|Year : 2020 | Volume
| Issue : 16 | Page : 74-80
Uterine exteriorization versus In situ repair of the uterine incision at cesarean delivery
Malachy Emeka Ayogu1, Teddy E Agida1, Yabaji Aliyu Isah1, BI Adeka1, Nathaniel Ketare2
1 Department of Obstetrics and Gynecology, University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria
2 Department of Obstetrics and Gynecelogy, Federal Medical Centre, Birninkebbi, Nigeria
|Date of Submission||13-Sep-2019|
|Date of Decision||27-Jan-2020|
|Date of Acceptance||21-May-2020|
|Date of Web Publication||26-Nov-2020|
Dr. Malachy Emeka Ayogu
Department of Obstetrics and Gynecology, University of Abuja Teaching Hospital, Gwagwalada, Abuja
Source of Support: None, Conflict of Interest: None
Background: Opinion appears divided on uterine exteriorization for uterine repair at Cesarean delivery. The available evidence appears insufficient to aid policy pronouncement of routine uterine exteriorization for repair of the lower segment incision. Aim: To evaluate the effect of extra-abdominal versus intra-abdominal repair of the uterine incision at Cesarean delivery. Materials and Methods: One hundred and seventy women were randomly assigned to groups; Group “A” had their repairs after exteriorization while Group “B” had in situ repair. It compared the effects of exteriorization of the uterus and in situ repair during Cesarean delivery. Outcome measures included: Intraoperative blood loss, postpartum anemia, transfusion rate, mean operative time, postoperative wound infection rate, nausea and vomiting, The data were analyzed using Statistical Package for the Social Sciences, version 20. Results: A data were available for analysis in 169 women that completed the study (exteriorization group [n = 85] and in situ repair group [n = 84]).Except for the statistically higher incidence of nausea/vomiting among the women that had exteriorization when compared with their counterpart whose uteri were repaired in situ(10.6% vs. 2.4%; P = 0.031). There were no statistically significant differences between the two groups in terms of the mean preoperative hematocrit (34.8% vs. 35.7%), P = 0.830; the mean postoperative hematocrit level (30.8 ± 4.7 vs. 30.8 ± 4.9), P = 0.958; the mean estimated blood loss (575 ml vs. 577 ml), P = 0.942; the postpartum anemia (35.3% vs. 26.2%), P = 0.200; transfusion rate was (15.3% vs. 17.9%), P = 0.518; operation time (57.5 vs. 53.2 min), and the surgical site infection rate (1.2% vs. 1.2%), P = 0.993. Conclusion: Exteriorization and in situ repair of uterine incisions had similar outcome but, the former is associated with significant higher incidence of nausea/vomiting.
Keywords: Cesarean delivery, exteriorization, in situ, repair
|How to cite this article:|
Ayogu ME, Agida TE, Isah YA, Adeka B I, Ketare N. Uterine exteriorization versus In situ repair of the uterine incision at cesarean delivery. N Niger J Clin Res 2020;9:74-80
|How to cite this URL:|
Ayogu ME, Agida TE, Isah YA, Adeka B I, Ketare N. Uterine exteriorization versus In situ repair of the uterine incision at cesarean delivery. N Niger J Clin Res [serial online] 2020 [cited 2021 Jan 24];9:74-80. Available from: https://www.mdcan-uath.org/text.asp?2020/9/16/74/301646
| Introduction|| |
Cesarean section rate had increased worldwide both in developed and developing countries in the last three decades Regardless of substantial improvements in the safety of anesthesia and surgery, mortality and morbidity are higher in Cesarean sections compared to vaginal deliveries.,
Uterine exteriorization at Cesarean section though popular among the obstetricians, its safety remains a matter of debate. Proponents believe that exteriorization of the uterus ease repair of the uterine incision by not only improving access, but also decreases blood loss by compressing of uterine blood vessels, whereas others opined that it is associated with intra-operative complications.,
Nonetheless, there are relatively few randomized trials to support many of the commonly used techniques in performing a Cesarean section.,
In study done by Hershey and Quilligan, it was found that exteriorization of the uterus was associated with a relative decrease in postoperative hematocrit when compared to in situ repair. Uterine exteriorization at Cesarean section was thus suggested by the authors and should rather not be condemned.,,,
A previous Cochrane review that addressed this issue was published in 2004 and amended in 2006; found that, with the exception of lower febrile morbidity and extended hospital stay in the exteriorized group, there were no differences in outcomes between the groups. They inferred that the available evidence was insufficient to draw conclusions about which method offers more advantages and they suggested that more research is needed.
