Appendicitis is the most common general surgery problem during pregnancy. Its diagnosis represents a challenge, as its classic clinical presentation is not always present, its common symptoms are nonspecific and often associated with normal pregnancy, and the gravid state may mask the clinical picture. Also, obstetric causes may obscure the diagnosis, and physical examination of the pregnant patient may be difficult as a result of the gravid uterus and its effect on displacing the appendix within the abdomen. Furthermore, biochemical and laboratory indicators used to support the diagnosis of appendicitis may be unreliable during pregnancy. General principles of pathophysiology, diagnosis, workup, and management for appendicitis during pregnancy follow the same pattern as in non-pregnant patients and are revised and discussed in the present review.
The cause of appendicitis is the obstruction of its lumen. Fecal stasis and fecaliths most commonly cause this phenomenon; however, lymphoid hyperplasia, neoplasms, fruit and vegetable material, ingested barium, and parasites are other possible agents responsible for the obstruction.
Maternal morbidity and mortality following appendectomy are low and comparable to non-pregnant women. The risk of fetal loss during uncomplicated appendectomies is 2%, however, in the presence of generalized peritonitis, and peritoneal abscess, the fetal loss may increase to 6%. In the presence of free perforation, the risk of fetal loss may rise to 36%.
The incidence of preterm labor due to appendectomy is 4%, and 11% in complicated cases. The association between negative appendectomy to preterm labor and fetal loss is 10% and 4%, respectively.
The obstruction of the appendix results in increased intraluminal pressure and distention due to ongoing mucus secretion as well as gas production by bacteria that lie within the appendix; this results in progressive impairment of the venous drainage, causing first mucosal ischemia, followed by full-thickness ischemia, and ultimately perforation of the appendiceal wall. Stasis distal to the obstruction allows bacterial overgrowth within the appendix, resulting in the release of a larger bacterial inoculum to the peritoneal cavity in cases of perforated appendicitis.
Intraluminal bacteria within the appendix are similar to those found in the colon; therefore, antibiotic therapy should include coverage for both gram-negative and gram-positive bacteria as well as anaerobes.
Distention of the appendix is responsible for the initial visceral and vague abdominal pain often described by the affected patient. The pain typically does not localize to the right lower quadrant until the tip becomes inflamed and irritates the adjacent parietal peritoneum or perforation occurs, resulting in localized peritonitis.
In the classic scenario of appendicitis, the patient first describes periumbilical pain that migrates to the right lower quadrant. Following the onset of pain, anorexia, nausea, vomiting, fever may develop. Non-classic symptoms include malaise, heartburn, flatulence, constipation, and diarrhea.
The abdominal examination usually reveals tenderness, rebound tenderness, and involuntary guarding on palpation of the right lower quadrant. The location of the tenderness is classically over the McBurney point, which is located one-third the distance between the anterior superior iliac spine (ASIS) and the umbilicus. Diffuse peritonitis or abdominal wall rigidity is strongly suggestive of appendiceal perforation.
When the appendix is in the retrocecal region, pain is usually described as dull rather than localized, and it will be elicited more likely by rectal or vaginal examination than by abdominal examination. Accordingly, a pelvic appendix may cause tenderness below the McBurney point, urinary frequency, dysuria, tenesmus, and diarrhea.
Several signs have been described to help in the diagnosis of appendicitis. Some of them are the Rovsing sign (presence of right lower quadrant pain on palpation of the left lower quadrant), the obturator sign (right lower quadrant pain on internal rotation of the hip), and the psoas sign (pain with extension of the ipsilateral hip).
Gravid women are less likely to have a classic presentation of appendicitis than age-matched nonpregnant women, especially in the late stages of pregnancy; however, the majority of pregnant women will still present abdominal pain, close to the McBurney point. As the location of the appendix may migrate cephalad with the enlarging uterus, pain may be described in the right flank or even in the right upper quadrant as pregnancy advances.
Abdominal tenderness may be less prominent during pregnancy because the gravid uterus lifts the anterior abdominal wall away from the inflamed appendix. In the pregnant patient, the uterus may also inhibit contact between the omentum and the inflamed appendix.
