gynecology and obstetrics research - openventio publishersgynecology and obstetrics research open...
TRANSCRIPT
Gynecology and
Obstetrics ResearchOpen Journal
ISSN 2377-1542PUBLISHERS
| December 2015 | Volume 2 | Issue 4 |
Editor-in-ChiefGhassan M. Saed, PhD
Associate EditorsSteven R. Lindheim, MD, MMM
Chi Chiu Wang, MD, PhDParveen Parasar, DVM, PhD
www.openventio.org
Gynecology and obstetrics research
Open JournalISSN 2377-1542
Gynecol Obstet Res Open J
Table of Contents
1. Heterotopic Pregnancy: A Case Report of Retrospective Diagnosis Following Surgical Treatment
– Olukayode Akinlaja*
3. Nausea and Vomiting in Pregnancy-The Bump in the road of Motherhood
4. Heterotopic Pregnancy
5. Interactions of Immunomodulatory HLA-G with Immune Cells during Pregnancy and Endometriosis
2. Case Report of Unusual Stromal Luteinization in High-Grade Papillary Serous Carcinoma of the Ovary
– Solwayo Ngwenya*
– Parveen Parasar*
– Modupeola O. Samaila, C. James Sung, W. Dwayne Lawrence and M. Ruhul Quddus*
– Solwayo Ngwenya*
Mini Review
Short Communication
Case Report
Case Report
Opinion
80-81
85-88
89-92
93-95
82-84
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-117
Gynecol Obstet Res Open J
ISSN 2377-1542
Heterotopic Pregnancy: A Case Report of Retrospective Diagnosis Following Surgical TreatmentSolwayo Ngwenya*
Consultant Obstetrician & Gynaecologist, Mpilo Central Hospital, Bulawayo Matabeleland 00263, Zimbabwe
*Corresponding author: Solwayo Ngwenya, MBChB, DFSRH, MRCOG
Consultant Obstetrician & Gynaecologist Mpilo Central Hospital Bulawayo Matabeleland 00263 Zimbabwe E-mail: [email protected]
Article History:Received: August 14th, 2015Accepted: September 9th, 2015 Published: September 10th, 2015
Citation: Ngwenya S. Heterotopic pregnancy: a case report of retrospective diag-nosis following surgical treatment. Gynecol Obstet Res Open J. 2015; 2(4): 80-81.
Copyright: © 2015 Ngwenya S. This is an open access article distributed under the Creative Commons Attribution Li-cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the origi-nal work is properly cited.
Volume 2 : Issue 4Article Ref. #: 1000GOROJ2117
Case Report
Page 80
ABSTRACT
Introduction: Heterotopic pregnancy is a rare occurrence. Very few clinicians may come across heterotopic gestations during their careers. It is a difficult condition to diagnose. It can lead to maternal mortality. Case presentation: I present a case of a 27-year-old patient who presented to me with signs and symptoms of a ruptured ectopic pregnancy. Prompt laparotomy was done and a left tubal ectopic pregnancy was found with a 1.5 litres of hematoperitoneum. The patient requested pre-mature discharge from hospital and on follow-up turned out to be having a viable intrauterine pregnancy. A retrospective diagnosis of heterotopic pregnancy was then made.Conclusion: The diagnosis of a heterotopic pregnancy can be difficult to make. In this case where laboratory, radiological and blood transfusion services are not readily available, prompt surgery based on a clinical picture was life-saving and allowed the intrauterine pregnancy to progress.
KEYWORDS: Heterotopic pregnancy; Catastrophic hemorrhage; Maternal demise; Laparotomy.
INTRODUCTION
Heterotopic gestation defines the co-existence of both intrauterine gestation and an ectopic gestation commonly in the fallopian tube and uncommonly in the cervix or ovary.1,2 The incidence is estimated to be 1:30,000 in spontaneous pregnancies.3 Pelvic inflammatory disease is believed to one of the aetiological factors associated with ectopic gestations. It can also occur in patients without any risk factors.3 Heterotopic gestation can follow natural conception1 or assisted reproductive techniques like ovulation induction.4 It can occur up to 10-15% of all ectopic gestations following in vitro fertilisation.
CASE REPORT
A 27-year-old, para 1 gravida 2, was referred to me by a casualty officer. She was complaining of intermittent lower abdominal pains on and off for 2 weeks. She had done a pregnancy test and it was positive. She said that she was about 5 weeks pregnant. The pain worsened of late and she was now complaining of dizziness too. She was married and worked as a temporary primary school teacher. She had no significant past medical, surgical or gynecological history. Initial examination revealed a pulse of 51 b/min, BP 101/50, and a temperature 34 ºC. She was pale and with a very tense and tender lower abdomen. The cervical os was closed with slight blood on the glove and the uterus was bulky. She was resuscitated with crystalloid intravenous fluids and blood sent for X-match and full blood count. She was counselled on her condition and the need for prompt surgery. She asked me why I was going to operate her without doing any ultrasonography on her. I remarked that she was bleeding internally from a suspected tubal pregnancy, and that any delay would compromise her life. Thankfully she did agree and gave me the consent. Her results from the full blood count were Hb 9, WBC 11.2 and Platelet count 98.
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-117
Gynecol Obstet Res Open J
ISSN 2377-1542
Page 81
At laparoyomy, a 1.5 litres of hematoperitoneum was found with on-going hemorrhage from the fimbrial end of the left fallopian tube which had an ectopic gestational sac imbedded in it. A left salpingectomy was done and the abdomen was cleaned with saline. The specimen was sent for histological examination. Post-operatively the patient remained stable and did not need any blood transfusion. She recovered promptly and requested to go home on day 2 post-operatively. Hematinics and antibiotics were prescribed for her. She was instructed to rest at home and to come for review in a week’s time.
At review her histology results were now available and had confirmed a tubal ectopic gestation. Her wound was healing well and her next review was at 6 weeks post-operatively when we planned to discuss contraception and folic acid supplementation during her next pregnancy.
When she came at her 6 weeks review, she asked why her pregnancy test remained positive and her periods had not returned. I sent her for an ultrasound scan which revealed a viable intrauterine pregnancy of 15 weeks gestation. The diagnosis of heterotopic pregnancy was explained to her and she understood. Her pregnancy progressed well and she delivered vaginally at term a baby girl weighing 3000 g.
DISCUSSION
The diagnosis of heterotopic pregnancy is a very difficult one to make. Like all ectopic gestations, delay in the diagnosis may lead to catastrophic hemorrhage and maternal demise including the intrauterine fetus. The management of heterotopic pregnancy is the gold standard laparoscopy or Laparotomy.5 In cases where there is a combination of an intrauterine pregnancy demonstrated by ulstrasonography and severe abdominal pains, clinicians should consider diagnostic laparoscopy without uterine instrumentation or laparotomy. This case needed no further delay as her health was at risk. During Laparotomy, she was indeed found to be hemorrhaging. If she had been sent for further tests she could have collapsed or needed blood transfusions. The survival rate of the intrauterine pregnancy with a favourable outcome is 50-60% of cases.6
CONCLUSION
Clinicians must remain vigilant in prompt management of suspected ectopic gestations, at times using clinical findings to institute life-saving surgery without waiting for tests as happened in this case. This is especially pertinent in resource-limited environments. Making a retrospective diagnosis in a live patient is better than making it during a post-mortem examination.
COMPETING INTERESTS
The author declares no competing interests exists.
REFERENCES
1. Govindarajan MJ, Rajan R. Heterotopic pregnancy in natural conception. J Hum Reprod Sci. 2008; 1(1): 37-38.
2. Peleg D, Bar-Hawa I, Neaman-Leaven M, Ashkenazi J, Ben-Rafael Z. Early diagnosis and successful non surgical treatment of viable combined intrauterine and cervical pregnancy. Fertil Steril. 1994; 62(2): 405-408.
3. Jerrad D, Tso E, Salik R, Barish RA. Unsuspected heterotopic pregnancy in a woman without risk factors. AM J Emerg Med. 1992; 10(1): 58-60.
4. Tal J, Haddad S, Gordon N, Timor-Tritsch L. Heterotopic pregnancy after ovulation induction and assisted reproductive technologies: a literature review from 1971 to 1993. Fertil Ster-il. 1996: 66(1): 1-12.
5. Gruber I, Lahodny J, Illmensee K, Losch A. Heterotopic pregnancy: report of three cases. Wien Klin Wocheschr. 2002; 114(5-6): 229-232.
