Ectopic pregnancy risk factors for ART patients undergoing the GnRH antagonist protocol: a retrospective study.

BACKGROUND: In-vitro fertilization is a known risk factor for ectopic pregnancies. We sought to establish the risk factors for ectopic pregnancy in GnRH antagonist cycles examining patient and stimulation parameters with an emphasis on ovulation trigger. METHODS: We conducted a retrospective, cohort study of 343 patients undergoing 380 assisted reproductive technology (ART) cycles with the GnRH antagonist protocol and achieving a clinical pregnancy from November 2010 through December 2015. RESULTS: Significant risk factors for ectopic pregnancy in the univariate analysis included prior Cesarean section (CS), endometriosis, mechanical factor infertility, longer stimulation, elevated estradiol and progesterone levels, GnRH agonist trigger, higher number of oocytes aspirated, and insemination technique. Independent risk factors for ectopic pregnancy in the multivariate analysis included GnRH agonist trigger, higher number of oocytes aspirated, insemination technique, and prior Cesarean section. CONCLUSION: Excessive ovarian response, IVF (as opposed to ICSI), prior Cesarean section and GnRH agonist trigger were found to be independent risk factors for ectopic pregnancy. Caution should be exercised before incorporating the GnRH agonist trigger for indications other than preventing OHSS. When excessive ovarian response leads to utilization of GnRH agonist trigger, strategies for preventing ectopic pregnancy, such as a freeze all policy or blastocyst transfer, should be considered. Further studies should elucidate whether adjusting the luteal support can reduce the ectopic pregnancy risk.

Empty follicle syndrome: successful treatment in a recurrent case and review of the literature.

Empty follicle syndrome is a condition in which no oocytes are retrieved after an apparently adequate ovarian response to stimulation and meticulous follicular aspiration. It is a rare condition of obscure etiology. A patient with primary infertility who underwent seven assisted reproductive technique cycles is described. In spite of a satisfactory ovarian response, aspiration yielded no oocytes in four cycles and 1-4 low quality oocytes in three cycles. In the index treatment cycle, ovulation was triggered using GnRH agonist 40 h prior to ovum pickup and hCG was added 6 h after the first trigger. Eighteen oocytes were recovered, of which 16 were mature and were inseminated by ICSI. Two embryos were transferred 48 h after aspiration and nine embryos were cryopreserved. The patient conceived and delivered a healthy boy at 38 weeks of gestation. The literature is reviewed and possible etiologies and treatment options of this enigmatic syndrome are suggested.

Effect of primary human endometrial stromal cells on epithelial cell receptivity and protein expression is dependent on menstrual cycle stage.

BACKGROUND: Successful implantation requires a receptive endometrium. We hypothesized that effects of endometrial stromal cells (ESC) on epithelial cell receptivity and trophoblast-endometrium interaction are menstrual cycle dependent. METHODS: An endometrial in vitro 3D co-culture model of primary human ESC with the endometrial epithelial cell line (RL95-2) was constructed. Co-cultures were prepared using primary ESC from biopsies taken before the window of implantation (ESCbw) and during the window of implantation (ESCw), on cycle days 10-17 and 19-23, respectively. RL95-2 served as a constant parameter upon which the influence of ESC from different phases of the cycle was investigated. proMMP-2 (MMP, matrix metalloproteinase) and proMMP-9 secretion was tested in response to progesterone. Progesterone receptor B (PR-B) and plexin B1 protein expression and mRNA levels were investigated using immunofluorescence and RT-PCR, respectively. RESULTS: Progesterone increased proMMP-2 secretion in primary ESCbw (P = 0.0046) but decreased proMMP-2 and proMMP-9 secretion in ESCw (P < 0.0005). In the presence of ESCbw, JAR spheroid attachment rate to overlying RL95-2 cells was decreased (P < 0.0001), whereas in the presence of ESCw, attachment rate was unchanged. Progesterone treatment restored epithelial cell receptivity in co-culture with ESCbw (P = 0.00004). A correlation between spheroid attachment rate and plexin B1 mRNA level was observed (P = 0.01). PR-B protein and mRNA level were influenced by the interplay between RL95-2 and stromal cells. CONCLUSION: The effects of human primary ESC on epithelial cell receptivity and trophoblast-endometrium interaction depended upon whether the ESC were taken before or during the window of implantation.

