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View of Fetal and neonatal outcomes after synergism between sildenafil citrate and nifidipine in patients with threatened preterm labour

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Fetal and neonatal outcomes after synergism between sildenafil citrate and nifidipine in patients with threatened

preterm labour

Yousef Abou- Elwan El-Sayed 1, Walid Abdallah Abdel- Salam1 , Basem Hamed .M.D2, Reda Hamed Abd El-Aziz Ahmed.Msc3

1 Professor of obstetrics and gynecology , Faculty of medicine, Zagazig University, Egypt

2 Lecturer of obstetrics and gynecology , Faculty of medicine, Zagazig University.

3Department, Obstetrics and Gynecology, Faculty of Medicine, Zagazig University, Egypt Corresponding author: Basem M. Hamed, Lecturer OB/GYN, Faculty of Medicine, Zagazig

University, Zagazig, Egypt, E-mail: [email protected] Abstract

Objective: The aim of the work is to detect the risk of adding sildenafil citrate to nifedipine for tocolysis on the fetal and neonatal outcomes in patients with threatened preterm labour.

Methods: This Included 192 pregnant women who suffered from threatened preterm labor. They were divided into two groups, group (A) included 96 cases who received Nifedipine only and group (B) included 96 cases who received Nifedipine with Sildenafil Citrate. Patients were be randomly allocated to receive either (1) Nifedipine 20 mg orally (stat dose), followed by 10 mg orally every 6 hours at the same time as oral administration of Sildenafil Citrate 20 mg at 8- hourly intervals or (2) Nifedipine alone. Medications continued for 48–72 hours. During therapy, fetal heart rate monitoring was performed every 30 minutes during the first 4 hours following the start of therapy, then every 4 hours during the rest of the treatment. At delivery, all data regarding labour, neonatal birth weight, neonatal APGAR score, neonatal respiratory distress, need for incubator and neonatal death, all were documented and analysed.

Results: there was no statistically significant difference between the two studied groups as regard age, BMI, gestational age on admission, cervical length on admission, cervical dilatation on admission, no statistically significant difference between the two studied groups in fetal heart rate . There is statistically significant difference between the studied groups regarding neonatal birth weight (higher in combined nifedipine and sildenafil group). Also was no statistically significant difference between the two studied groups as regard fetal outcome and the occurrence of neonatal infection but with more neonatal respiratory distress among the nifedipine with sildenafil group.

Conclusions: combination between nifedipine and sildenafil citrate have a better fetal outcome according to neonatal birth weight but with poor outcome according to neonatal respiratory distress in comparison to nifedipine alone in patients with threatened preterm labour.

Key words: nifedipine, preterm labour, sildenafil citrate, fetal outcome, neonatal outcome.

INTRODUCTION

Preterm labour (PTL) is defined as any delivery after 20 weeks and before the end of 37 weeks’ gestation. Despite attempts aimed to decrease its incidence, statistics done in 2010 revealed that 14.9 million preterm deliveries were born and of these 1.6 million very preterm

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were born (before 32 weeks’). So it is important to establish a protocol for management of such cases [1,2].

Mode of action of nifidipine as calcium channel blockers is to decrease contractility of the muscle by decreasing calcium entering inside the cells. Nifedipine was more potent and safer than ritodrine In one meta-analysis [3], while advised it as the drug of choice for threatened PTL in another meta-analysis [4].

On the other hand Sildenafil citrate (SC) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)– specific phosphodiesterase (PDE)-5. SC is a smooth muscle relaxant acting by preventing second messenger cGMP degradation through phosphodiesterase. The cGMP relaxant action in smooth muscle, is done by the down regulation action of the kinase G protein that results in decreasing the calcium level in the smooth muscle cells and so it decreases the calcium sensitivity to the contractile elements [5].

Unfortunately, all tocolytic medications have side effects and while severe morbidity in the infants is rare, any harm deserves close scrutiny [6]. Nifedipine and other calcium channel blockers have been communicated with maternal myocardial infarction and hypotension as well as fetal bradycardia and demise [7].