6. Noor N, Bano I, Parveen S. Heterotopic pregnancy with suc-cessful pregnancy outcome. J Hum Repro Sci. 2012; 5(2): 213-214.
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-118
Gynecol Obstet Res Open J
ISSN 2377-1542
Case Report of Unusual Stromal Luteinization in High-Grade Papillary Serous Carcinoma of the Ovary
Modupeola O. Samaila, C. James Sung, W. Dwayne Lawrence and M. Ruhul Quddus*
Department of Pathology, Women & Infants Hospital, Alpert Medical School of Brown Univer-sity, 101 Dudley Street Providence, RI 02905, USA
*Corresponding author: M. Ruhul Quddus, MD, M. Phil (Path) Professor Department of Pathology Women & Infants Hospital Alpert Medical School of Brown University 101 Dudley Street Providence RI 02905, USA Tel. 401-274-1122 Fax: 401-453-7681 E-mail: [email protected]
Article History:Received: September 2nd, 2015Accepted: October 8th, 2015Published: October 9th, 2015
Citation: Samaila MO, Sung CJ, Lawrence WD, Quddus MR. Case report of unusual stromal luteinization in high-grade papillary serous carcinoma of the ovary. Gynecol Obstet Res Open J. 2015; 2(4): 82-84.
Copyright: © 2015 Quddus MR. This is an open access article distributed under the Creative Commons At-tribution License, which permits unrestricted use, distribution, and reproduction in any medium, pro-vided the original work is properly cited.
Volume 2 : Issue 4Article Ref. #: 1000GOROJ2118
Case Report
Page 82
ABSTRACT
Stromal luteinization has been reported to be associated with benign and malignant epithelial ovarian tumors, predominantly mucinous and often endometrioid ovarian neoplasm. We report here an unusual case of marked ovarian stromal luteinization in a 67-year old post-menopausal female with a high-grade serous papillary carcinoma of the ovary. Stromal lutein-ization was so prominent that the tumor mimicked a Sertoli-Leydig cell tumor of the ovary.
KEYWORDS: Stromal luteinization; Ovarian tumors; Sertoli-Leydig; Carcinoma.
INTRODUCTION
Ovarian stromal luteinization has been observed in a number of female pelvic patholo-gies ranging from the benign to malignant, and predominantly in mucinous neoplasms.1 Its occurrence is associated with an increase in estrogen secretion and has often been reported in endometrial carcinoma.2-5 We report an unusual case of high-grade papillary serous carcinoma of the ovary with stromal luteinization in a 67-year old postmenopausal woman. The morpho-logic appearance of this tumor was somewhat similar to Sertoli-Leydig cell tumor of the ovary. This report emphasizes that stromal luteinization can be encountered in any epithelial ovarian tumors, including serous carcinoma, and may mimic ovarian sex cord stromal tumors. Interest-ingly, this patient also had an independent primary uterine papillary serous carcinoma of the endometrium.
CASE PRESENTATION
A 67-year-old gravida 0 presented with a history of lower abdominal pain for one month and vaginal spotting for 3 weeks. The pain was dull in nature, initially intermittent and became constant. She also noticed abnormal bloating, early satiety, 10-pounds weight gain, and altered bowel movement in two weeks prior to presentation. She attained menarche at 9 years and menopause at 52 years. Her past medical history included hypertension, gastro-esophageal reflux, and basal cell carcinoma. Bimanual examination revealed definite palpable bilateral adnexal masses, which were minimally tender with mass effect, abutting the rectum.
A pelvic ultrasound revealed a large 11 cm cystic and solid mass in the left adnexa and a 5.5 cm adnexal mass on the right side. Ascites was noted. The 6.3×3.3×2.8 cm uterus revealed 12 mm thick endometrial stripe on ultrasound examination. CA-125 was elevated at 1202. CT scan confirmed the findings of the ultrasound. Omental thickening noted on CT scan.
Prior to laparotomy, an endometrial biopsy was done and it demonstrated a high-grade papillary serous carcinoma and Endometrial Intraepithelial Carcinoma (EIC). Because of an endometrial serous carcinoma with bilateral adnexal masses and possible omental disease, she underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy.
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-118
Gynecol Obstet Res Open J
ISSN 2377-1542
Page 83
Histologic examination of the uterus, right ovary, left ovary, omentum and plaques from sigmoid colon surface and left pelvic side-wall all showed high-grade papillary serous car-cinoma with psammoma bodies and necrosis. The psammoma bodies and necrosis were also seen in the tumors of ovaries, omentum, and all serosal lesions. The findings raised a question whether the patient has an advanced IVB endometrial carcinoma or two independent primary tumors of the ovary and endome-trium? The following unique features noted in the histologic sec-tions which guided the final diagnoses: The serous carcinoma of the endometrium was superficially invasive and associated with endometrial intraepithelial carcinoma (EIC), a feature that justifies a primary endometrial serous carcinoma designation. In addition, no lymph vascular space invasion was noted in the uterus which would have supported a diagnosis of an advanced endometrial carcinoma. Similarly, the ovarian serous carcinoma had features that were consistent with tumor arising from the epithelial inclusion cysts in the ovary. No serous carcinoma, in-vasive or in-situ, was seen in the fallopian tube fimbria or in the mucosa. The distribution of the serous carcinoma in this case was typical of a primary ovarian carcinoma, which involved bi-lateral ovaries, serosa of bilateral fallopian tubes, uterine serosa, bilateral pelvic walls, sigmoid colon serosa, and the omentum. In the absence of an in-situ and invasive carcinoma, either in the fimbria or mucosa of the fallopian tube, it appeared prudent to assign the ovary as second primary site in this patient. The omental tumor deposits measured 0.5 to 1.0 cm in maximum dimensions and no gross omental caking.
Although the two primary serous carcinomas in the same individual are not uncommon, the most unusual feature, and the basis of this case report, was noted in the right ovary. The strikingly prominent stromal luteinization around the inva-sive serous tumor was seen in bilateral ovaries (Figure 1). Immu-nohistochemical staining with p53 and inhibin-alpha showed the tumor cells were strongly and diffusely reactive to p53 whereas, the luteinized stroma cells were reactive to inhibin (Figure 1). Figure 2 shows Invasive and in-situ serous carcinoma of the ovary in the left and endometrium in the right hand column re-spectively.
DISCUSSION
Stromal Luteinization has been described to be asso-ciated with ovarian mucinous and endometrioid neoplasms.2-5 Rome, et al. observed that stromal luteinization in postmeno-pausal women with mucinous ovarian tumors often has higher than normal estrogen secretion.2
It has been postulated that a mutation of GT198 pro-tein (a tumor suppressor gene and steroid hormone receptor) in ovarian stromal cell results in stromal activation with resultant luteinization due to the presence of luteinized theca cells at dif-ferent developmental stage.6
These mutant stromal cells are often found in endome-trioid, mucinous, serous, clear cell and granulosa cell tumors, and as well as, endometrial and metastatic gastrointestinal ade-nocarcinoma.3,7 A few isolated cases of stromal luteinization has been reported in primary B cell lymphoma of the ovary,8 ovar-ian carcinoid,9 ovarian teratomas,10
ovarian hemangiomas11 and Brenner tumors.6 However, the significance of these luteinized stromal cells is largely unknown.
High-grade serous carcinoma constitute 60%-80% of ovarian epithelial carcinoma while ovarian cancer in general ac-counts for only 3% of all cancers in women.12 Despite its high prevalence, the serous carcinoma of the ovary is usually not as-sociated with stromal luteinization. The morphologic appearance of this tumor may be confused with a sertoli-leydig cell tumor of the ovary. At a lower magnification, the admixture of epithelial-like element and luteinized stromal cells created a morphologic appearance that is often seen in Seroli-Leydig cells. However, the strong p53 positivity in the epithelial component of the ovar-ian tumor differentiated this tumor from a sertoli-leydig cell tu-mor. This is an important differential diagnosis as the prognosis and treatment of these two entities is vastly different. Immu-nostaining can confirm the presence of luteinization of ovarian
Figure 1: High-grade papillary serous carcinoma with marked stromal luteinization (H&E x 10) left had column. p53 immunostaining (x20), right column, upper. Inhibin immunostaining (x10), right column, lower.
Figure 2: High-grade papillary serous carcinoma, ovary (H&E 10x, left upper; H&E 20x left lower column). High grade serous carcinoma, endometrium (H&E, 10x, right upper; H&E 20x, right lower). Both photomicrographs showing evidence that these tumors are arising from these sites.