Enthalpy of collagen interfibrillar bonds in fetal membranes.

During pregnancy, the fetal membrane (FM) is subjected to mechanical stretching that may result in preterm labor. The structural integrity of the FM is maintained by its collagenous layer. The disconnection and reconnection of molecular bonds between collagen fibrils are the fundamental processes that govern the irreversible mechanical and supermolecular changes in the FM. Here, we study the activation enthalpy of interfibrillar bonds in ex-vivo human FM. We analyze the strain-rate and temperature dependence of the irreversible deformations in FM subjected to inflation tests, which apply mechanical conditions similar to those experienced by the FM prior to and during the initiation of labor contractions. The obtained activation enthalpy of interfibrillar bonds matches the typical enthalpy values of polyvalent ionic bonds, implying on another important role that ions like Ca and Mg may play in the gestation and labor.

Collagen bundling and alignment in equibiaxially stretched human amnion.

We study irreversible collagen arrangement processes in ex-vivo human amnions subjected to inflation tests, which simulate the mechanical conditions prior to and during the initiation of labor uterine contractions. The investigation is focused on the center of the membrane where the stresses are maximal and equibiaxial. Second harmonic generation reveals an unexpected collagen rearrangement in the compact layer that is responsible for the structural integrity of the fetal membrane. The observed bundling and alignment of the collagen fibers indicate a deviation from the expected equibiaxial stress state. The statistical analysis of the fiber orientations provides information on two driving forces for collagen alignment: microscale flaws and macroscale deviation from the equibiaxial strain. As the pressure increases, the macroscale effect becomes dominant, and a high density of fibers that are aligned along a specific direction is observed. A model that explains these observations and relates them to the material properties is presented. The results of this study indicate that a temporal increase in intrauterine pressure or uterine cervix dilatation causes irreversible changes in collagen molecular connections that may lead to biological changes, such as the initiation of term and preterm labor.

Osteosclerosis, hypoplastic nose, and proptosis (Raine syndrome): further delineation.

We describe a newborn girl with a lethal sclerosing bone dysplasia leading to prenatal skeletal alterations and microcephaly, proptosis, hypoplastic nose and midface, small jaw, cleft palate, hypertrophied gums, intracranial calcifications, and generalized osteosclerosis. There is a remarkable similarity between our patient and six previously reported infants subsequently categorized as having a distinct entity: Raine syndrome. Autosomal recessive inheritance is postulated based on parental consanguinity in several of the previous cases and in our patient.

Doppler fetal echocardiography in endocardial fibroelastosis.

BACKGROUND: Endocardial fibroelastosis is a congenital heart disease known to cause congestive heart failure in early infancy. We report a case using new modalities for early prenatal diagnosis of endocardial fibroelastosis causing fetal heart failure. CASE: A multipara with two children, who died of endocardial fibroelastosis, was referred for fetal echocardiography at 20 weeks' gestation. A mildly asymmetric four-chamber view with slightly enlarged atria and no other fetal heart abnormalities suggested endocardial fibroelastosis. Doppler studies demonstrated abnormal cardiac function with extremely low atrioventricular E/A ratio, defined as the ratio between the rapid ventricular filling (E wave) and the atrial systole (A wave), and abnormal venous flow velocity waveforms establishing the diagnosis. On a repeat scan 2 weeks later, the abnormal morphologic signs suggesting endocardial fibroelastosis were more prominent, and pregnancy was terminated. CONCLUSION: When morphologic signs are not definitive, Doppler studies of the fetal heart may be useful in making the diagnosis of endocardial fibroelastosis.

Internal jugular vein blood flow in normal and growth-restricted fetuses.