As opposed to most of the non-pregnant patients with appendicitis who have a preoperative leukocytosis (greater than 10000 cells/microL) and a neutrophilic predominance, leukocytosis as high as 16900 cell/microL may be a normal finding in pregnant women, and during labor the count may rise as high as 29000 cells/microL, with a slight neutrophilic predominance. Therefore the presence of leukocytosis is an unreliable indicator in the workup of appendicitis.
Microscopic hematuria and pyuria may occur when the inflamed appendix is close to the bladder or ureter, but these findings are not specific and generally reported in less than 20 percent of patients.
Mild elevations in serum bilirubin (total bilirubin over 1.0 mg/dL) have been described as a marker for appendiceal perforation (70% sensitivity and 86% specificity). However, clinicians should not use this finding alone as a diagnostic tool.
An elevated c-reactive protein level occurs in appendicitis, but it is a nonspecific sign of inflammation. (citation needed)
Due to the risks of negative appendectomies, routine imaging is recommended in all pregnant patients with suspected appendicitis, to obtain accuracy in diagnosis. The initial study of choice is ultrasound with graded compression of the right lower quadrant starting at the point of maximal tenderness and scanning between the border of the pelvis, iliac artery, and psoas muscle. Ultrasound has the advantage of being pregnancy-safe and easily available. Ultrasound is also helpful for providing information on fetal well-being and obstetric causes of abdominal pain. The criteria for US diagnosis are the same as in the nonpregnant patient; the inflamed appendix appears enlarged (greater than 6 mm), immobile, and noncompressible. However, ultrasound is a user-dependent tool, and the presence of the gravid uterus during pregnancy will reduce ultrasound sensitivity (78%) and specificity (83%).
If ultrasound findings are inconclusive, magnetic resonance imaging (MRI) without gadolinium contrast remains a safe alternative for confirmation or exclusion of appendicitis during pregnancy, as it provides good soft-tissue resolution and lacks ionizing radiation, with excellent sensitivity and specificity that remains intact in the pregnant patient. Routine use of MRI in pregnant patients reduces the negative appendectomy rate by almost 50% and does not increase the rate of perforation. For these reasons, when available, the liberal use of MRI in pregnant patients suspected to have acute appendicitis is recommended. When MRI is not available or is available only on a limited basis, the decision about any delay in appendectomy to obtain an MRI study requires all available clinical and imaging information available, as the potential consequences associated with both negative appendectomy and appendiceal perforation are severe. MRI has been shown to perform relatively well in a few limited retrospective studies ranging from 97 to 100% sensitive.
Although debatable, the use of CT scanning might be permissible when ultrasound is inconclusive and MRI not available. The use of CT scanning reduces the rate of negative appendectomy significantly compared to clinical assessment alone or combined with ultrasound imaging, and some authors conclude that it should be used if ultrasound findings are equivocal. Arguably, the amount of radiation during a limited CT scan is below the threshold required to cause fetal malformations, and most cases of appendicitis in pregnancy occur in later stages of pregnancy when organogenesis is already complete. If it is decided to use CT during pregnancy for inconclusive cases, care should be taken to perform a study as limited as possible with no intravenous administration of contrast material.
Usually, the curative treatment of acute appendicitis is appendectomy. Perioperative antibiotic treatment should provide coverage for Gram-negative and Gram-positive bacteria (usually with a second-generation cephalosporin) and coverage for anaerobes (clindamycin or metronidazole). Delaying surgical intervention for more than 24 hours after the symptoms first appear increases the risk of perforation.
If an appendiceal perforation is present, the management will depend on the nature of the perforation. A free perforation that causes the dissemination of pus and fecal material into the peritoneal cavity will likely result in a very ill-looking and septic patient with an increased risk of preterm labor and delivery and fetal loss. These patients require urgent laparotomy for appendectomy with irrigation and drainage of the peritoneal cavity.