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-118
Gynecol Obstet Res Open J
ISSN 2377-1542
stromal cells. The luteinized stromal cells are positive for alpha Inhibin, Calretinin and Melan A.9
In conclusion, stromal luteinization may be seen in high-grade serous epithelial ovarian tumors as demonstrated in this case and such occurrence should not be overlooked or con-fused with other tumors by the astute surgical pathologist.
CONFLICTS OF INTEREST
The authors declare that they have no conflicts of interest.
ETHICAL APPROVAL
The patient has provided written consent for the use of the imag-es and case presentation for educational and scientific purposes provided unique identification is not revealed.
AUTHORSHIP ROLE
1. Mopupeola O. Samalia, MBBS: (Fellow in training and wrote the case report) Fellow, Stuart Lauchlan Fellowship in Gynecologic and
Breast Pathology, Women & Infants Hospital/Alpert Medical School of Brown University, Providence, RI 02905, USA.
2. C. James Sung, MD: (Helped writing the case report) Program Director, Stuart Lauchlan Fellowship in Gyne-
cologic and Breast Pathology, Women & Infants Hospi-tal/Alpert Medical School of Brown University, Provi-dence, RI 02905, USA.
3. W. Dwayne Lawrence, MD, MSc (Path) (Reviewed the case and helped in diagnosis) Chief of Pathology, Stuart Lauchlan Fellowship in Gy-
necologic and Breast Pathology, Women & Infants Hos-pital/Alpert Medical School of Brown University, Provi-dence, RI 02905, USA.
4. M. Ruhul Quddus, MD, M. Phil (Path) (Attending on the case) Program Co-Director, Stuart Lauchlan Fellowship in
Gynecologic and Breast Pathology, Women & Infants Hospital/Alpert Medical School of Brown University, Providence, RI 02905, USA.
REFERENCES
1. Pascal RR, Grecco LA. Mucinous cystadenoma of the ovary with stromal luteinization and hilar cell hyperplasia during preg-nancy. Human Pathology. 1988; 19: 179-180.
2. Rome RM, Fortune DW, Quinn MA, Brown JB. Function-ing ovarian tumors in postmenopausal women. Obstet Gynecol.
1981; 57: 705-710.3. Nagamani M, Hannigan EV, Dinh TV, Stuart CA. Hyperin-sulinemia and stromal luteinization of the ovaries in postmeno-pausal women with endometrial cancer. J Clin Endocrinol Metab. 1988; 67: 144-148. doi: 10.1210/jcem-67-1-144 4. Shinada T, Tsukui J, Seitchi M. Estrogen synthesis by Brenner tumors. Am J Obstet Gynecol. 1973; 116: 408-411.
5. Morimura Y, Ohishi M, Hoshi K. A case of ovarian Brenner tumor with stromal estrogenic activity. Asia-Oceania J Obstet Gynaecol. 1994; 20: 165-171.
6. Yang DM, Heller DS, Ganesh V, Gittens L. Brenner tumor of the ovary with extensive stromal luteinization presenting in pregnancy: report of a case and review of the literature. J Ma-tern Fetal Neonatal Med. 2002; 12: 281-283. doi: 10.1080/jmf.12.4.281.283 7. Peng M, Zhang H, Jaafar l, et al. Human ovarian cancer stro-ma contains luteinized theca cells habouring tumor suppressor gene GT198 mutations. J boil Chem. 2013; 288: 33387-33397. doi: 10.1074/jbc.M113.485581 8. Mittal KR, Blechman A, Greco MA, Alfonso F, Demopoulos R. Lymphoma of ovary with stromal luteinization presenting as secondary amenorrhea. Gynecologic Oncology. 1992; 45: 69-75.
9. Engohan- Aloghe C, Buxant F, Noel JC. Primary ovarian car-cinoid tumor with luteinized stromal cells. Arch Gynecol Obstet. 2009; 280: 119-121. doi: 10.1007/s00404-008-0853-7 10. Itoh H, Wada T, Michikata K, et al. Ovarian teratoma show-ing a predominant hemangiomatous element with stromal lutein-ization: report of a case and review of the literature. Pathol Int. 2004; 54: 279-283. doi: 10.1111/j.1440-1827.2004.01621.x 11. Anand MS, Shetty S, Mysorekar VV, Kumar RV. Ovarian hemangioma with stromal luteinization and HCG producing mononucleate and multinucleate cells of uncertain histiogenesis: a rare co-existence with therapeutic dilemma. Indian J Pathol Microbiol. 2012; 55: 509-512. doi: 10.4103/0377-4929.107793 12. Li J, Fadare O, Xiang L, Kong B, Zheng W. Ovarian serous carcinoma: recent concepts on its origin and carcinogenesis. J Haematol Oncol. 2012; 5: 8-19. doi: 10.1186/1756-8722-5-8
Page 84
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-119
Gynecol Obstet Res Open J
ISSN 2377-1542
Nausea and Vomiting in Pregnancy-The Bump in the road of Motherhood
Olukayode Akinlaja*
Assistant Professor, Department of Obstetrics and Gynecology, University of Tennessee Col-lege of Medicine, Chattanooga, TN, USA
*Corresponding author: Olukayode Akinlaja, MD, FWACS, FACOG Assistant Professor Department of Obstetrics and Gynecology University of Tennessee College of Medicine, Chattanooga, TN, USA E-mail: [email protected]
Article History:Received: October 23rd, 2015 Accepted: November 5th, 2015 Published: November 6th, 2015
Citation: Akinlaja O. Nausea and vomiting in pregnancy-the bump in the road of motherhood. Gynecol Obstet Res Open J. 2015; 2(4): 85-88.
Copyright: © 2015 Akinlaja O. This is an open access article distributed under the Creative Commons Attribution Li-cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the origi-nal work is properly cited.
Volume 2 : Issue 4Article Ref. #: 1000GOROJ2119
Short Communication
Page 85
INTRODUCTION
Early pregnancy is commonly associated with nausea and/or vomiting, known by the lay term morning sickness and this can impact the Quality of Life (QoL) of the pregnant woman despite being considered a part of the first trimester of pregnancy’s physiology.
Hyperemesis gravidarum refers to severe vomiting associated with systemic effects and the diagnosis criteria includes pregnancy related vomiting that occurs greater than three times per day in conjunction with a weight loss greater than 3 kg or 5% of body weight and ketonuria unrelated to other causes.1
INCIDENCE Nausea with/without vomiting tends to be more common in the younger primigravid of western nations but generally occurs in 50-90% of all pregnancies while hyperemesis gravi-darum has been reported in 0.3 to 3% of pregnancies.2
RISK FACTORS
There is an increased association with multiple gestation,3 hydatidiform mole,4 acid-reflux disease5 and a similar pregnancy history.
An increased incidence has also been noted in those who experience nausea and vom-iting related to estrogen based medications while alcohol use, cigarette smoking6 and anosmia do appear to be protective.7
Pathogenesis
Unknown but theories propagated include:
• Hormonal changes: Although not firmly established, higher levels of serum HCG has been observed in women with hyperemesis including those with multiple gestations and hyda-tidiform mole. Serum concentrations of HCG also peak in the first trimester, which cor-responds to the time hyperemesis gravidarum is typically seen.
• Psychological factors: Individual response to stress and the pregnancy has been proposed as contributing factors.8
• Abnormal gastrointestinal motility: Dysrhythmic gastric motility has been suggested as well as gastroesophageal reflux but this does not account for why symptoms get better as pregnancy progresses.2
• Helicobacter pylori: Case reports have shown improvement in symptoms with treatment of
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-119
Gynecol Obstet Res Open J
ISSN 2377-1542
Page 86
infection but this is in need of confirmatory evidence.9
DIAGNOSIS AND CLINICAL COURSE
The onset of symptoms is usually between 5 and 6 weeks with peak around 9 weeks of gestation. It usually abates at 16-20 weeks but in 15-20% of pregnancies, it does continue till the third trimester and till delivery in 5% of cases.10,11
It can occur at any time of the day and in most instanc-es, normal vital signs, physical and laboratory examinations are the norm.
In contrast, women with hyperemesis have orthostatic hypotension, physical signs of dehydration as well as laboratory abnormalities and often need hospitalization for stabilization.
The Motherisk-PUQE scoring index and the Rhodes index have been used in research with higher scores indicating a need for serum electrolyte check and evaluation for dehydration.
Evaluation
Standard evaluation includes:
• Measurement of weight
• Orthostatic blood pressures
• Heart rate check
• Serum Electrolytes/urea and creatinine
• Urine Ketones and specific gravity
• Obstetrical Ultrasound for gestational age, no. of gestations and to rule out hydratiditiform mole.
