-rank tests were used to compare the start points and end points of the SDP of the two groups. Null hypothesis rejection risks (P) were calculated, and P values less than 0.05 were considered statistically significant.
Group differences in Caesarean section frequency, as well as odds ratios and confidence intervals, were calculated. If the value 1 was not included in the confidence interval, a significant difference was indicated.
If SDP became equal or greater than 3 cm at endpoints, it defined cure. The cure ratio of treated and untreated groups was compared by the Fisher’s exact test. Null hypothesis rejection risks (P) were calculated, and P values less than 0.05 were considered statistically significant.
The baseline characteristics, gestational ages at the start and end points, intervals between the start and end points for the subjects, and other factors in the 2 groups (the treatment group and the untreated group) are presented in Table 2; no significant differences were detected.
| Groups | Untreated | Treated | P (t) | P (U) |
|---|---|---|---|---|
| Number | 24 | 27 | ||
| Age | 29.0±4.7 | 29.2±5.7 | 0.31 | 0.66 |
| Nulliparity | 14 (58%) | 16 (59%) | — | — |
| Length (cm) | 157.9±6.1 | 158.4±6.4 | 0.35 | 0.91 |
| Weight (kg) | 56.9±10.3 | 57.8±9.6 | 0.34 | 0.68 |
| Numbers of C/S | 2 | 3 | — | — |
| Vacuum extraction | 1 | 1 | — | — |
| Neonatal distress | 0 | 0 | — | — |
| PH of umblical blood | 7.29±0.11 | 7.32±0.10 | 0.16 | 0.33 |
| Weeks of delivery | 40.05±0.84 | 39.72±1.05 | 0.12 | 0.29 |
| Weight of baby (g) | 3,003±417 | 3,009±293 | 0.26 | 0.55 |
| Start point (weeks of gestation) | 37.33±2.99 | 36.9±3.98 | 0.33 | 0.99 |
| Interval to endpoint (day) | 7.67±3.1 | 7.48±4.51 | 0.33 | 0.64 |
| Interval to delivery (day) | 11.4±4.1 | 12.3±4.3 | 0.24 | 0.52 |
| SDP range at SP (cm) | 1.6–2.9 | 1.6–2.9 | — | — |
| SDP<2 cm at SP | 1 (4.1%) | 5 (18.5%) | — | — |
| SDP range at EP (cm) | 1.1–3.6 | 2.0–4.8 | — | — |
| SDP<2 cm at EP | 4 (16.7%) | 0 (0%) | — | — |
| 24 | 27 |
Data are expressed as mean±SD.
C/S: delivered by cesarean section.
Interval to delivery (days between endpoint and delivery)
Interval to endpoint (days between startpoint and endpoint)
Neonatal distress: Apgar score<7.
P (U): Mann-Whitney U-test.
P (t): Two sample t-test.
SDP range at SP: Range of single deepest pocket (cm) at start point.
SDP range at EP: Range of single deepest pocket (cm) at end point.
SDP<2 cm at SP: Number and rate% of sever ologohydramnios at start point.
SDP<2 cm at EP: Number and rate% of sever ologohydramnios at end point.
Weight: before pregnancy.
In a pairwise comparison of Caesarean section frequency between the untreated and Gorei-San treated groups, the odds ratio was 0.818, whereas the confidence interval was 0.125 to 5.34. This difference was not statistically significant.
Figure 1 presents the individual changes in SDP in the treated group at the start and end points (after treatment with Gorei-San). SDP increased to 3.15±0.62 cm after treatment with Gorei-San from a start point of 2.37±0.41 cm (when the SDP values had fallen below 3 cm).
Changes in the single deepest pocket (SDP) in the treated group.
Data are expressed as means±SD.
End point: after treatment with Gorei-San
Jaque-Bera test of the distribution of end point SDP was P=0.363, normally distributed.
Jaque-Bera test of the distribution of start point SDP was P=0.374, normally distributed.
Start point: before treatment with Gorei-San.
The P-values of the Wilcoxon signed-rank test were P<0.001.
The individual changes in SDP in the untreated group during the same period are presented in Figure 2. No significant changes were detected between the start point 2.5±0.3 (medians±quartile) cm and the end point 2.63±0.68 cm.
Changes in the single deepest pocket (SDP) in the untreated group.
Data are expressed as means±SD at the end point.
Data are expressed as medians±quartile at the start point.
Jaque-Bera test of the distribution of end point SDP was P=0.257, normally distributed.
Jaque-Bera test of the distribution of start point SDP was P=0.0026, non-normally distributed.
Start point SDP values were not normally distributed (P<0.05).
The Wilcoxon signed-rank test was not significant.
In 17 of 27 cases, the SDP became equal to or greater than 3 cm following therapy. The therapeutic cure ratio was 63%. In 8 of 24 cases, the SDP became equal or greater than 3 cm following end point measurement. The spontaneous cure ratio was 33%. The therapeutic effect of the Gorei-San were examined. There were significant differences between treated groups and untreated groups (Table 3).
| Treated | Untreated | P value | |
|---|---|---|---|
| Proportion of Cure | 17/27 (63%) | 8/24 (33%) | P=0.025 |
We previously demonstrated that the Gorei-San is effective in the treatment of gestational edema. During edematous treatment, Gorei-San exhibits a diuretic effect. After edema improvement, Gorei-San does not exhibit a compulsory diuresis effect. These effects were ascertained by examining the change in the expectant mother’s weight. Gorei-San appeared to normalize the gross volume of the body water. At the same time, Gorei-San improved the symptoms associated with the stagnation of the water at the level of the head, including vertigo and headache. We speculate that Gorei-San normalized the distribution of water throughout the body.4) Thus, because Gorei-San influenced the distribution of water throughout the body, it was expected to influence the amniotic fluid.