OBJECTIVE: To assess internal jugular vein blood flow patterns during the second half of pregnancy in normal and growth-restricted fetuses. METHODS: We did Doppler ultrasound studies of internal jugular veins and the inferior vena cavas longitudinally on 21 normal singleton fetuses from 20 weeks to term, and on eight growth-restricted fetuses with absent end-diastolic flow at the umbilical artery (UA). The three components of the venous flow velocity waveforms were used to calculate peak velocity ratio: Peak systolic velocity (S wave) minus reverse peak velocity (R wave) divided by peak velocity during early diastole (D wave) and velocity time integral ratio: systolic velocity time integral minus reverse velocity time integral divided by velocity time integral during early diastole. Statistical analysis of longitudinal measurements used K-related samples Friedman test; groups were compared with Mann-Whitney U test and chi(2) test. RESULTS: In normal fetuses we found significant increases in peak velocity ratio and velocity time integral ratio of internal jugular veins and the inferior vena cavas throughout gestation. The mean +/- standard deviation (SD) of the internal jugular veins peak velocity ratio (1.12 +/- 0.4 versus 1.46 +/- 0.15, P <.05) and velocity time integral ratio (1.1 +/- 0.2 versus 1.55 +/- 0.17, P <.05) were significantly lower in growth-restricted fetuses compared with normal fetuses at 28-32 weeks' gestation but inferior vena cava indices were not. None of the eight growth-restricted fetuses had umbilical venous pulsations or changes in inferior vena cava or ductus venosus blood flow patterns. All had arterial pH above 7.15 at birth. CONCLUSION: Growth-restricted fetuses with absent end-diastolic velocity in the UA have changes in internal jugular vein blood flow patterns that probably indicate increased cerebral blood flow, more evidence of redistribution of blood flow in growth-restricted fetuses that can be used to maintain them.

Comparison of 12- and 72-hour expectant management of premature rupture of membranes in term pregnancies.

OBJECTIVE: To compare 12-hour and 72-hour expectant management of premature rupture of membranes (PROM) in singleton term pregnancies. METHODS: In a prospective, nonrandomized study, 566 low-risk women with singleton term pregnancies presenting with PROM were assigned to either 12-hour or 72-hour expectant management. Patients who had not entered labor at the end of the assigned period were induced with oxytocin. The pregnancy outcome of both methods was compared with regard to infectious complications and method of delivery. RESULTS: There was no statistical difference in the rate of chorioamnionitis between the 12-hour and 72-hour expectant management groups (11.7 versus 12.7%; relative risk [RR] 0.9, 95% confidence interval [CI] 0.6-1.5; P = .83). Cesareans were performed to a similar degree in both groups (4.7 versus 6.7%; RR 0.7, 95% CI 0.3-1.4; P = .39). Fifty-five percent of the 12-hour group underwent oxytocin induction, compared with 17.5% of those in the 72-hour group (RR 5.8, 95% CI 3.9-8.5; P < .001). Women undergoing induction after 72-hour expectant management had an increased risk of cesarean delivery compared with those after a 12-hour wait (RR 5.9, 95% CI 2.3-15.1; P < .001). Overall, women in the 12-hour group had shorter admission-to-discharge times than the 72-hour group (5 versus 6 days, 95% CI of the difference 0.6-1.3; P < .01). CONCLUSION: Regimens of 12-hour and 72-hour expectant management of PROM are comparable regarding infectious complications and pregnancy outcome. However, the longer wait prolongs the interval to delivery and increases hospitalization costs.

Laparoscopic management of adnexal cystic masses in postmenopausal women.

OBJECTIVE: To evaluate laparoscopic treatment of postmenopausal women with an adnexal cystic mass predicted to be benign. METHODS: Selection criteria were transvaginal sonographic appearance other than a complex cyst and a normal serum CA 125 level. During the period May 1988 to June 1993, 55 women fulfilled the criteria and underwent operative laparoscopy. During the same period, 75 postmenopausal women underwent exploratory laparotomy for an adnexal cystic mass that was complex in appearance or associated with elevated serum CA 125. RESULTS: Laparoscopic bilateral oophorectomy was performed in all 55 women. All had benign masses (positive predictive value 100%). Malignant tumors were found in 23 of the 75 women undergoing laparotomy (negative predictive value 30.7%). There was no significant difference in size of the tumors between women undergoing laparoscopy or laparotomy. CONCLUSION: Because of its safety and efficacy, laparoscopic management is the preferred procedure in postmenopausal women with a non-complex adnexal mass and a normal CA 125 level.