Other researchers have been making effort at addressing this unanswered question including a number of large randomized trials.,,,
Orji et al. noted significant reductions in intraoperative blood loss, number of analgesic dose and duration of hospital stay in the uterine exteriorisation group as compared to those in the nonexteriorisation group but, no significant difference in operating time, febrile morbidity and operating time.
A recent report by El-Khayat et al. revealed that surgery duration was significantly longer in exteriorization group than in situ group and findings were similar to the report by Ozba.
No clinically significant differences between the two groups in terms of mean hematocrit differences, intraoperative blood loss, perioperative nausea, tachycardia and postoperative analgesic doses was noted by Gode et al. However, the mean operative time and surgical site infection rate were significantly lower in the in situ repair group just as was reported from Iran.
Thus, there is yet to be accepted strict pronouncement on the need or otherwise of uterine exteriorization at uterine repair during Cesarean section to the best of the researchers' knowledge. Whether or not it should be adopted as a routine remains an unanswered question.
The aim of this study, therefore, was to evaluate if in situ repair or repair after exteriorization confers any advantage over the other in terms of intraoperative blood loss, postpartum anemia rate, blood transfusion rate, duration of operation, rate of surgical site infection and the rate of development of nausea and vomiting in our setting.
If one of these techniques is associated with less maternal morbidity, this could have an important impact on women's health in view of the large number of Cesarean section performed in Nigeria each year.
| Subjects and Methods|| |
The study location was at the Department of Obstetrics and Gynecology, University of Abuja Teaching Hospital, Abuja, Nigeria. It is a 350-bed tertiary health facility. This tertiary public health institution serves as a referral centre and provides specialized health care services to the inhabitants of Nigeria's Federal Capital Territory and its neighboring states.
The study was a prospective, randomized and single blinded study conducted from April 2016 to December 2016 comparing uterine exteriorization with in situ repair of uterine incision at Cesarean section and the study population comprised of all women undergoing primary Cesarean section during the study period.
It involved all the pregnant women undergoing primary Cesarean section at 35 weeks of age and above and had given consent to the study. Those cases randomized to exteriorization whose uterus cannot be delivered were assigned to in situ group.
Pregnant women whose pregnancy was complicated by antepartum hemorrhage, placental previa, abruptio placentae, anemia, multiple pregnancy, uterine rupture were excluded as well as risk factors for surgical site infection like chorioamnionitis, prolonged labor, prolonged rupture of membrane and diabetes. Also, those with previous laparotomy or Cesarean section were excluded. In addition, those who were slated for Cesarean section under general anaesthesia were excluded.
Following approval to conduct the study from the Hospital's Research and Ethical Committee, awareness about this study was created among hospital staffs at the maternity, labor and postnatal wards at University of Abuja Teaching Hospital Abuja. All eligible pregnant women undergoing primary Cesarean section for various indications were counseled on the objectives of the study and consent was obtained after ensuring that the prospective subject fully understood the concept of the research.
The women were randomly assigned to group in a 1:1 ratio; (exteriorization [n = 85] and in situ repair group [n = 85]). Group “A” were women who had uterine repair after exteriorization of the uterus and Group “B” were those who had repair insitu. Randomization was by computer generated random sampling method and the randomized allotments were kept secure in opaque sealed envelopes. Consecutive participants were asked to draw 1 allocation slip from the sealed envelope without possibility of replacement. The files of the participant were tagged for identification. Clinical data for each participant was collected and recorded on a data sheet for analysis.
Whenever an elective or emergency primary Cesarean section is planned, it is jointly discussed with the patient and her spouse. If elective, the patients are admitted about 24 h before the surgery. A general examination of the patient is carried out to assess the state of health of the patient with emphasis on abdominal examination.
A signed consent is obtained from the patient or from the spouse or very close relative after anesthetic review of the patient.
Three other senior registrars, one from the three other teams in the department who are proficient in carrying out the two techniques were recruited into the study as research assistants during the study period. They were fully informed of the objectives of the study. There are total of four teams in the department.