For example, the risk of oligohydramnios rises when pregnant mothers are given nonsteroidal anti-inflammatory agents,10) or angiotensin-II receptor antagonists,11) during the 2nd or 3rd trimesters. Any medicine that contributes to oligohydramnios in this way is a contraindication. Thus, the influence of any medicine on amniotic fluid quantity should be examined, and the safety of a medicine in pregnant mothers also needs to be examined.
Many obstetricians use amnion pocket or single deepest pocket for measurement of amniotic fluid quantity, especially less than normal amount of amniotic fluid. These definitions of oligohydramnios are less than 2 cm. The fetal well being is on risky condition. The hypoamnion is the front step of the oligohydramnios. The hypoamnion needs a strict follow-up. It is desirable to treat in the hypoamnion to prevent an oligohydramnios. But to date, effective treatments of hypoamnion have not been established. Miyamura previously demonstrated that a single deepest pocket (SDP) measurement of <3 cm is the most useful criterion for oligohydramnios in the prediction of fetal distress.7) In the present study, we have defined as oligohydramnios in the case of SDP of less than 3 cm and began the treatment. We demonstrated that the reduction in amniotic fluid quantity was often apparent in the presence of edema after 36 weeks of gestation. The treatment of gestational edema by Gorei-San prevented the reduction of amniotic fluid quantity. Gorei-San did not exhibit any side effects related to reductions in amniotic fluid. Conversely, Gorei-San retrospectively appeared to exhibit a therapeutic effect on oligohydramnios.6)
Transabdominal amnioinfusion is a useful procedure to reduce complications that result from oligohydramnios. Importantly, as this procedure increases the latency period, it may be useful in preterm pregnancies, where prolonging the duration of the pregnancy may result in better perinatal outcomes by improving important factors that influence survival, including increased birth weight. However, transabdominal amnioinfusion may cause chorioamnionitis or premature rupture of the membranes at the time of amnioinfusion.12)
Maternal hydration therapy improves the quantity of amniotic fluid.13) However, increased water intake (1,500–2,500 ml/day) and fluid-infusions (1,500 ml/day) aggravate edema and may increase the risk of pre eclampsia. Thus, to date, effective treatments for oligohydramnios have not yet been established.
On the other hand, purified herbal extract of Salvia miltiorrhiza can improve the amniotic fluid volume in pre-term oligohydramnios by improving uteroplacental circulation. The therapeutic effects on oligohydramnios were speculated to include improvement in the placental-blood circulation and control of membrane permeability at the placenta.14) So it was speculated that some types of herbal medicines have been effective for the treatment of oligohydramnios.
Membrane permeability is controlled by expression of aquaporin (AQP). AQP is the water channel of membranes that control the membrane permeability without electrolyte participation.15) Salvia miltiorrhiza could regulate AQP3 expression in human amniotic epithelial cells. Salvia miltiorrhiza showed more obvious effects on the AQP3 expression level in human amniotic epithelial cells of oligohydramnios human term pregnancies.16)
There are reports that an ingredient of Gorei-San modulates AQP expression. Atractylodes macrocephala modulates AQP2 expression in the inner medullary collecting duct of mouse kidneys.17) Sclederma of Poria cocos (hoelen) modulates AQP2 expression in rat kidneys.18) Sclerotia of Polyporus umbellatus modulates the expression of AQP1, AQP2, and AQP3 in rat kidneys.19) We speculate that an ingredient of Gorei-San modulates AQP expression in the placenta and improve the amniotic fluid volume by improving uteroplacental circulation as herbal extract of Salvia miltiorrhiza.
Thus the study of AQP is progressing. Although to date, the study how Gorei-San’s ingredients modulate on the AQP expression of the placenta, isn’t yet accomplished. We expect that the mechanism of Gorei-San efficacy will be soon made clear.
None of the patients treated with Gorei-San therapy in our studies suffered skin eruptions or other symptoms indicative of allergic reactions, aggravation of fatigue and similar symptoms indicative of electrolyte anomalies or dehydration, or other noteworthy severe side effects.4,6)
Figure 1 show that Gorei-San treatment for oligohydramnios significantly increased the quantity of amniotic fluid at the end of pregnancy over a short period of time (average 7.48 days) in this study.
Purified herbal extract of Salvia miltiorrhiza also useful to treat oligohydramnios but daily infusion of 500 ml,14) the ambulatory-treatment isn’t easy to manage, although is low degree, have same risk as maternal hydration therapy.13)
On the other hand the risk of Gorei-San treatment is low. This treatment is easy to manage, and the benefit-cost ratio is high.
The present study demonstrated that Gorei-San therapy is useful in the treatment of oligohydramnios. Although further studies are needed to confirm our findings, we believe that this new application of Gorei-San for the treatment of oligohydramnios is a clinically applicable strategy.
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