• Others include a complete blood count, liver function tests, thyroid function tests, amylase/lipase and calcium level.
• If liver disease is suspected, an ultrasound examination of the liver is indicated.
Associated findings include
Electrolyte derangements- hypokalemia, hypochlore-mic metabolic alkalosis and ketosis.
Hematocrit increase due to hemoconcentration.
Abnormal liver enzymes, especially an elevation of alanine aminotransferase.
Serum amylase and lipase may increase by 5 fold.10
Mild hyperthyroidism may occur due to an elevated se-rum level of HCG and this tends to resolve without any need for intervention.
Treatment
Management should generally be aimed at reducing symptoms, minimizing the effects on the fetus and reversing consequences.
i. Non-Pharmacologic Interventions include:
Dietary measures through the ingestion of small, fre-quent carbohydrate meals, eliminating coffee and spicy, odor-ous, fatty and sweet foods while cold carbonated drinks can also be helpful.
Triggers such as Iron supplements, heat, humidity and odors should be avoided until symptoms resolve while hypnosis, psychotherapy and acupuncture might be of help.
ii. Pharmacologic Interventions include:
Ginger in the form of ginger supplements or ginger containing food such as ginger tea is used based on the mild improvement seen in randomized controlled studies.12
Pyridoxine or vitamin B6 is a water-soluble vitamin that can be used alone or in conjunction with doxylamine suc-cinate.13 Pyridoxine has a good safety profile with minimal side effects and is usually given as 25 mg orally every six to eight hours.
Anti-Histamines including doxylamine, meclizine, di-menhydrinate, promethazine and diphenhydramine do signifi-cantly reduce pregnancy related nausea and vomiting as illus-trated in controlled trials.14 The mechanisms of action involve the inhibition of histamine at the H1 receptor and an indirect effect on the vestibular system by reducing the vomiting center stimulation. Lightheadedness, dry mouth, constipation and seda-tion are some of the associated side effects.
Dopamine antagonists mediate the inhibition of gastric motility through their action on dopamine receptors in the stom-ach and the three main classes are the butyrophenones (droperi-dol), phenothiazines (Promethazine) and benzamides (metoclo-pramide).
Serotonin antagonists are mainly selective antagonists at 5-HT3 serotonin receptor such as ondansetron, given at 4 to 8 mg orally every eight hours, as needed or intravenously. Side effects include headache, constipation, drowsiness and fatigue. The use of this class of drugs for the treatment of nausea and vomiting of pregnancy has not been associated with congenital anomalies or other adverse effects.
Acid reducing agentsare used as adjuncts to antiemet-ics and include antacids (aluminum or calcium containing), H2 receptor antagonists (Ranitidine) or Proton pump inhibitors
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-119
Gynecol Obstet Res Open J
ISSN 2377-1542
Page 87
(Omeprazole).
Hospitalization for hydration and medication is war-ranted in cases of failed outpatient therapy and emotional sup-port is needed to deal with the stressful nature of the illness although a recent study demonstrates that individualizing care with the aid of the hyperemesis impact of symptoms question-naire was not associated with any significant improvement in the quality of care.15
Dehydration may need correction with up to 2 liter of lactated Ringers solution over 3 to 6 hours while also giving appropriate electrolytes and vitamins. It is then changed to dex-trose 5% in 0.45% saline and hydration is commonly continued for one to two days with urine output maintained at about 100 mls/hr.
Vitamins and minerals such as thiamine (Vitamin B1) is replaced by giving 100 mg intravenously with the initial rehy-dration fluids and 100 mg daily for the next two or three days to prevent the development of Wernicke encephalopathy. Multivi-tamin (MVI) 10 ml, folic acid 0.6 mg and vitamin B6 25 mg are given in every liter of fluid.
With hypocalcaemia, correct the low magnesium level by giving 2 g (16 meq) magnesium sulfate as a 10% solution over 10 to 20 minutes then 1 g (8 meq) in 100 ml of fluid per hour to raise the magnesium level to more than 0.8 meq/l. If the serum calcium is still low, 1-2 g calcium gluconate in 50 ml of 5% dextrose solution over 10 to 20 minutes is added.
Dietary measures including a period of bowel rest are followed by a BRAT diet (bananas, rice, apple sauce and toast) or full liquid diet and this is then advanced as tolerated.
Medications are usually given through non-oral routes until tolerated and for unresponsive patients, there is a role for the use of glucorticoids such as methylprednisolone (16 mg) in-travenously every eight hours for 48 to 72 hours, converted to oral prednisone tapered over a two-week period with response, though the mechanism of action is still not well understood.
Enteral (tube feeding) or parenteral nutrition and intra-venous fluids might be needed as long as necessary.
Generally, nausea and vomiting of pregnancy is associ-ated with a lower rate of miscarriage than in women without these symptoms whereas with hyperemesis gravidarum, there is an increased risk of preterm delivery, low birth weight/small for gestational age infants and an association with placental dysfunction. Adverse effects of malnutrition such as Wernicke encephalopathy (Vitamin B1 deficiency), bleeding diathesis (Vi-tamin K deficiency), esophageal tears and rupture, pneumotho-raxes, osmotic demyelination syndrome, hepatic insufficiency and acute tubular necrosis might occur with persistent severe
vomiting.
Prevention comprises of managing acid reflux disor-ders prior to pregnancy and the preconceptional intake of daily multivitamins with folic acid may help decrease the frequency and severity of nausea and vomiting during pregnancy.
DIFFERENTIAL DIAGNOSIS
Many conditions unrelated to pregnancy such as pan-creatitis, cholecystitis, hepatitis and thyroid disease can result in nausea and vomiting of pregnancy while preeclampsia; HELLP syndrome and acute fatty liver of pregnancy are associated with emesis occurring in the latter half of pregnancy in combination with other clinical and laboratory findings.
REFERENCES
1. Golberg D, Szilagyi A, Graves L. Hyperemesis gravidarum and helicobacter pylori infection: a systematic review. Obstet Gynecol. 2007; 110: 695.
2. Lee NM, Saha S. Nausea and vomiting of pregnancy. Gastro-enterol Clin North Am. 2011; 40: 309.
3. Basso O, Olsen J. Sex ratio and twinning in women with hy-peremesis or pre-eclampsia. Epidemiology. 2001; 12: 747.
4. Hou JL, Wan XR, Xiang Y, et al. Changes of clinical features in hydratidiform mole: analysis of 113 cases. J Reprod Med. 2008; 53: 629.
5. Gill SK, Maltepe C, Koren G. The effect of heartburn and acid reflux on the severity of nausea and vomiting of pregnancy. Can J Gastroenterol. 2009; 23: 270.
6. Weigel MM, Weigel RM. The association of reproductive his-tory, demographic factors, and alcohol and tobacco consumption with the risk of developing nausea and vomiting in early preg-nancy. Am J Epidemiol. 1988; 127: 562.
7. Heinrichs L. Linking olfaction with nausea and vomiting of pregnancy, recurrent abortion, hyperemesis gravidarum and mi-graine headache. Am J Obstet Gynecol. 2002; 186: S215.
8. Buckwalter JG, Simpson SW. Psychological factors in the etiology and treatment of severe nausea and vomiting in preg-nancy. Am J Obstet Gynecol. 2002; 186: S210.
9. Mansour GM, Nashaat EH. Role of helicobacter pylori in the pathogenesis of hyperemesis gravidarum. Arch Gynecol Obstet. 2011; 284: 843. doi: 10.1007/s00404-010-1759-8
10. Goodwin TM. Hyperemesis gravidarum. Clin Obstet Gyne-col. 1998; 41: 597.
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-119
Gynecol Obstet Res Open J
ISSN 2377-1542
11. Fell DB, Dodds L, Joseph KS, et al. Risk factors for hy-peremesis gravidarum requiring hospital admission during pregnancy. Obstet Gynecol. 2006; 107: 277. doi: 10.1097/01.AOG.0000195059.82029.74
12. Viljoen E, Visser J, Koen N, Musekiwa A. A systematic re-view and meta-analysis of the effect and safety of ginger in the treatment of pregnancy-associated nausea and vomiting. Nutr J. 2014; 13: 20. doi: 10.1186/1475-2891-13-20
13. Practice Bulletin No. 153: Nausea and Vomiting of pregnan-cy. Obstet Gynecol. 2015; 126: e12.
14. Magee LA, Mazzotta P, Koren G. Evidence- based view of safety and effectiveness of pharmacologic therapy for nausea and vomiting of pregnancy (NVP). Am J Obstet Gynecol. 2002; 186: S256.