Pseudomonoamniotic twins with cord entanglement following genetic funipuncture.

Amniocentesis was performed twice on a twin gestation, and twice there was cell growth failure in one of the twins. Therefore, funipuncture was attempted at 24 weeks. The anatomical relationship and position of the fetuses, placental cord insertion, and membranous septum dictated needle entry into the cord of the lower left fetus through the sac of the upper right fetus and the septum. The procedure was uneventful and the pregnancy was carried to 39 weeks. However, the septum between the twins had been disrupted, creating a pseudomonoamniotic pregnancy. This was noticed only after delivery of the first fetus, when it was found that the two umbilical cords were entangled. We believe that, whenever possible, puncture of the membrane between twins should be avoided. Should puncture be necessary, the possibility of pseudomonoamniotic twins must be considered.

Prenatal diagnosis of fetal primary cytomegalovirus infection.

OBJECTIVE: To evaluate the validity of prenatal diagnosis work-up for congenital cytomegalovirus (CMV) in women with primary infection. METHODS: Sixty-three pregnant women with primary cytomegalovirus disease (including two with twin pregnancies), referred to three tertiary perinatal centers over 4 years, underwent evaluation for congenital cytomegalovirus. Fetal diagnosis was made after 21 weeks' gestation by amniocentesis and fetal blood sampling (40 subjects), or amniocentesis only (23 subjects). RESULTS: Twenty-two (35%) pregnancies showed evidence of vertical transmission: 13 of them underwent funipuncture, but only ten (77%) of the 13 showed positive immunoglobulin (Ig)-M results in fetal blood. No cases of positive fetal serum Ig-M with negative amniotic fluid culture or polymerase chain reaction were observed. In nine (41%) of the 22 pregnancies with evidence of vertical transmission, abnormal ultrasonographic findings were recorded. Six (27%) women with evidence of vertical transmission continued their pregnancies and in only one (with prenatal ultrasonographic abnormalities) was an infant born with neurologic sequelae. In 41 (65%) pregnancies, no evidence of vertical transmission was found, and 37 continued to term. Only one newborn from this subgroup subsequently showed mild motor disability during a median of 23 months of follow-up. CONCLUSION: Among pregnant patients with primary CMV infection, analysis of amniotic fluid detected all of the infected fetuses. Thus, this is a reliable tool for counseling pregnant women with primary infection. This may guide the patient as to whether or not pregnancy can be continued with a high level of confidence.

External bladder--amniotic fluid shunt for fetal urinary tract obstruction.

Ultrasound diagnosis of bilateral hydronephrosis, hydroureters, and megacystis together with oligohydramnios secondary to urethral stenosis was made in a male fetus at 29 weeks' gestation. In utero decompression of the obstructed urinary tract and expansion of the amniotic fluid was achieved by placing an external bladder-amniotic fluid shunt using two catheters, one inserted into the fetal bladder and the other placed in the amniotic sac. The infant was delivered by cesarean section at 35 weeks' gestation and had a favorable outcome.

Laparoscopic gonadectomy in 46XY female patient.

The risk of gonadal neoplasia in XY gonadal streaks is high, dictating early prophylactic removal of the streaks. Laparoscopic removal of the streaks is recommended.

Can we abandon routine evaluation of serum estradiol levels during controlled ovarian hyperstimulation for assisted reproduction?