Nonpregnant patients that present with a long duration of symptoms (more than five days) and have findings of a contained perforation (phlegmon or abscess) are usually treated initially with antibiotics, intravenous fluids, and bowel rest. Since the appendiceal process has already been walled-off, most of these patients will present a good clinical response to nonoperative management. Immediate surgery in these patients correlates with increased morbidity because of the presence of adhesions and inflammation that requires extensive dissection that may lead to injury of adjacent structures. There may be the development of serious postoperative complications such as abscesses or enterocutaneous fistulae, requiring reoperation for more extensive resections and the need for colostomies. Therefore, in these patients, a nonoperative approach is a reasonable option as long as they are not ill-appearing. Although there is solid evidence to support this approach to contained perforation in nonpregnant individuals, the evidence regarding pregnant women is only sparse . For this reason, when a walled-off perforation of the appendix occurs in a pregnant woman, it is advisable to proceed with caution and monitor these patients in the hospital to avoid sepsis, preterm labor, or fetal loss. Information regarding interventional drainage of appendiceal abscesses in pregnant patients is not available.
The two mainstream approaches for appendectomy are laparoscopic and open techniques. No randomized trials have been performed to suggest that one technique is better than another; therefore, the choice of technique should have its basis on the patient's clinical status and preferences, gestational age, and the surgeon's experience level. However, current guidelines state that laparoscopic appendectomy is the standard of care in pregnant patients as it is safe, allows easier identification of the variable location of the appendix, and offers an opportunity for an evaluation of the abdomen for any associated pathologic process.
Some of the recommendations for the laparoscopic technique are modifications that include a slight left lateral positioning of the patient (during the second half of pregnancy), the use of an open-access approach (Hasson technique) for initial trocar placement to avoid injury to the gravid uterus, limiting intraabdominal insufflation pressure to less than 12 mmHg, and adjustment of port position for fundal height.
When performing an open appendectomy technique in a pregnant woman, a transverse incision is made at the point of maximal tenderness, and not necessarily at McBurney's point. When the diagnosis is less certain, a lower midline vertical incision may be a possible option since it allows exposure of the abdomen for diagnosis and treatment of other surgical conditions that mimic appendicitis.
The differential diagnosis of suspected acute appendicitis during pregnancy includes disorders typically considered in non-pregnant individuals. Therefore the clinician should consider cecal diverticulitis, Meckel diverticulitis, acute ileitis, inflammatory bowel disease (Crohn and ulcerative colitis), renal colic, and urinary tract infections. Gynecological conditions in the differential diagnosis include tubo-ovarian abscess, pelvic inflammatory disease, ruptured ovarian cyst, ovarian, and fallopian tube torsion.
Also, and more importantly, pregnancy-related causes of lower abdominal pain, fever, leukocytosis, nausea/vomiting, and changes in bowel function need to be considered, such as placental abruption, uterine rupture, preeclampsia, HELLP (hemolysis, elevated liver function tests, low platelets) syndrome. During early pregnancy, ectopic pregnancy requires exclusion. Also, consider round ligament syndrome as a possibility. This condition is a common cause of mild right lower quadrant pain in early pregnancy.
Untreated appendicitis can develop into severe complications with high morbidity, appendiceal perforation and will manifest as one of two outcomes: free perforation, or contained or "walled-off" perforation. Open perforations cause the dissemination of pus and fecal material into the peritoneal cavity, which will likely result in a very ill-looking and septic patient with an increased risk of preterm labor and delivery and fetal loss. Contained perforations can cause peritoneal abscess or phlegmon that forms around a burst appendix and require extended antibiotic treatment and likely drainage.
Complications of the surgery itself can be extensive and include infections (postoperative peritoneal abscess), bleeding, and damage to adjacent structures.
Any suspected case of appendicitis in pregnancy requires an ob-gyn consultation to rule out obstetric and gynecological causes of pain as well to establish the well being of the fetus before and after anesthesia.
The appendix is a thin pouch hanging down from the large intestine. When it gets infected and inflamed, it causes a condition called appendicitis. This condition can be very painful, and if left untreated, very serious, as the appendix can burst, causing a life-threatening infection. Fortunately, appendicitis, when caught on time, can be easily treatable.
Appendicitis usually first presents as severe abdominal pain. This pain can start near the belly button and then move to the lower right side. Other usual symptoms include loss of appetite, nausea, and vomiting, and elevated fever. However, a wide variety of symptoms can be present, including upset stomach, irregular bowel movements (constipation or diarrhea). During pregnancy, identification of the picture and its diagnosis might be challenging as many of these symptoms are present during a normal pregnancy.