15. Fletcher SJ, Waterman H, Nelson L, et al. Holistic assess-ment of women with hyperemesis gravidarum: a randomized controlled trial. International Journal of Nursing Studies. 5(11): 1669-1677. doi: 10.1016/j.ijnurstu.2015.06.007
Page 88
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-120
Gynecol Obstet Res Open J
ISSN 2377-1542
Heterotopic Pregnancy
Solwayo Ngwenya*
Consultant Obstetrician & Gynaecologist, Head of Department, Obstetrics & GynaecologyMpilo Central Hospital, Vera Road, Mzilikazi, Bulawayo, Zimbabwe
*Corresponding author: Solwayo Ngwenya, MBChB, DFRSH, MRCOG Consultant Obstetrician & Gynaecologist Head of Department Obstetrics & Gynaecology Mpilo Central Hospital Vera Road, Mzilikazi Bulawayo, Zimbabwe E-mail: [email protected]
Article History:Received: October 26th, 2015 Accepted: November 10th, 2015 Published: November 13th, 2015
Citation: Ngwenya S. Heterotopic pregnancy. Gynecol Obstet Res Open J. 2015; 2(4): 89-92.
Copyright: © 2015 Ngwenya S. This is an open access article distributed under the Creative Commons Attribution Li-cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the origi-nal work is properly cited.
Volume 2 : Issue 4Article Ref. #: 1000GOROJ2120
Mini Review
Page 89
KEY CONTENT
• Heterotopicpregnancyisararebutlife-threateningcondition• Veryfewclinicianswillcomeacrossthisveryseriousgynaecologicalconditionduring
theircareers• Itisverydifficulttodiagnoseandthepatientmaycollapseanddieduringinvestigations• Life-savingemergencylaparotomyisessentialinseriouslysickpatients
LEARNING OBJECTIVES
• Toincreaseawarenessamongstcliniciansaboutthisrarecondition• Tohelpinthediagnosisandmanagementofthisseriouspregnancycomplication• Tohelpsavelives
ETHICAL ISSUES
• Thesafetyofthemotherandtheintrauterinefetus• Theremovaloftheextrauterinefetustosavethemotherandtheintrauterinefetus
KEYWORDS: Heterotopicpregnancy;Life-threatening;Riskfactors;Life-saving;Maternalcol-lapseanddeath;Emergencylaparotomy.
INTRODUCTION
Heterotopicpregnancyisararegynaecologicalconditionwherebythereisapresenceofanintrauterinepregnancyandextrauterinepregnancyatthesametime.ItwasfirstdefinedbyDuverneyin1708asanautopsyfindinginapatientwhohaddiedofarupturedectopicpreg-nancyandhadanintrauterinepregnancy.1Rarelyanintrauterinetwingestationcanco-existwithaheterotopicpregnancyorvice versa.Higherorderheterotopicgestationsareextremelyrare.2Thisconditionmaycausediagnosticdifficultiesand thepatientmaycollapseanddieduringinvestigations.Thoseoccurringafterfertilitytreatmentsmayfaceethicalandemotionaldilemmaofhavingtoloseoneoftheirbabies.Itisararelife-threateningconditionthatveryfewclinicianswouldcomeacrossduringtheircareers.Itisthereforeanimportantclinicalcon-dition,hencetheneedtobringthesubjectprominencethroughareviewarticlelikethisone.
INCIDENCE
Thereportedincidenceofheterotopicpregnancyinaspontaneousnaturalcycleis1in30,000.3Thisisindeedveryrarethatsomecliniciansmaynevercomeacrossitduringtheircareers.Thisposesadangertothemotherandtheintrauterinepregnancyasveryfewclini-cianswillconsiderthisdiagnosisuntilitistoolate.Itismostlylikelytobeoutsidethelistofinitialdifferentialdiagnoses.Thereisadirectincreaseintheincidencerelatedtothenumberofembryosbeingtransferredduringin vitrofertilisation.4,5Theincidencehasincreasedto2.9%1withovulationinductionandto1%withassistedreproductivetechniques.6Couplesundergo-
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-120
Gynecol Obstet Res Open J
ISSN 2377-1542
Page 90
ingsuchprocessesmustbefullycounselledontheserisks.Theymayfacetheprospectofhavingtoundergotransabdominalfetalreduction.4
RISK FACTORS
Heterotopic pregnancy can have several aetiologicalfactors.Risk factors associatedwith this type of gestation in-cludeahistoryofpelvicinflammatorydisease,previoussurgery,pelvictrauma,congenitaluterinemalformationsandtheuseofassistedreproductivetechniques.7Thesefactorsmayactsingu-larlyortogethertocausethecondition.About1%ofthepreg-nanciesareectopicofwhich,95-97%areinthefallopiantube,the ampullaryportionbeing themost commonaccounting for80%,theisthmicportionaccountsfor10%,fimbrialregion5%andcornualandinterstitialregions2-4%.8Othersitesforectopicimplantationincludeovarian,cervicalandabdominalcavity.
CLINICAL FEATURES
Heterotopicpregnancycanbe asymptomatic inup to54% of cases1 or present with a haemodynamically compro-misedpatient.Sinceitisarareconditioncliniciansmustbealertto seek it out in patients presenting to them. Cliniciansmustmaintainahighindexofclinicalsuspicioninanyfemalepatientofreproductiveagegrouppresentingwithfeaturessuggestiveofanabnormalpregnancywithorwithoutriskfactors.
Thepatientmaypresentwithahistoryof6-8weeksofamenorrhoea, lower abdominal pains, shoulder tippain, faint-ing,dizzinessandurinarysymptoms.Theycanalsopresentwithatypical symptomsof epigastricpains andvomiting9 andmaybeimproperlytreatedforgastrointestinaldiagnoses.Theremaybe confusion with the diagnosis of ovarian hyperstimulationsyndrome especially in patients that have recently undergonein vitro fertilisation. This syndrome can present with similarsymptoms.
Inacompromisedpatient,theremaybepallor,tachy-cardia, tachyponea, hypotension/hypovolemia, abdominal ten-derness/distension and guarding1,10-12 and the patientmay col-lapseanddieespeciallywitharupturedheterotopicpregnancy.Thisisadiregynaecologicalemergency.Prolongedcardiovas-cularcompromisecanresultinmulti-organfailurenecessitatingamultidisciplinary team approach.The intrauterine fetuswilldemisewiththemother.
INVESTIGATIONS
Diagnosisofheterotopicpregnancyisdifficult inthatthe clinical symptoms can be scanty/vague or the intrauterinegestation can mislead clinicians. Those patients suspected tohave thisdiagnosismustbepromptly investigated.Transvagi-nalultrasonography inheterotopicpregnancyhasa sensitivityof only 56%.5 The presence of an intrauterine gestation doesnot exclude an ectopic gestation.13,14 The use of colour Dop-
plerscanscanimprovethechanceofdiagnosingit.15Cliniciansshould relentlessly investigate further patients complaining ofundeterminedpelvic/abdominalpainsdespiteascanreportcon-firminganintrauterinegestation.Alife-threateningheterotopicpregnancymaybeco-existing.At thesametimeascanreportcanbefalselyreassuring.
Theuseofß-hCGserumassayingisdifficultinhetero-topicpregnancyastheintrauterinegestationobscurestheecto-picgestation.16Theuseofmagnetic resonance imagingof thepelvismaybeusedtoassistinthediagnosis.16,17
Adiagnosticlaparoscopy,withoututerineinstrumenta-tionremainsagoldstandardprocedure18wherethereisclinicaldiagnosticdoubtandthepatientisclinicallystable.Ifthepatientdeterioratesduringtheprocedurethelaparoscopyshouldbecon-vertedtoalaparatomy.Itiscontraindicatedinpatientsthatarehaemodynamicallyunstableandtheseneedanemergencylife-savinglaparotomy.
In settings, where there are limited investigative re-sources, cliniciansmust practice puremedicine of; a detailedhistory, physical examination and make life-saving decisionssuchaspromptrecoursetoexploratorysurgery.