PATIENTS AND METHODS

This interventional Study was conducted at Obstetrics and Gynecology Department, Faculty of Medicine, Zagazig University from April 2019 to February 2020. Included 192 pregnant women who suffered from threatened preterm labor. They were divided into two classes, class (A) included 96 cases who received Nifedipine only and class (B) included 96 cases who received Nifedipine with sildenafil. Inclusion criteria included singleton pregnancy between 28 and 34 weeks with intact membranes. Labour was diagnosed when painful regular uterine contractions (3-5 contractions in 10 minutes for more than one hour) associated with cervical changes.

Exclusion criteria included twin pregnancy, dilated cervix more than 4 cm, with or without bulging of the membranes from the cervix into the vagina, preterm premature rupture of membranes, any clinical sign of chorioamnionitis, any cause of Nifedipine and/or sildenafil citrate contraindication, Nifedipine allergy and unwillingness to be involved in this study, chronic maternal disease (like chronic renal impairment, chronic hypertension, and pregestational diabetes mellitus).

Written consent was obtained from all cases, this study was done by the research ethical committee of Faculty of Medicine, Zagazig University. The work was carried out for studies involving humans in accordance with the World Medical Association's Code of Ethics (Helsinki Declaration).

Randomization was done in a 1:1 ratio with a computerized random number table into two classes. ultrasound examination was done to all the study participants before randomization where gestational age and other ultrasound parameters were evaluated. Antenatal corticosteroid in the form of 24 mg total dose dexamethasone was given to all the women except it was given before. The patients then were randomly allocated in the 2 groups (group 1) received nifedipine 20 mg orally (stat dose), followed by 10 mg every 6 hours by oral administration at the same time as well as sildenafil citrate 20 mg oral administration at 8-hourly intervals or (group 2) recieved nifedipine alone. Drugs continued for 48–72 hours.

Evaluation of the fetal heart rate was done during the treatment and repeated every thirty minutes in the first four hours, and in the rest of the treatment it is done every four hours. if the uterine contractions stopped, the patients were asked to follow up after one week. Before discharge, the

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patients were asked to have vaginal progesterone as a prophylaxis (Prontogest 400 mg; Marcyrl pharmaceutical) to inhibit recurrent PTL.

At delivery, all the information about the baby was documented and analysed including neonatal birth weight, neonatal respiratory distress, neonatal APGAR score, need for incubator and neonatal death.

Statistical Analysis

Data were checked, entered and analyzed using SPSS version 23 for data processing. Data were expressed as number and percentage for qualitative variables and mean + standard deviation (SD) for quantitative one. The results of the "t" value was then checked using student "t" table at degree of freedom (df=n1 +n2 – 2) to find out the level of significance (p-value).

Paired T-test:- to compare quantitative normally distributed data before and after treatment.

The threshold of significance was fixed at 5% level (P-value). The smaller the P value obtained the more significant are the results.

RESULTS

This study included 192 pregnant women who suffered from threatened preterm labor.

They were divided into two classes, class (A) included 96 cases who received Nifedipine only and class (B) included 96 cases who received Nifedipine

Table (1) The baseline characteristics of cases

Variable Group (A)

No. (96)

Group (B)

No. (96) t-test P

Age (years) mean ± SD (range)

30.6±4.9 (19-38)

31.3±6.1

(20-41) 0.877 0.382

BMI mean ± SD (range)

27.7±4.6 (20-36)

28.6±5.7

(19-39) 1.204 0.23

Gestational age on admission (weeks)

mean ± SD (range)

30.7±2.2 (27-34)

30.4±2.1 (27-34)

0.967 0.335

Cervical length (TVU/S)

mean ± SD (range)

2.6±0.5 (1.6-3.4)

2.7±0.6 (1.5-3.5)

1.255 0.211

table (1) Showed there was no statistically significant difference between the two studied groups as regard age, BMI, gestational age on admission, cervical length on admission, cervical dilatation on admission.