OBJECTIVE: To assess whether abandoning measurement of serum estradiol (E2) and spacing ultrasound evaluations at greater intervals had an effect on the results of assisted reproduction technology (ART). DESIGN: A retrospective comparison of two consecutive periods. SETTING: Division of Assisted Reproduction Technology, Department of Obstetrics and Gynecology, Ha'Emek Medical Center, Afula, Israel. PATIENT(S): One thousand nine hundred and eighty-five controlled ovarian hyperstimulation (COH) cycles for ART were initiated during the years 1996 to 1999. INTERVENTION(S): During the first 2 years an intensive follow-up protocol was used that included E2 blood levels measurements. In the next 2 years a less intensive protocol was adopted that did not use E2 measurements. MAIN OUTCOME MEASURE(S): ART results and the rate of ovarian hyperstimulation syndrome (OHSS). RESULT(S): The patients' background characteristics did not differ between the two periods. The cancellation rate was not different (9.8% vs. 7.2%). There was no difference in the duration of stimulation or the amount of gonadotropins used. The number of oocytes retrieved (12.1 +/- 9.3 vs. 9.6 +/- 6.3), fertilization rates (74% vs. 75%), and clinical pregnancy rates (26.2% vs. 27.9%) did not differ. The incidence of severe ovarian hyperstimulation syndrome was not significantly different between the two periods. CONCLUSION(S): Controlled ovarian hyperstimulation for ART can be done reliably without routine, serial serum E2 measurements without compromising the treatment results.

Laparoscopic subtotal hysterectomy and bilateral adnexectomy in a child with congenital adrenal hyperplasia.

OBJECTIVE: To report the results of a subtotal hysterectomy and bilateral adnexectomy in a child with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. DESIGN: Case report. SETTING: Gynecology department, Afula, Israel. PATIENT(S): An 11-year-old child with a female genotype and saltwasting type congenital adrenal hyperplasia who was being raised as a boy. INTERVENTION(S): Laparoscopic subtotal hysterectomy and bilateral salpingo-oophorectomy were performed. MAIN OUTCOME MEASURE(S): Surgical efficiency, operating time, recovery, and aesthetic result. RESULT(S): The procedure was performed without complications in 26 minutes, and the child was dismissed the following day. Three 5-mL abdominal incisions were required. CONCLUSION(S): Laparoscopic subtotal hysterectomy and bilateral adnexectomy can be safely performed in children and is the procedure of choice in the rare cases in which it is indicated.

Spontaneous resolution of ectopic tubal pregnancy: natural history.

OBJECTIVE: To determine the characteristics and long-term outcome of women succeeding or failing expectant management of ectopic pregnancy (EP). DESIGN: Prospective, defined protocol. SETTING: University-affiliated gynecology department. PATIENTS: We used a protocol that selected women with laparoscopic confirmed ectopic tubal pregnancy and declining plasma hCG values. Over a 5-year period, 60 women representing 20.1% of EPs fulfilled the inclusion criteria. Women were followed with serial hCG testing and transvaginal ultrasound. MAIN OUTCOME MEASURE: Success or failure of expectant management. RESULTS: Expectant management was successful in 28 (47.7%) of the patients. Thirty-two (53.3%) failed expectant management, and a treatment procedure was required. There was no difference in the resultant ipsilateral tubal patency or 1-year fertility rates of those women succeeding or failing expectant management. Analysis showed that in the face of declining values and with a starting hCG > 2,000 mIU/mL (conversion to SI unit, 1.00), 93.3% failed expectant management, whereas < 2,000 mIU/mL, 60.0% succeeded. CONCLUSION: We conclude that expectant management should be offered as a treatment option only in those women fulfilling the criteria for a good prognosis.

Limited role for intratubal methotrexate treatment of ectopic pregnancy.