MANAGEMENT
The management of heterotopic pregnancy must bedecisive once the diagnosis has beenmade to save lives.Themanagementofheterotopicpregnancyislaparoscopy7avoidinguterineinstrumentationorlaparotomyforthetubalpregnancy.19Emergencylaparotomyisthelife-savingoptioninpatientswithsignificant intra-abdominalhaemorrhageor inapatient that iscardiovascularlycompromised.Anexperiencedanaesthetistandsurgeonmaybeneededinalife-savingoperation.Patientsmayneedintra-operativeandpost-operativebloodtransfusions.TheymaybeverysickneedingadmissiontoIntensiveCareUnit/HighDependencyUnit.Inresource-challengedsettingspromptlapa-rotomywithbasicinvestigationssaveslives.
Atsurgeryfindingsvaryfromun-rupturedtubalectopicimplantationstovariousdegreesofhaemoperitoneum10depend-ingonthelengthofbleedingaftertherupture10-12ofthehetero-topicpregnancy.Attimes,bleedingisfoundtobecomingfromthefimbrialendwithatubalpregnancystill intact.Specimensobtainedshouldbesentforhistologicalconfirmationofectopicimplantation.
Medicaltherapywithmethotrexateishighlyeffectivewithratesof88.1%onsingledoseregimesand92.7%onmulti-doseregimes.1,20,21Thishastheadvantageofavoidingrisksas-sociatedwithsurgery,preservesthetubeandhaslessneedforhospitalisation.Itissuitableforstablepatients,thosewithsmallgestationalsacs<3.5cmonscan,nofreefluid,absenceoffetalcardiacactivityandacompliantpatienttofollow-up.1Theuseoffolinicacidasanantagonisttomethotrexatehelpsreduceside
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-120
Gynecol Obstet Res Open J
ISSN 2377-1542
Page 91
effectsofmethotrexateespeciallyifhighdosesofmethotrexateareused.21
Complete resolution of an ectopic pregnancy takes2-3weeksbutcantakeaslongas6-8weeks.20Serialscansandß-hCG levels would confirm this resolution.20,21 Patients mayfind this long and become apprehensive hence counselling iscrucial.
Other medical treatments described in the literatureincludetheuseofhyperosmolarglucoseultrasound-guidedin-jectionintotheheterotopicpregnancy.22Theuseofultrasound-guided intracardiac injection of potassium chloride can allowthe intrauterinepregnancy to progress.23Nonsurgicalmanage-mentwithtransvaginalultrasound-guidedinjectionofpotassiumchlorideandmethotrexateintoacervicalpregnancyresultedinasuccessfuloutcome.24Suchmanagementstrategiesarefewasmostcasesdescribedintheliteraturehavebeenmanagedeitherby laparoscopyor laparotomy.There areno randomised trialscomparingmedicaltreatmentversussurgicaltreatment.1
Expectantmanagementhasalsobeendescribedbutisrarelyusedasitneedsintensemonitoring,25andleavesthepa-tienttopotentialharmiftubalruptureoccurswithoutwarningleadingtocatastrophichaemorrhageandmaternalandintrauter-inefetaldeath.Ectopicgestationscansuddenlyruptureleadingto instant collapse and demisewithinminutes. Few cliniciansandpatientsmaybewillingtoembarkonthisoption.Meticu-louscounsellingand recordkeepingwouldbeneeded if cata-strophicresultsweretooccur.
PROGNOSIS
The prognosis for the intrauterine fetus followingbothmedicalandsurgical treatmentoftheectopicgestationisgood.1,2,7Inacomparativereviewof80caseswithheterotopicpregnancytreatedsurgicallythesurvivalrateoftheintrauterinepregnancieswas68.7%.15Therateoflivebirthsinheterotopictripletsisaround60%butinonereviewtherateoflivebirthswas92.3%.26-28Thesefigurescanbeuseful incounsellingpa-tientsandreassuringthemaboutthegoodchancesofthenormal-ly-sitedpregnancyprogressingwelltotermdeliveries.
CONCLUSION
Heterotopic pregnancy is a very rare life-threateningclinicalcondition.Itposesgreatclinicaldiagnosticdifficulties.Very few clinicians worldwide will come across this seriouscomplicationduringtheirtrainingandcareers.Itcancontributetomaternalmorbidityandmortalityandlossoftheintrauterinefetus.Itcanhappeninanaturalcycle29,30andinwomenwithoutriskfactors.Inpatientswhopresentinacuteformswhereinves-tigationssuchasultrasoundscansarenotpossibletodo,uterineinstrumentationshouldbeavoidedatlaparoscopy.30
Therefore, cliniciansmust remain vigilant in seeking
andpromptlytreatingthisdangerouscondition.Cliniciansmustcarryoutlife-savingemergencylaparotomyifthereisdiagnosticdoubtinthefaceofaclinicallysickpatientwithanacuteabdo-mendespitehavinganintrauterinepregnancy.Thehistoryandclinicalfindingsmustbetakenintogreatconsiderationaheadofscanreports.Itisbettertomakearetrospectivediagnosisinalivepatient.30-32thanapost-mortemdiagnosiswithalossofliveslikewhatDuverneyfoundin1708.1Inmodernpractice,wearebackedupbymoderndiagnosticandtherapeuticstrategies.13
CONTRIBUTION OF AUTHORSHIP
ThispaperwasthesoleworkofMr.Ngwenya.
REFERENCES
1.LavanyaR,DeepikaK,PatilM.Successfulpregnancy fol-lowingmedicalmanagementofheterotopicpregnancy.J Hum Reprod Sci.2009; 2(1):35-40.doi:10.4103/0974-1208.51350
2.FelekisT,AkrivisC,TsirkasP,KorkontzelosI.Heterotopictripletpregnancyafterinvitrofertilisationwithfavourableout-comeoftheintrauterinetwinpregnancysubsequenttosurgicaltreatment of the tubal pregnancy. Case Rep Obstet Gynecol.2014;2014:356131.doi:10.1155/2014/356131
3. Reece EA, Petrie RH, SirmansMF, FinsterM,ToddWD.Combinedintrauterineandextrauterinegestations:areview.Am J Obstet Gynecol.1983;146:323-330.
4.TabshKM.Transabdominalmultifetalpregnancyreduction:Reportof40cases.Obstet Gynecol.1990;57:739-741.
5.RowlandDM,GeaganMB,PaulDA.Sonographicdemon-stration of combined quadruplet gestationwith viable ectopicandconcomitant intrauterine tripletpregnancies.J Ultrasound Med.1987;6:89-91.
6. Dundar O, tutuncu L, Mungen E, Muhcu M,YergokYZ.Heterotopicpregnancy:Tubalectopicpregnancyandmonocho-rionicmonoamniotic twin pregnancy: a case report.Perinatal Journal.2006;14:96-100.
7.KwonY-S,LeeS-H,ImKS,RoJH.Laparoscopicmanage-mentofheterotopicinterstitialpregnancywithsubsequenttermdelivery.Int J Fertil Steril.2015;9(2):265-267.
8.CallenPW.Ultrasonography inobstetricsandgynaecology.In: Levine D, editor. Ectopic pregnancy. 5th ed. Philadelphia:SaundersElsevier;1020-1047.
9.PelegD,Bar-HavaI,Neuman-LevinM,ETEL.Earlydiag-nosisandsuccessfulnonsurgicaltreatmentofviablecombinedintrauterineandcervicalpregnancy.Fertil Steril. 1994;62:405-408.
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-120
Gynecol Obstet Res Open J
ISSN 2377-1542
Page 92
10.ShettySK,ShettyAK.Acaseofheterotopicpregnancywithtubal rupture.J Clin Diagn Res. 2013;7(12):3000-3001.doi:10.7860/JCDR/2013/7526.3826
11.RathodS,SamalSK.Ararecaseofheterotopicpregnancywithrupturedleftrudimentaryhornpregnancy.J Clin Diagn Res.2015;9(3):QD03-QD04.doi:10.7860/JCDR/2015/10677.5639
12.GibsonKR,HorneAW.Rupturedheterotopicpregnancy:anunusualpresentationofuncommonclinicalproblem.BMJ Case Rep.2012;bcr2012007423.doi:10.1136/bcr-2012-007423
13.FernandezH,GervaiseA.Ectopicpregnanciesafter infer-tilitytreatment:moderndiagnosisandtherapeuticstrategy.Hu-man Reproduction Update.2004;10(6):503-513.doi:10.1093/humupd/dmh043
14.XiaoHM,GongF,MaoZH,ZhangH,LuGX.Analysisof92ectopicpregnancypatientsafterinvitrofertilisationandem-bryotransfer.Journal of Central South University. 2006;31(4):584-587.