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Table (2): Comparison between the two studied groups as regards fetal heart rate and weight:

Variable Group (A) No. (96)

Group (B)

No. (96) t-test P

Fetal heart rate mean ± SD (range)

150.5±13.4 (110-166)

153.4±11.4 (115-166)

-2.9 0.108 Neonatal birth

weight (Kg) mean ± SD (range)

2.8±0.3 (1.4-3.9)

2.6±0.4 (1.3-3.7)

3.919 <0.001*

Table 2, Showed that there was no statistically significant difference between the two studied groups in fetal heart rate . There is statistically significant difference between the studied groups regarding neonatal birth weight (higher in combined nifedipine and sildenafil group)

Figure (1): Simple bar chart showing comparison between the studied groups regarding neonatal birth weight

Table (3):Compare between the two studied groups as regards fetal outcome

Group (A) Group (B) test

χ² P

No(96) % No(96) %

Normal 74 77.1 62 64.6

2.69 0.101

distressed 16 16.7 26 27.1

Death Intranatal

Postnatal

6 0.0

6

6.3 0.00

6.3

8 2 6

8.3 1.1 6.2

Table 3, Showed that there was no statistically significant difference between the two studied groups as regard fetal outcome.

0 0.5 1 1.5 2 2.5 3 3.5

Nifedipine with Sildanefil group

Nifedipine group

Neonatal birth weight (kg)

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Figure (2): Multiple bar chart for comparing the studied groups regarding fetal outcome Table (3): Comparison between the two studied groups as regards neonatal infection and

neonatal respiratory distress

Group (A) Group (B) test

χ² P

No(96) % No(96) %

Neonatal infection

No 80 83.3 84 87.5

0.669 0.413

Yes 16 16.7 12 12.5

Neonatal respiratory distress

Absent 66 68.7 82 85.4

0.376 0.006*

present 30 31.3 14 14.6

Table 4, Showed that there was no statistically significant difference between the two studied groups as regard the occurrence of neonatal infection, but there was statistically significant difference between the two studied groups in neonatal respiratory distress with more neonatal respiratory distress among the nifedipine with sildenafil group

Figure (3): Multiple bar chart for comparing the studied groups regarding neonatal respiratory distress

0.0%

20.0%

40.0%

60.0%

80.0%

Normal Distressed Death Nifedipine with Sildanefil group Nifedipine group

0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

Absent Present

Nifedipine with Sildanefil group Nifedipine group

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DISCUSSION

Preterm labour, is birth before 37 weeks of gestation, is the single most serious determinant of adverse infant outcomes, in terms of survival and quality of life. Globally, it is the leading cause of perinatal and neonatal mortality and morbidity [8]. Preterm offspring are particularly vulnerable to complications due to difficult respiration, difficulty in feeding, poor body temperature regulation and high risk of infection [9].

In this study there was no statistically significant difference between the two studied groups as regard age, BMI, gestational age on admission, cervical length on admission, cervical dilatation on admission.

In another study which was done from January 2015 to November 2016, randomization for 239 patient: from whom 121 in the SC and nifidipine group , while 118 in the nifedipine alone group; 94.6% of the patients (226) completed the study. According to parity, age, preterm labour history, BMI, gestational age, total days of admission, cervical length, nifedipine dose and progesterone compliance when the patient was discharged[10].

This study shows that there was no statistically significant difference between the two studied groups as regard fetal heart rate, fetal outcome and the occurrence of neonatal infection.

This study shows that there was statistically significant difference between the two studied groups in neonatal respiratory distress with more neonatal respiratory distress among the nifedipine with sildenafil group.

In a study by Maher et al [10], when SC was added, there was less NICU admission (31.4 versus 44.1%; P = 0.043), with less labour in the very preterm (from 28 to less than 32 weeks, 20.7 versus 38.1%; P = 0.003) with increase in the weight of the neonate (1900 versus 1500 g; P

= 0.018).

There is still no optimal dose of SC in cases with threatened PTL, however, the common used dose is 3 per 24 hours which is referred to the average concentration in the maternal plasma which is reached in sixty minutes with four hours as half-life (11), however during pregnancy the patient may be in need of a higher dose due to the change that happens in the volume of maternal plasma (12).

The vaginal route in this study was preferred for SC due to its high efficacy and safety also with less side effects (13),also to decrease the sequelae for the baby through the placenta.

The dose of SC used in the study was advised from pharmacokinetic data reported in a previous 2 studies (14).

About SC safety, there was no teratogenic or fetal cytotoxic effects for SC used in animals even in the high doses (15), even follow up in human detected no developmental problems for the babies (16). Even in the patients when SC was used in the 3rd trimester, the risk/ benefit for the babies and the mother was much better (10).