After delivery of the baby, the Green-Armytage focerps was applied to the lower segment and the placenta was extracted. Following standard procedure for Cesarean section, the uterus was delivered out of the abdominal wound laid on top of the abdominal skin and the uterine incision sutured in two layers using polyglactin suture size 2. After completion of double layer closure of the uterine incision and achievement of satisfactory hemostasis, the uterus is then replaced into the abdominal cavity and abdomen closed in layers with the skin apposed in subcuticular technique using polyglactin (vicryl 2/0).
The procedure was the same as in Group A except that the uterus was not exteriorized and was repaired while in the abdominal cavity.
All the women had the following procedures perfumed: Preoperative hematocrit levels estimation, peri-operative bladder catheterization, under spinal anesthesia, lower segment Cesarean section through Pfannenstiel incision, repair of the uterine incision in two layers, intra-operative antibiotics using a combination of metronidazole and amoxicillin-clavulanic acid and continued for 7 days postoperatively and 2nd postoperative day hematocrit levels estimation.
Blood loss was measured by weighing the number of packs soaked plus blood in suction bottle.
The estimated blood loss and operation time (from skin incision to skin closure) were recorded by the anesthetists who were aware of the ongoing study.
The primary outcome measure was postpartum anemia. The secondary outcome measures were intraoperative blood loss, need for blood transfusion, mean operation time, perioperative nausea/vomiting and surgical site infection rate.
Following surgery, urinary catheter was removed after 24 h of surgery. The surgical wounds in all patients were inspected on postoperative day 3 and thereafter all wounds were left open. The women were discharged between postoperative day 4 and day 7 except where postoperative complications necessitate extended hospital stay.
Surgical site infection was described as wound in which there are indurations and swelling of the wound edges with discharge of pus or wound dehiscence.
The data were compared using Fisher's exact test, Chi-square and Student's t-test. The variables analyzed using Statistical Package for the Social Sciences package Windows 20.0 version (IBM, Chicago, IL, Delaware, USA) include sociodemographic characteristics, postpartum anemia, blood transfusion rate, mean estimated blood loss, mean operation time, perioperative nausea/vomiting and surgical site infection rate. Intention to treat analysis was used. The odd ratios and 95% confidence interval were obtained where appropriate. P < 0.05 were considered statistically significant.
| Results|| |
One hundred and sixty nine out of 170 women were available for analysis; exteriorization (n = 85) and in situ repair group (n = 84). There was no protocol violation between the two groups and the data for each group was available for analysis.
Based on the sociodemographic and reproductive characteristics [Table 1], the results revealed mean maternal age of (29.0 ± 5.6 vs. 30.0 ± 5.5), mean parity (2.0 ± 1.7 vs. 2.0 ± 1.8), mean gestational age at delivery (38.7 ± 2.8 vs. 38.5 ± 2.0), booking status, (booked, 68 vs. 66 and unbooked, 17 vs. 18) for exteriorization and in situ group respectively.
With regard to the category of Cesarean delivery [Table 2], 20% of the women had an elective delivery and 80% had an emergency delivery in the exteriorization group, while 31% were elective deliveries and 69% were emergency deliveries among the in situ group.
Considering the cadre of surgeons that undertook the surgeries [Table 3]; most of the surgeries were done by senior registrars in both groups; 89.4% % in exteriorization group and 95.2% in situ group. Consultants carried out only 10.6% of the surgeries in exteriorization group and 4.8% of the surgeries amongst the in situ group.
The outcome measures are shown on the [Table 4]; the mean preoperative hematocrit in exteriorization versus in situ uterine repair was (34.8% vs. 35.7%), while the mean postoperative hematocrit level (30.8 ± 4.7 vs. 30.8 ± 4.9) was noted in exteriorization and in situ repair respectively.
Also, the mean estimated blood loss was (575 ml vs. 577 ml) in exteriorization and in situ repair respectively. Sixteen (17.9%) women in the in situ group were transfused blood as against 13 (15.3%) in the exteriorization group. The postpartum anemia was 30 (35.3%) in the exteriorization group and 22 (26.2%) in situ group, The other maternal outcome measures of operation time (57.5 vs. 53.2 min) was recorded in exteriorization versus in situ respectively while, the surgical site infection rate of 1.2% was recorded in both groups, however, the incidence of nausea/vomiting was (10.6% vs. 2.4%) in exteriorization versus in situ respectively.
| Discussion|| |
In this present study an attempt has been made to compare the following outcome measures between the two groups: Intraoperative blood loss, postoperative anemia, blood transfusion rate, duration of surgery, frequency of surgical site infection and incidence of nausea/vomiting among the randomized women in University of Abuja Teaching Hospital.