15.BarrenetxeaG,Barinaga-RementeriaL,LopezdeLarruzeaA,Agirregoikoa JA, Mandiola M, Carbonero K. Heterotopicpregnancy: two cases and a comparative review.Fertility and Sterility. 2007; 87(2): 417. e9-417.e15. doi: 10.1016/j.fertn-stert.2006.05.085
16.SunSY,AraujoJúniorE,ElitoJúniorJ,etal.Diagnosisofheterotopicpregnancyusingultrasoundandmagneticresonanceimaginginthefirsttrimesterofpregnancy:acasereport.Case Rep Radiol.2012;2012:317592.doi:10.1155/2012/31759217. Tamai K, KoyamaT, Togashi K.MR features of ectopicpregnancy.European Radiology. 2007;17(12):3236-3246.doi:10.1007/s00330-007-0751-6
18.Louis-SylvesterC,MoriceP,ChapronC,etal.Theroleoflaparoscopy in the diagnosis and management of heterotopicpregnancies.Hum Reprod.1997;12:1100-1102.doi:10.1093/humrep/12.5.1100
19. Gruber I, Lahodny J, Illmensee K, LoschA. Heterotopicpregnancy:reportofthreecases.Wien Klin Wochenschr.2002;114:229-232.
20.GamzuR,AlmogB,LevinY, et al.Theultrasonographicappearanceof tubalpregnancy inpatients treatedwithmetho-trexate.Hum Reprod.2002;17:2585-2587.doi:10.1093/hum-rep/17.10.2585
21.ThePracticeCommitteeoftheAmericanSocietyforrepro-ductiveMedicine.Medicaltreatmentofectopicpregnancy.Fer-til Steril.2006;86:S96-S102.
22. Timor-Tritsch IE. Hyperosmolar glucose injection for the
treatment of heterotopic ovarian pregnancy. Obstet Gynecol.2012;120(5):1212.
23.YehJ,AzizN,ChuehJ.Nonsurgicalmanagementofhetero-topicabdominalpregnancy.Obstet Gynecol.2013;121(2Pt2Suppl1):489-495.doi:10.1097/AOG.0b013e3182736b09
24.DekaD,BahadurA,SinghA,MalhotraN.Successfulman-agement of heterotopic pregnancy after fetal reduction usingpotassiumchlorideandmethotrexate.J Hum Reprod Sci. 2012; 5(1):57-60.doi:10.4103/0974-1208.97807
25.BaxiA,KaushalM,KarmalkarH,etal.Successfulexpectantmanagementoftubalheterotopicpregnancy.J Hum Reprod Sci.2010;3:108-110.doi:10.4103/0974-1208.69333
26.NoorN,BanoI,ParveenS.Heterotopicpregnancywithasuccessfulpregnancyoutcome.J Hum Reprod Sci.2012;5(2):213-214.doi:10.4103/0974-1208.101024
27.DivryV,HadjS,BordesA,GenodA,SalleB.Caseofpro-gressiveintrauterinetwinpregnancyaftersurgicaltreatmentofcornualpregnancy.Fertility and Sterility. 2007;87(1):190.el-190.e3.doi:10.1016/j.fertnstert.2006.04.053
28. Bugatto F, Quintero-Prado R, Kirk-Grohar J, Melero-JimenezV,Hervias-VivancosB,BarthaJL.Heterotopictriplets:tubalectopicandtwinintrauterinepregnancy.Areviewofob-stetricoutcomeswithacasereport.Archives of Gynecology and Obstetrics. 2010; 282(6): 601-606. doi: 10.1007/s00404-010-1577-z
29.LudwigM,KaisiM,BauerO,etal.Heterotopicpregnancyinaspontaneouscycle:donotforgetit!.Eur J Obstet Gynecol Re-prod Biol.1999;87:91-93.doi:10.1016/S0301-2115(99)00079-2
30.Kratschla-ApochalA,NauerC,BollaD.Heterotopicpreg-nancy after natural conception: a case report. Gerburtshilfe Frauenheilkd. 2012; 72(7): 639-642. doi: 10.1055/s-0032-1314993
31.YamoahKK,GirnZ.Heterotopicpregnancy:shouldwein-strumenttheuterusatlaparoscopyforectopicpregnancy.BMJ Case Rep.2012;2012:bcr2012006497.
32.NgwenyaS.Heteretopicpregnancy:acasereportofretro-spectivediagnosisfollowingsurgicaltreatment.Gynecol Obstet Res Open J.2015;2(4):80-81.
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-121
Gynecol Obstet Res Open J
ISSN 2377-1542
Interactions of Immunomodulatory HLA-G with Immune Cells during Pregnancy and Endometriosis
Parveen Parasar*
Boston Center for Endometriosis, Brigham and Women’s Hospital, Boston Children’s Hospi-tal, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
*Corresponding author: Parveen Parasar, DVM, PhD Boston Center for Endometriosis Brigham and Women’s Hospital Boston Children’s Hospital Harvard Medical School 300 Longwood Avenue Boston, MA 02115, USA E-mail: [email protected]
Article History:Received: November 14th, 2015 Accepted: November 30th, 2015Published: December 1st, 2015
Citation: Parasar P. Interactions of immuno-modulatory HLA-G with immune cells during pregnancy and endometriosis. Gynecol Obstet Res Open J. 2015; 2(4): 93-95.
Copyright: © 2015 Parasar P. This is an open access article distributed under the Creative Commons Attribution Li-cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the origi-nal work is properly cited.
Volume 2 : Issue 4Article Ref. #: 1000GOROJ2121
Opinion
Page 93
The Major Histocompatibility Complex (MHC), the genetic region that encodes the proteins responsible for tissue graft rejection,1 encodes MHC Class I (MHC-I) and MHC Class II (MHC-II) glycoproteins. There are two subclasses of MHC-I proteins. Classical MHC-I (MHC-Ia) proteins are membrane-bound isoforms that are expressed in all nucleated cells of the body and present intracellular pathogen-derived peptides or the animal’s own peptides on the cell surface for immune recognition by CD8 T cells. Contrary to MHC-Ia proteins, non-classical MHC-I (MHC-Ib) molecules are less polymorphic, possess specific molecular mo-tifs in their transmembrane domains and contain premature stop codons. MHC-II proteins are expressed only by professional Antigen Presenting Cells (APC), which present extracellular pathogen-derived or self-peptides bound to MHC-II proteins on their cell surface for recogni-tion by CD4 T cells. Immunological recognition of pathogens involves proteolysis of foreign pathogen into peptides which are assembled on MHC-I and -II glycoproteins. Interaction of MHC-I and MHC-II-peptide complexes with CD8 and CD4 T Cell Receptors (TCR), respec-tively, leads to effector functions including removal of infected cells to clear the infection. The fetal allograft must remain unharmed by the mother’s potentially hostile immune system throughout the term. Several mechanisms have been reported which contribute to immune tol-erance to the fetus including the production of Transforming Growth Factor beta 1 (TGF)-β1 and Interleukin-10 (IL-10) by T-regulatory cells (Tregs), secretion of prolactin, progesterone and gonadotropin by both fetal and endometrial cells, secretion of immunosuppressive cyto-kines, chemokines, and prostaglandins which dampen T lymphocyte proliferation.2
An appropriate regulation of MHC class I genes at the maternal fetal interface is criti-cal for immunological acceptance of allogeneic conceptus.3 Trophoblast cells do not express MHC-II antigens that are expressed mainly on antigen presenting cells (APCs). However, tro-phoblast cells express immunomodulatory non-classical HLA-I antigens (HLA-Ib) molecules. Contrary to ubiquitous and highly polymorphic classical class I glycoproteins (HLA-Ia), HLA-Ib proteins are oligomorphic, undergo alternative splicing to produce membrane and soluble isoforms in specific cell/tissue types. Examples of class Ib proteins are Human Leukocyte An-tigens HLA-E, -F and -G,4-6 Qa-2 in mice,7 Mamu-AG in Rhesus Macaques,8 and Paan-AG in Olive baboons.9
HLA-G has been studied most and is a potent immunomodulatory during pregnancy. This protein is alternatively spliced to produce seven messenger RNA (mRNA) isoforms, four membrane-bound isoforms (HLA-G1, -G2, -G3, and -G4) and three soluble isoforms (HLA-G5, -G6 and -G7).10 Expression of membrane and soluble HLA-G isoforms is critically im-portant phenomenon which renders maternal immune cells inactive by serving as a ligand for leukocyte receptors during pregnancy. HLA-G is expressed, in the first trimester and at term, by extravillous and placental villous syncytiotrophoblast cells; latter only expressing non-membrane forms.10 Membrane HLA-G isoforms induce suppression of CD4+ T cells and Natural Killer (NK) cells.11 Soluble HLA-G is primarily shed or released by trophoblast cells. A minute quantity is also produced by regulatory T cells and antigen presenting cells (APCs) such as monocytes and dendritic cells.12,13 Soluble HLA-G in non-pregnant individuals reflects
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-121
Gynecol Obstet Res Open J
ISSN 2377-1542
Page 94
the quantity expressed by monocytes. Soluble HLA-G1 isoform induces apoptosis of activated CD8 T cells,14,15 down regulates CD4+ T cell proliferation and inhibits NK-cell mediated cytotox-icity.16-19 HLA-G interacts with Immunoglobulin-like transcript 2 (ILT2), Immunoglobulin-like transcript 4 (ILT4), killer cell immunoglobulin-like receptor KIR2DL4, and CD94/NKG2A receptors expressed by maternal NK-cells and inhibits their cell lysis properties. The ILT receptors are expressed by NK cells, monocytes and macrophage cells; ILT2 by B-lymphocytes, and some CD4+ and CD8+ T-lymphocytes. HLA-G, therefore, is an important immunomodulatory protein during pregnancy circum-venting the maternal immune system during pregnancy and pro-tecting the fetus.