OBJECTIVE: To test the effectiveness of laparoscopic intratubal methotrexate (MTX) injection or salpingostomy in the treatment of ectopic pregnancy (EP). DESIGN: Prospective predefined protocol. SETTING: Department of Obstetrics and Gynecology of a university-affiliated hospital. PATIENTS AND INTERVENTIONS: Between January 1988 and December 1993, we treated 342 women with EP, of which 99 were treated by either laparoscopic salpingostomy (n = 55) or intratubal MTX injection (n = 44). MAIN OUTCOME MEASURES: The success and failure rates were calculated for each treatment protocol. Also analyzed were subsequent tubal patency and fertility rates. RESULTS: Salpingostomy was successful in 51 of 55 patients (92.7%), whereas intratubal MTX injection was successful in only 27 of 44 women (61.4%). Methotrexate injection particularly was unsuccessful if the initial hCG was > 2,000 mIU/mL (conversion factor to SI unit, 1.00) or the size of the tubal mass was > 2.0 cm as measured during laparoscopy. There was no difference in the subsequent tubal patency rates of fertility rates between women undergoing MTX injection or salpingostomy. CONCLUSIONS: These results suggest that salpingostomy is effective in the treatment of EP. Methotrexate injection failed in more patients despite preferential selection criteria, suggesting that its use should be limited to the subgroup of women with initial hCG < 2,000 mIU/mL and size at laparoscopy < 2.0 cm.

Transvaginal sonography as the ultimate diagnostic tool for the management of ectopic pregnancy: experience with 840 cases.

OBJECTIVE: To evaluate the efficacy of transvaginal sonography and serum beta-hCG levels as diagnostic tools for deciding whether to perform operative laparoscopy in the treatment of presumed ectopic pregnancy (EP). DESIGN: A prospective protocol for the evaluation and treatment of women with presumed EP. SETTING: Department of Obstetrics and Gynecology, Haemek Medical Center, Afula, Israel. PATIENT(S): Eight hundred forty women with presumed EP who were seen in our emergency department from January 1988 through December 1995. INTERVENTION(S): On the basis of specific sonographic signs and beta-hCG levels, we performed immediate operative laparoscopy in patients with demonstrable extrauterine fetal heart activity or >100 mL of fluid in the pelvic cavity. We followed up all other patients, using defined criteria for laparoscopic intervention. MAIN OUTCOME MEASURE(S): The accuracy of transvaginal sonography in predicting EP was evaluated as part of the described protocol. RESULT(S): Overall, 380 patients were found to have EP. Of these, 331 were identified positively by transvaginal sonography and 49 were not. In 27 of 358 laparoscopies, no EP was found. The sensitivity of transvaginal sonography for the prediction of EP was 87% and the specificity was 94%. The positive and negative predictive values were 92.5% and 90%, respectively. CONCLUSION(S): In this protocol, which invariably captured the true location of the products of conception, using transvaginal sonography as the primary modality in the evaluation of patients with presumed EP resulted in the use of laparoscopy mainly as a treatment tool. This approach is both safe and economical.

Methotrexate as a possible cause of ovarian cysts formation: experience with women treated for ectopic pregnancies.

OBJECTIVE: To evaluate ovarian morphology after either salpingostomy or local injection of methotrexate (MTX) to cause regression of tubal pregnancies and to define potential correlation to other clinical parameters. DESIGN: Prospective longitudinal follow-up. SETTING: Department of Obstetrics and Gynecology, Haemek Medical Center, Afula, Israel. PATIENT(S): One hundred one women who were treated for tubal pregnancy: 58 by salpingostomy and 43 by local MTX injection. INTERVENTION(S): Serial blood sampling for beta-hCG and serial transvaginal sonographic evaluation. MAIN OUTCOME MEASURE(S): Appearance of cysts in the ovaries and their location with regard to the side in which the tubal pregnancy occurred. RESULT(S): In 6 of 42 (14.3%) patients who were treated with MTX, multiple (range, three to six) ovarian cysts occurred, as compared with 1 of 55 (1.8%) in those who underwent salpingostomy. The largest cyst was 9.4 cm in diameter. No relation of cyst occurrence to the side of the ectopic pregnancy was recorded. The women who developed cysts did not differ in either initial serum beta-hCG levels or in the rate of its subsequent regression. CONCLUSION(S): Multiple ovarian cysts may occur in 15% of patients who are treated with intra-amniotic MTX to cause regression of tubal ectopic pregnancy.