A clinician or clinician team will make the diagnosis of appendicitis through a thorough interview and physical examination. If necessary, they will order special tests such as an ultrasound or MRI to provide more precise information as to the source of the abdominal pain. It is crucial that during this time, a gynecologist should examine the pregnant patient.
When any of the symptoms listed above present, it is imperative to seek medical care. The risk for the appendix to burst rises after the first 24 hours of the onset of the symptoms; therefore, early identification and treatment is of great importance and will directly impact on the results of the patient's health and pregnancy.
The treatment for appendicitis is surgery to remove the appendix that can be done in two ways: open surgery during which the appendix will be removed through a single incision that is large enough through which to pull the appendix or laparoscopic surgery in which thin instruments and a camera are introduced to the abdomen through a few small cuts to perform the surgery, and appendix removal occurs through one of the small openings.
Treatment for a complicated or a "burst" appendix will probably be more complicated than it would be if it had not burst, as all the material spilled out of the appendix needs to be washed away. If an appendix did burst, but a few days have passed, it is likely that the body already formed a pocket around the appendix blocking the infection. In this case, treatment consists of antibiotic therapy and close monitoring and not having surgery right away. However, surgery will be eventually needed.
Treatment for simple appendicitis without surgery is not the standard of care, but it is conceivable to do so. However, the chances of appendicitis returning are high. Patients and their physicians should discuss alternatives, including risks for both the patient and the pregnancy itself.
Acute appendicitis during pregnancy poses a diagnostic dilemma. These patients may exhibit non-specific signs and symptoms such as vomiting, nausea, and leukocytosis. The cause of acute abdominal pain may be due to a myriad of diagnoses, including gynecological, obstetrical, gastrointestinal, urological, metabolic, and vascular etiologies. While the physical exam may reveal that the patient has a surgical abdomen, the cause is difficult to know without proper imaging studies. The disorder is best managed by an interprofessional team to ensure prompt diagnosis and treatment.
The general surgeon should always be involved in the care of pregnant patients with suspected appendicitis. However, it is essential to consult with an obstetrician and gynecologist to rule out problems related to the pregnancy, and any other specialist according to clinical findings and suspicion.
The nurses are also a vital member of the interprofessional group, as they will monitor the patient's vital signs. The nurses should refrain from administering pain medications until the surgeon has examined the patient.
In the postoperative period, the pharmacist will ensure that the patient is on the right analgesics, antiemetics, and appropriate antibiotics, perform a medication record check for drug interactions and verify dosing on all drugs administered.
The radiologist also plays a vital role in determining the cause.
The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) guidelines state that laparoscopic appendectomy is safe in pregnancy and is the standard of care in pregnant patients. These are evidence-based guidelines that are reviewed by an interprofessional expert committee. The current guidelines have been developed after an exhaustive review of current medical literature from peer-reviewed journals to determine the appropriateness of radiological imaging and treatment procedures by the committee. In cases where evidence is not definitive or minimal, expert opinion from the specialist may be utilized to recommend the type of imaging or treatment. [Level 1] With the unique challenges of appendicitis in pregnancy, an interprofessional team approach is the best path for guiding successful outcomes for both mother and unborn child. [Level 5]