Interactions of HLA-G with immune cells on one hand modulates the climate favorably within uterus but on the other is associated with gynecologic diseases such as preeclampsia.10 Endometriosis is an estrogen dependent disease that is character-ized by the presence of endometrial glands and stroma in ectopic locations, mainly the pelvic peritoneum, ovaries and rectovagi-nal septum. Studies suggest that eutopic endometrium expressed HLA-G only in menstrual phase and not in secretory or prolifer-ative phase. They also identified HLA-G expressing cells in the peritoneal cavity.20 In contrast, another study revealed expres-sion of HLA-G by glandular epithelium of peritoneal endome-triotic lesions and not eutopic epithelium of the subjects.21 The HLA-G expressing endometrial cells may dampen peritoneal NK cell-cytotoxicity via HLA-G-leukocyte receptor interaction thus letting endometrial implants survive and establish onto the peritoneal sites and consequently develop into endometriotic tissue implants. Eutopic endometrium of women with endome-triosis is more resistant to NK cell lysis compared to eutopic en-dometrium from women without the disease. Impaired NK cell function can favor endometrial cells evade immune system and thus develop lesions in the peritoneum.22
Endometriosis is an enigmatic and multifactorial dis-ease. An intriguing factor in the onset of endometriosis is that refluxed endometrial implants that are cleared off normally by immune cells evade the maternal immune system and establish during progression of the disease. Immunomodulatory interac-tions of HLA-G and other class Ib molecules with immune cells which protect fetal allograft may play a role in pathophysiology of endometriosis and therefore need to be addressed and consid-ered during development of research platform and therapeutic strategies for this disease.
REFERENCES
1. Klein J. Biology of the mouse histocompatibility-2 complex: principles of immunogenetics applied to a single system, Berlin and New York: Springer-Verlag, 1975.
2. Hunt JS, Petroff MG, McIntire RH, Ober C. HLA-G and im-mune tolerance in pregnancy. FASEB J. 2005; 19: 681-693.
3. Davies CJ. Why is the fetal allograft not rejected? J Anim Sci. 2007; 85(13 Suppl): E32-E35.
4. Ellis SA, Sargent IL, Redman CW, McMichael AJ. Evidence for a novel HLA antigen found on human extravillous tropho-blast and a choriocarcinoma cell line. Immunology. 1986; 59: 595-601.
5. Redman CW, McMichael AJ, Stirrat GM, Sunderland CA, Ting A. Class 1 major histocompatibility complex antigens on human extra-villous tro-phoblast. Immunology. 1984; 52(3): 457-468.
6. Geraghty DE, Koller BH, Orr HT. A human major histocom-patibility complex class I gene that encodes a protein with a shortened cytoplasmic segment. Proc Natl Acad Sci USA. 1987; 84(24): 9145-9149.
7. Warner CM, Gollnick SO, Flaherty L, Goldbard SB. Analysis of Qa-2 antigen expression by preimplantation mouse embryos: possible relationship to the preimplantation-embryo-develop-ment (Ped) gene product. Biol Reprod. 1987; 36(3): 611-616. doi: 10.1095/ biolreprod36.3.611
8. Boyson JE, Iwanaga KK, Golos TG, Watkins DI. Identifica-tion of the rhesus monkey HLA-G ortholog. Mamu-G is a pseu-dogene. J Immunol. 1996; 157: 5428-5437.
9. Langat DK, Morales PJ, Fazleabas AT, Mwenda JM, Hunt JS. Baboon placentas express soluble and membrane-bound Paan-AG proteins encoded by alternatively spliced transcripts of the class Ib major histocompatibility complex gene, Paan-AG. Im-munogenetics. 2002; 54: 164-173. doi: 10.1007/s00251-002-0454-8
10. Djurisic S, Hviid TV. HLA Class Ib molecules and immune cells in pregnancy and preeclampsia. Front Immunol. 2014; 5: 652. doi: 10.3389/fimmu.2014.00652
11. LeMaoult J, Krawice-Radanne I, Dausset J, Carosella ED. HLA-G1-expressing antigen-presenting cells induce immu-nosuppressive CD4+ T cells. Proc Natl Acad Sci USA. 2004; 101(18): 7064-7069. doi: 10.1073/pnas.0401922101
12. Feger U, Tolosa E, Huang YH, et al. HLA-G expression de-fines a novel regulatory T-cell subset present in human periph-eral blood and sites of inflammation. Blood. 2007; 110(2): 568-577. doi: 10.1182/blood-2006-11-057125 13. Alegre E, Diaz-Lagares A, Lemaoult J, Lopez-Moratalla N, Carosella ED, Gon-zalez A. Maternal antigen presenting cells are a source of plasmatic HLA-G during pregnancy: longitudinal study during pregnancy. Hum Immunol. 2007; 68(8): 661-667.
14. Le Bouteiller P, Legrand-Abravanel F, Solier C. Soluble
Gynecology and obstetrics research
Open Journalhttp://dx.doi.org/10.17140/GOROJ-2-121
Gynecol Obstet Res Open J
ISSN 2377-1542
Page 95
HLA-G1 at the maternofoetal interface-a review. Placenta. 2003; 17: S10-S15. doi: 10.1053/plac.2002.0931
15. Solier C, Aguerre-Girr M, Lenfant F, et al. Secre-tion of pro-apoptotic soluble HLA-G1 by human villous trophoblast. Eur J Immunol. 2002; 32: 3576-3586. doi: 10.1002/1521-4141(200212)32:12<3576::AID-IMMU3576> 3.0.CO;2-M
16. Lila N, Rouass-Freiss N, Dausset J, Carpentier A, Carosella ED. Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the alloproliferative response: a CD4+ T cell regulatory mechanism. Proc Natl Acad Sci USA. 2001; 98: 12150-12155. doi: 10.1073/pnas.201407398
17. Lindaman A, Dowden A, Zavazava N. Soluble HLA-G mol-ecules induce apoptosis in natural killer cells. Am J Reprod Im-munol. 2006; 56: 68-76. doi: 10.1111/j.1600-0897.2006.00395.x 18. Park GM, Lee S, Park B, et al. Soluble HLA-G generated by proteolytic shedding inhibits NK-mediated cell lysis. Bio-chem Biophys Res Commun. 2004; 313: 606-611. doi: 10.1016/j.bbrc.2003.11.153
19. Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L. Hu-man leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural kill-er function and to induce CD4+ CD25highFOXP3+ regulatory T cells. Stem Cells. 2008; 26(1): 212-222. doi: 10.1634/stem-cells.2007-0554 20. Maeda N, Izumiya C, Taniguchi K, Matsushima S, Fukaya T. Role of NK cells and HLA-G in endometriosis. Front Biosci (Schol Ed). 2012; 4: 1568-1581.
21. Barrier BF, Kendall BS, Ryan CE, Sharpe-Timms KL. HLA-G is expressed by the glandular epithelium of peritoneal endo-metriosis but not in eutopic endometrium. Hum Reprod. 2006; 21(4): 864-869. doi: 10.1093/humrep/dei408
22. Oosterlynck DJ, Cornillie FJ, Waer M, Vandeputte M, Koninckx PR. Women with endometriosis show a defect in natu-ral killer activity resulting in a decreased cytotoxicity to autolo-gous endometrium. Fertil Steril. 1991; 56(1): 45-51.