It is important to highlight that existing studies on the subject matter lacked standardization of anesthetic management, which play a key role in the development of intraoperative complications and in this study efforts were made to standardized as many as possible therapeutic variables between the two groups.
It is worthy of note that based on the sociodemographic and reproductive characteristics, there were no statistically significant differences found between the two groups. These results are similar to other studies in another population.
We found no significant difference between the two groups regarding the cadre of surgeons. Most of the surgeries were done by senior registrars in both groups. This finding may not be unconnected with the fact that primary Cesarean sections are usually considered less complicated procedures that could be readily assigned to be undertaken by the residents.
Concerning intraoperative blood loss, the estimated blood loss between the two methods of uterine repair, exteriorization in comparison with in situ (575 ± 220.3 ml vs. 577 ± 214.4 ml) was not statistically significant (P = 0.942). This result is virtually similar to (625 ml vs. 653 ml) found in the work done by Coutinho et al. as well as findings by Nasir et al. Nasir et al. recruited women with primary Cesarean sections as well as previous Cesarean sections and this could create confounding results unlike the present study that dwelt only on primary Cesarean deliveries. It is also corroborated by a study done by Edi-Osagie et al. However, it is at variance with the studies done in other populations where it was noted that uterine repair by exteriorization may significantly reduce blood loss during surgery.,, Also, Wahab et al. made similar observation of reduced blood loss with exteriorization, but in their study, they employed both regional and general anesthesia and this may have led to inaccuracies. In this study, no correlation could be found between the development of increased or reduced blood loss in either of the two surgical techniques. In the same vein, transfusion rate in this present study was (15.3% vs. 17.9%), P = 0.518. These findings were not consistent with the work done by Ezechi et al., who documented that in situ group had approximately four-fold blood transfusion rate higher compared to the exteriorization group. They were, however, silent on the choice of anesthesia for their patients. It is also worthy of note that reduction in hematocrit was less in women who had an elective Cesarean section than if the operation was performed in labor. This finding is possibly due to the edema and distention of the lower segment and the use of oxytocic drugs in labor which may lead to postpartum uterine atony. However, the number of emergency and elective Cesarean deliveries in both groups were comparable and the difference was not statistically significant, P = 0.072.
With regard to postpartum anemia, our findings revealed more anemic women amongst the exteriorization group; 30 (35.3%) versus 22 (26.2%), however, this result did not suggest a strong association between postpartum anemia and technique of uterine repair as it was not statistically significant. Contrary to this result, a study done in Lagos revealed that number of women with postpartum anemia was significantly more in the in situ group compared to the exteriorization group. Interestingly, there were good correlations between visually estimated blood loss and postoperative hematocrit following Cesarean deliveries.
Concerning operation time, this study revealed no clinically significant difference between the exteriorization and in situ uterine repair groups for mean operation time, though operation time was marginally shorter when the uterus is repaired in situ (57.5 ± 16.4 vs. 53.2 ± 20.1 min), P = 0.131. This result is consistent with findings in other studies., However, contrary to these findings the present study did not agree with other studies which found a significant shorter operation time in in situ uterine repair compared to exteriorization,, Gode etal., though had a larger sample size, documented their findings based on a retrospective study unlike ours that was a prospective study. Typically, a prospective design has been ranked higher in the hierarchy of evidence. Our findings also differed with some other studies which demonstrated that operation times were significantly reduced in exteriorization group compared to the in situ group.,
With respect to surgical site infections, the incidences were low and similar between the groups with complication rate of 1.2% in both groups. This could be attributable to good aseptic techniques and prophylactic use of potent and the same antibiotics for all the patients according to the research protocol. The affected patient in the exteriorization group had a relatively prolonged surgical exposure due to difficulty encountered during the repair of a lateral uterine extension while the patient involved in the in situ group had primary posthemohrrage and severe postoperative anemia. These observations were not surprising and it corroborated the findings by Dhar who noted higher risks of wound infections among those women who were anemic than those without anemia. The literature also indicates that prolonged duration of operation is associated with the risk of surgical site infection. This result of similar infection rate between the two groups are consistent with findings in other studies,,, however, it did not agree with findings in other studies that documented lower risks of surgical site infections in the in situ uterine repair.