|||Brown JJ,Wilson C,Coleman S,Joypaul BV, Appendicitis in pregnancy: an ongoing diagnostic dilemma. Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2009 Feb; [PubMed PMID: 18513191]|
|||Prystowsky JB,Pugh CM,Nagle AP, Current problems in surgery. Appendicitis. Current problems in surgery. 2005 Oct; [PubMed PMID: 16198668]|
|||Andersson RE,Lambe M, Incidence of appendicitis during pregnancy. International journal of epidemiology. 2001 Dec; [PubMed PMID: 11821329]|
|||Zingone F,Sultan AA,Humes DJ,West J, Risk of acute appendicitis in and around pregnancy: a population-based cohort study from England. Annals of surgery. 2015 Feb; [PubMed PMID: 24950289]|
|||Silvestri MT,Pettker CM,Brousseau EC,Dick MA,Ciarleglio MM,Erekson EA, Morbidity of appendectomy and cholecystectomy in pregnant and nonpregnant women. Obstetrics and gynecology. 2011 Dec; [PubMed PMID: 22105255]|
|||McGory ML,Zingmond DS,Tillou A,Hiatt JR,Ko CY,Cryer HM, Negative appendectomy in pregnant women is associated with a substantial risk of fetal loss. Journal of the American College of Surgeons. 2007 Oct; [PubMed PMID: 17903726]|
|||Babaknia A,Parsa H,Woodruff JD, Appendicitis during pregnancy. Obstetrics and gynecology. 1977 Jul; [PubMed PMID: 876520]|
|||Chen CY,Chen YC,Pu HN,Tsai CH,Chen WT,Lin CH, Bacteriology of acute appendicitis and its implication for the use of prophylactic antibiotics. Surgical infections. 2012 Dec; [PubMed PMID: 23231389]|
|||Wray CJ,Kao LS,Millas SG,Tsao K,Ko TC, Acute appendicitis: controversies in diagnosis and management. Current problems in surgery. 2013 Feb; [PubMed PMID: 23374326]|
|||Lee SL,Walsh AJ,Ho HS, Computed tomography and ultrasonography do not improve and may delay the diagnosis and treatment of acute appendicitis. Archives of surgery (Chicago, Ill. : 1960). 2001 May; [PubMed PMID: 11343547]|
|||Birnbaum BA,Wilson SR, Appendicitis at the millennium. Radiology. 2000 May; [PubMed PMID: 10796905]|
|||Chung CH,Ng CP,Lai KK, Delays by patients, emergency physicians, and surgeons in the management of acute appendicitis: retrospective study. Hong Kong medical journal = Xianggang yi xue za zhi. 2000 Sep; [PubMed PMID: 11025842]|
|||House JB,Bourne CL,Seymour HM,Brewer KL, Location of the appendix in the gravid patient. The Journal of emergency medicine. 2014 May; [PubMed PMID: 24484624]|
|||Mourad J,Elliott JP,Erickson L,Lisboa L, Appendicitis in pregnancy: new information that contradicts long-held clinical beliefs. American journal of obstetrics and gynecology. 2000 May; [PubMed PMID: 10819817]|
|||Hodjati H,Kazerooni T, Location of the appendix in the gravid patient: a re-evaluation of the established concept. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2003 Jun; [PubMed PMID: 12767564]|
|||Popkin CA,Lopez PP,Cohn SM,Brown M,Lynn M, The incision of choice for pregnant women with appendicitis is through McBurney's point. American journal of surgery. 2002 Jan; [PubMed PMID: 11869697]|
|||Oto A,Srinivasan PN,Ernst RD,Koroglu M,Cesani F,Nishino T,Chaljub G, Revisiting MRI for appendix location during pregnancy. AJR. American journal of roentgenology. 2006 Mar; [PubMed PMID: 16498125]|
|||Pates JA,Avendanio TC,Zaretsky MV,McIntire DD,Twickler DM, The appendix in pregnancy: confirming historical observations with a contemporary modality. Obstetrics and gynecology. 2009 Oct; [PubMed PMID: 19888038]|
|||Cunningham FG,McCubbin JH, Appendicitis complicating pregnancy. Obstetrics and gynecology. 1975 Apr; [PubMed PMID: 1121371]|
|||McGee TM, Acute appendicitis in pregnancy. The Australian [PubMed PMID: 2698614]|
|||Sivanesaratnam V, The acute abdomen and the obstetrician. Bailliere's best practice [PubMed PMID: 10789262]|
|||Mahmoodian S, Appendicitis complicating pregnancy. Southern medical journal. 1992 Jan; [PubMed PMID: 1734528]|
|||Coleman C,Thompson JE Jr,Bennion RS,Schmit PJ, White blood cell count is a poor predictor of severity of disease in the diagnosis of appendicitis. The American surgeon. 1998 Oct; [PubMed PMID: 9764707]|