In a systematic review of experimental and clinical studies of sildenafil citrate for pre- term labour (15), The information was taken from: three in vitro studies, five studies did in experimental animal models, four studies on women with fertility and sterility disorders receiving 100 mg/day of sildenafil intravaginally, and two case reports of pregnant women who took sildenafil for the treatment of pulmonary hypertension. No evidence of teratogenicity was observed in the studies performed in mice, rats and dogs. Sildenafil increased fetal weight in rats.

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No abnormal fetal outcomes were detected in the two pregnant women with pulmonary hypertension receiving sildenafil late in their pregnancy.

In another systematic review of maternal tolerance and obstetric and perinatal outcome of sildenafil in pregnancy (17), Sixteen studies were included ( n = 165). Neonatal outcomes including nursery admission (67.3%, 35/52), Apgar scores <7 at 5 min (7.1%, 4/56), and cord arterial pH <7.1 (0%, 0/17) were reported. Stillbirths (4.3%, 3/69) and neonatal deaths (3.9%, 5/129) were comparable to SC groups. There were no congenital malformations (0%, 0/35).

CONCLUSION

Combination between nifedipine and sildenafil citrate have a better fetal outcome according to neonatal birth weight but with poor outcome according to neonatal respiratory distress in comparison to nifedipine alone in patients with threatened preterm labour.

REFERENCES

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2) van’ t Hooft J, Duffy JM, Daly M, Williamson PR, Meher S, Thom E, et al. A core outcome set for evaluation of interventions to prevent preterm birth. Obstet Gynecol 2016;127:49–58.

3) King JF, Flenady V, Papatsonis D, Dekker G, Carbonne B. Calcium channel blockers for inhibiting preterm labour; a systematic review of the evidence and a protocol for administration of nifedipine. ANZJOG 2003; 43 (3): 192–98.

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2000;131:871-74.

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8) Kinney MV, Lawn JE, Howson CP, Belizan J. 15 million preterm births annually: what has changed this year? Reproductive Health. 2012; 9: 28.

9) Escobar GJ, McCormick MC, Zupancic JAF, Coleman‐Phox K, Armstrong MA, Greene JD, et al. Unstudied infants: outcomes of moderately premature infants in the neonatal intensive care unit. Archives of Disease in Childhood Fetal and Neonatal Edition. 2006;91(4):F238-44.

10) Maher, M. A., Sayyed, T. M., & El‐Khadry, S. W. (2019). Expression of concern: Nifedipine alone or combined with sildenafil citrate for management of threatened preterm labour: a randomised trial. BJOG: An International Journal of Obstetrics & Gynaecology, 126(6), 729- 735.‏

11) McDonough PG. Safety data for sildenafil. Fertil Steril 2002;78(6): 1353–4.

12) Dunn L, Greer R, Flenady V, Kumar S. Sildenafil in pregnancy: a systematic review of maternal tolerance and obstetric and perinatal outcomes. Fetal Diagn Ther 2017; 41: 81– 8.

13) Dmitrovic R, Kunselman AR, Legro RS. Sildenafil citrate in the treatment of pain in primary dysmenorrhea: a randomized controlled trial. Hum Reprod 2013; 28: 2958–65.

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14) El-Far M, Hashem IMA. Novel biopharmaceutical use of sildenafil citrate in treatment of unexplained recurrent miscarriage: first longitudinal clinical study of 50 cases from Egypt.

World J Pharm Pharmaceut Sci 2014;3:63–86.

15) Villanueva-Garcia D, Mota-Rojas D, Hernandez-Gonzalez R, Sanchez- Aparicio P, Alonso- Spilsbury M, Trujillo-Ortega ME, et al. A systematic review of experimental and clinical studies of sildenafil citrate for intrauterine growth restriction and pre-term labour. J Obstet Gynecol.

2007; 27:255–9.

16) Premalatha HL, Raghupathi KMS, Srinivas DNB, Venkatesh V, Laxmi K. Study of effect of sildenafil citrate in pregnant women with intrauterine growth restriction/oligohydramnios. Int J Reprod Contracept Obstet Gynecol 2016; 5: 3094–7.

17) Dunn, L., Greer, R., Flenady, V., & Kumar, S. (2017). Sildenafil in pregnancy: a systematic review of maternal tolerance and obstetric and perinatal outcomes. Fetal diagnosis and therapy, 41(2), 81-88.‏

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