According to this results the incidence of perioperative delivery nausea/vomiting was significantly higher when uterine repairs were performed exteriorized, compared with in situ (10.6%) and (2.4%) respectively, and there was a statistically significant different between the two, P < 0.031. These findings of strong association between occurrence of nausea/vomiting and uterine exteriorization during uterine repair have been reported in several other studies.,,,,,, This findings however, were not in conformity with the other literature reports which showed no statistically significant differences between the two in terms of development of nausea and vomiting.,, Different factors have been implicated in the etiology of intraoperative nausea and vomiting. Hypotension and visceral pain are among the most important one and are to large extent preventable. Patients in the exteriorization group exhibited nausea/vomiting immediately after exteriorization and then again at time the required repositioning of the uterus into the abdominal cavity.
| Conclusion|| |
Exteriorization and in situ repair of uterine incisions have similarity in associated intraoperative blood loss, postoperative anemia, duration of operation time and surgical site infections but the former is associated with significant higher incidence of nausea/vomiting. The choice of either method may therefore be at the surgeon's discretion and familiarity provided the complaints of nausea/vomiting can be monitored and addressed accordingly. The findings could not categorically affirm the superiority of one over the other and perhaps, a large multi centre trials may be necessary to address the dilemma of which is to be considered superior.
Proper regional anesthetic techniques and prophylactic use of anti emetics can reduce the occurrence of nausea/vomiting where exteriorization is the chosen option.
Additional robust randomized controlled trial that will focus specifically on nausea and vomiting as primary outcome measures may need to be conducted to validate the finding above.
Strengths of the study
Standardization of the anesthetic procedures in our patients is one of the highlight.
Standardization of antibiotics, choice of skin incision and choice of primary Cesarean deliveries in all the patients.
The study was single centre randomized trial. Perhaps, if it were to be a multicenter trial, it may produce a more quality evidence to addressing the question in search of answer which of the two methods (insitu repair or repair at exteriorization) is associated with least morbidity.
Inter observer variation may be a limitation as the procedures were not carried out by the researcher alone.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Villar J, Valladares E, Wojdyla D, Zavaleta N, Carroli G, Velazco A, et al
. Caesarean delivery rates and pregnancy outcomes: The 2005 WHO global survey on maternal and perinatal health in Latin America. Lancet 2006;367:1819-29.
Ezechi OC, Kalu BK, Njokanma FO, Nwokoro CA, Okeke GC. Uterine incision closure at cesarean morbidity and mortality in a private hospital in Lagos. Nigeria Trop J Obstet Gynaecol 2002;19:97-100.
Das A. Cesarean delivery on maternal request. Saudi J Health Sci 2013;2:141-5. [Full text]
Stock RJ, Skellion H. Fatal pulmonary embolism occurring two hours after exteriorization of the uterus for repair at cesarean section. Mil Med 1985;150:549-51.
James A. Greenberg Alexis®
O™ C-section retractor. Rev Obstet Gynecol 2008;1:142-3.
Alexander JW, Fisher JE, Boyajiam M, Palmquist J, Morris JM. The influence of hair removal methods on wound infections. Arch Surg 1983;118:347-52.
Cheng WX, Allan BC, Haim AA. The effect on perioperative bleeding of placental extraction from an exteriorized uterus during cesarean section. J Obstet Gynecol Can 2014;36:384-90.
Hershey DW, Quilligan EJ. Extra abdominal uterine exteriorization at cesarean section. Obstet Gynecol 1978;52:189-92.
Nasir H, Imram R, Naz I. Uterine exteriorization compared with in situ
repair at ceserean delivery. J Rawalpinds Med Coll JRMC 2011;15:110-2.
Wahab, MA, Karantzis P, Eccersley PS, Russell IF, Thompson JW, Lindow SW. A randomised controlled study of uterine exteriorisation and in situ
repair at cesarean section. Br J Obstet Gynecol 1999;106:903-6.