|||Tehrani HY,Petros JG,Kumar RR,Chu Q, Markers of severe appendicitis. The American surgeon. 1999 May; [PubMed PMID: 10231216]|
|||Thompson MM,Underwood MJ,Dookeran KA,Lloyd DM,Bell PR, Role of sequential leucocyte counts and C-reactive protein measurements in acute appendicitis. The British journal of surgery. 1992 Aug; [PubMed PMID: 1393485]|
|||Lurie S,Rahamim E,Piper I,Golan A,Sadan O, Total and differential leukocyte counts percentiles in normal pregnancy. European journal of obstetrics, gynecology, and reproductive biology. 2008 Jan; [PubMed PMID: 17275981]|
|||KUVIN SF,BRECHER G, Differential neutrophil counts in pregnancy. The New England journal of medicine. 1962 Apr 26; [PubMed PMID: 14460983]|
|||Bailey LE,Finley RK Jr,Miller SF,Jones LM, Acute appendicitis during pregnancy. The American surgeon. 1986 Apr; [PubMed PMID: 3954275]|
|||Sand M,Bechara FG,Holland-Letz T,Sand D,Mehnert G,Mann B, Diagnostic value of hyperbilirubinemia as a predictive factor for appendiceal perforation in acute appendicitis. American journal of surgery. 2009 Aug; [PubMed PMID: 19306980]|
|||Khandelwal A,Fasih N,Kielar A, Imaging of acute abdomen in pregnancy. Radiologic clinics of North America. 2013 Nov; [PubMed PMID: 24210441]|
|||Parks NA,Schroeppel TJ, Update on imaging for acute appendicitis. The Surgical clinics of North America. 2011 Feb; [PubMed PMID: 21184905]|
|||Kereshi B,Lee KS,Siewert B,Mortele KJ, Clinical utility of magnetic resonance imaging in the evaluation of pregnant females with suspected acute appendicitis. Abdominal radiology (New York). 2018 Jun [PubMed PMID: 28849364]|
|||Kearl YL,Claudius I,Behar S,Cooper J,Dollbaum R,Hardasmalani M,Hardiman K,Rose E,Santillanes G,Berdahl C, Accuracy of Magnetic Resonance Imaging and Ultrasound for Appendicitis in Diagnostic and Nondiagnostic Studies. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2016 Feb [PubMed PMID: 26765503]|
|||Ames Castro M,Shipp TD,Castro EE,Ouzounian J,Rao P, The use of helical computed tomography in pregnancy for the diagnosis of acute appendicitis. American journal of obstetrics and gynecology. 2001 Apr; [PubMed PMID: 11303204]|
|||Lazarus E,Mayo-Smith WW,Mainiero MB,Spencer PK, CT in the evaluation of nontraumatic abdominal pain in pregnant women. Radiology. 2007 Sep; [PubMed PMID: 17709829]|
|||Bickell NA,Aufses AH Jr,Rojas M,Bodian C, How time affects the risk of rupture in appendicitis. Journal of the American College of Surgeons. 2006 Mar; [PubMed PMID: 16500243]|
|||Yilmaz HG,Akgun Y,Bac B,Celik Y, Acute appendicitis in pregnancy--risk factors associated with principal outcomes: a case control study. International journal of surgery (London, England). 2007 Jun; [PubMed PMID: 17509502]|
|||Vasireddy A,Atkinson S,Shennan A,Bewley S, Surgical management of appendicitis remains best option during pregnancy. BMJ (Clinical research ed.). 2012 May 22; [PubMed PMID: 22619205]|
|||Korndorffer JR Jr,Fellinger E,Reed W, SAGES guideline for laparoscopic appendectomy. Surgical endoscopy. 2010 Apr; [PubMed PMID: 19787402]|
|||Al-Fozan H,Tulandi T, Safety and risks of laparoscopy in pregnancy. Current opinion in obstetrics [PubMed PMID: 12151826]|
|||Yumi H, Guidelines for diagnosis, treatment, and use of laparoscopy for surgical problems during pregnancy: this statement was reviewed and approved by the Board of Governors of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), September 2007. It was prepared by the SAGES Guidelines Committee. Surgical endoscopy. 2008 Apr; [PubMed PMID: 18288533]|
|||Choi JJ,Mustafa R,Lynn ET,Divino CM, Appendectomy during pregnancy: follow-up of progeny. Journal of the American College of Surgeons. 2011 Nov; [PubMed PMID: 21856183]|
|||Sachs A,Guglielminotti J,Miller R,Landau R,Smiley R,Li G, Risk Factors and Risk Stratification for Adverse Obstetrical Outcomes After Appendectomy or Cholecystectomy During Pregnancy. JAMA surgery. 2017 May 1; [PubMed PMID: 28114513]|