Walash CA, Walash SR. Extra-abdominal vs. intra-abdominal uterine repair at cesarean delivery. A meta-analysis. Am J Obstet Gynecol 2009;200:625.
Siddique M, Goldszmidt E, Ella S, Kingdom J, Windrim R, Carvalho JC. Complication of exteriorized compared with in situ
repair at caesarean delivery under spinal anaesthesia: A randomized controlled trial. Obstet Gynecol 2007;110:570-5.
Coutinho IC, Ramos de Amorim MM, Katz L, Bandeira de Ferraz AA. Uterine exteriorization compared with in situ
repair at cesarean delivery: A randomized controlled trial. Obstet Gynecol 2008;111:639-47.
Nafisi S. Influence of uterine exteriorization versus in situ
repair on post-cesarean maternal pain: A randomized trial. Int J Obstet Anesth 2007;16:135-8.
Orji EO, Olaleye AO, Loto OM, Ogunniyi SO. A randomised controlled trial of uterine exteriorisation and non-exteriorisation at caesarean section. Aust N
Z J Obstet Gynaecol 2008;48:570-4.
El-Khayat W, Elsharkawi M, Hassan A. A randomized controlled trial of uterine exteriorization versus in situ
repair of the uterine incision during cesarean delivery. Int J Gynaecol Obstet 2014;127:163-6.
Ozbay K. Exteriorized versus in situ
repair of the uterine incision at cesarean delivery: A randomized controlled trial. Clin Exp Obstet Gynecol 2011;38:155-8.
Gode F, Okyay RE, Saatli B, Ertugrul C, Guclu S, Altunyurt S. Comparison of uterine exteriorization and in situ
repair during cesarean sections. Arch Gynecol Obstet 2012;285:1541-5.
Sakhavar N, Teimoori B, Mirteimoori M. In situ
compared with exteriorized uterine repair at cesarean delivery. Iran J Reprod Med IJRM 2011;9:37-41.
Ezechi OC, Edet A, Akinlade H, Gab-Okafor CV, Herbertson E. Incidence and risk factors for cesarean wound infection in Lagos. BMC Res Notes 2009;2:186-9.
Bushra Z, Farrukh S, Azra N, Aqeel S. Exteriorisation or In situ
repair comparison of options for uterine repair at caesarean delivery. Pak Armed Forces Med J 2016;66:570-3.
Edi-Osagie EC, Hopkin RE, Ogbo VO, Lockhat-Clegg F, Ayeka M, Akpala WO, et al
. Uterine exteriorization at cesarean section: Influence on maternal morbidity and mortality. Br J Obstet Gynecol 1998;105:1070-8.
George RB, Boyd JC, Habib AS. Uterine exteriorization compared with in situ
repair for cesarean delivery: A systemic review and meta-analysis. Can J Anesth 2015;62:1209-20.
Das KK, Ali J, Sourabia N. Comparative study between exteriorization of uterus during cesarean section versus in situ
repair. Sch J App Med Sci 2015;3:2724-8.
Ezechi OC, Kalu BK, Njokanma FO, Nwokoro CA, Okeke GC. Uterine incision closure at cesarean section: A randomized comparative study of intraperitoneal closure and closure after temporary exteriorization. West Afr J Med 2005;24:1-3.
Shuja A, Akhtar S, Khan S. Comparison of intra operative and postoperative complication of intra-abdominal versus extra-abdominal uterine repair at cesarean delivery. Pak Armed Forces Med J 2015;65:191-4.
Das S, Das P, Mahli A, Biswas S. Comparative study of uterine repair during cesarean section: Intra-abdominal vs. exteriorization of uterus. J Dent Med Sci 2015;14:5-8.
Dhar H. A study of post-cesarean section wound infections in a region of referral Hospital Oman. Sultan Qaboos Univ Med J 2014;14:E 211-7.
Bottoms SF, Rosen MG, Sokol RJ. The increase in caesarean birth rate. N
Engl Med 1980;302:559-63.
Zafar B, Shehzad F, Naseem A, Safdar A. Exteriorization or in situ
; comparison of options for uterine repair at caesarean section delivery. Pak Armed Forces Med J 2016;66:570-3.
[Table 1], [Table 2], [Table 3], [Table 4]