Implanting Uncertainty Into the Emergency Dept

Infertility is a growing medical problem affecting 1 in 6 couples with a median prevalence of 9%. Approximately 40.5 million people are currently seeking infertility medical care. As the use of Assisted Reproductive Technology (ART) continues to grow in an effort to overcome infertility, EP’s must be aware of the process, presentation, and potential complications associated with this treatment…

Infertility is a growing medical problem affecting 1 in 6 couples with a median prevalence of 9%. Approximately 40.5 million people are currently seeking infertility medical care. As the use of Assisted Reproductive Technology (ART) continues to grow in an effort to overcome infertility, EP’s must be aware of the process, presentation, and potential complications associated with this treatment modality given the potential for both morbidity and mortality in an otherwise “healthy” population. A high index of suspicion coupled with an expanded obstetrical/gynecologic history and utilization of ultrasound is pivotal to successful outcomes in this patient population.

Case 1:
A 36-year-old female presents to the ED with CC of generalized abdominal pain/distension for the past 5d with three episodes of emesis PTA. PMHx/Obstetrical history is significant for current ART treatment with a recent trigger injection of HCG and oocyte retrieval 3d ago. Vitals on presentation are unremarkable. Exam reveals increasing abdominal girth and nonspecific tenderness in the B/L lower quadrants. Pelvic exam reveals no gross blood/discharge, normal cervix (os closed), and mild B/L adnexal tenderness/fullness. Patient is HCG (-). During the patients ED course, the patient’s reports increasing dyspnea with an abrupt change in hemodynamic status. Repeat vitals: 90/P; HR 122; RR 28; Sat 92% RA. Stat CXR reveals a right sided pleural effusion and bedside US performed has fluid in Morrison’s pouch. Paracentesis was performed along with administration of albumin which resulted in improvement in patient’s status.

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Ovarian Hyperstimulation Syndrome (OHSS)
OHSS is an iatrogenic complication of ovarian stimulation that results when fluid shifts from the intravascular to third space due to increased vascular permeability. Any medication that induces ovulation or ovarian stimulation can cause OHSS – most commonly, clomiphene or gonadotropins. There are two distinct forms of OHSS based on the number of days since oocyte aspiration. Early OHSS (10 days) is due to endogenous release of HCG secondary to pregnancy and is often more severe in presentation.

There are multiple classification schemes in the literature that incorporate ultrasound to determine the presence/absence of ascites coupled with ovarian enlargement. For practical purposes in the ED, the EP should rely on clinical features (e.g. abdominal pain, umbilical circumference, nausea, vomiting, diarrhea, dyspnea) and laboratory parameters (e.g. HCT, renal function, hypoalbuminemia) rather than ovarian enlargement (often a false negative in the context of IVF after oocyte retrieval) to guide management decisions. Initial diagnostics should include a CBC, BMP, LFT’s, and coagulation studies. In general, the clinical course is self limiting and requires supportive treatment with resolution usually within two weeks (unless pregnancy occurs). Intravenous fluid resuscitation should be initiated on all patients regardless of classification upon their ED presentation.

Case #2:

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A 32-year-old female presents to the ED with CC of RLQ abdominal pain x 3h with one episode of emesis. PMHx/Obstetrical history is significant for current ART treatment with a recent frozen embryo transfer 10 days ago. Patient is afebrile with a WBC of 13,000 and HCG (+). Examination reveals RLQ TTP with accompanying adnexal tenderness – no peritoneal signs. You perform a diagnostic sonogram that reveals diffuse enlargement of the ovary (with loss of margin) with Doppler flow present. Laparoscopy was performed with salpingo-oophrectomy.

Adnexal Torsion (AT)
To risk stratify this patient, an understanding of the process and timeline of ART as it relates to in vitro fertilization embryo transfer (IVF-ET) and its terminology is presented here.
In IVF-ET, there are two types of transfer – fresh or frozen. The above cycle represents a fresh cycle transfer. Couples have the option of cryofreezing embryos to be used at a later date. In either case, embryo transfer (and the luteal phase) is supported with additional medications (e.g. progesterone, estrogen) for the next 2-12 weeks after implantation.

Within ART, there are multiple entry points at which time patients may present to your ED with short/ long term complications of IVF. These may be as simple as medication side effects (e.g. .headache, abdominal pain, vomiting, drowsiness, vaginal bleeding, cellulitis/abscess secondary to IM injections); infectious sequelae following instrumentation during oocyte retrieval, thromboembolic phenomena, or AT. Along with the traditional risk factors of ovarian cysts and pregnancy, ART predisposes patients to the development of this rare but organ threatening condition as a result of the effect of exogenous hormones on the ovaries. As a general rule, torsion typically occurs in patients with an ovarian size between 5-10 cm. Recall that Doppler flow may be present on US even in the case of torsion, thus making this diagnosis a challenging one.

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Case #3:
A 41 yo female presents to the ED with abdominal pain and dizziness. PMHx/Obstetrical history is significant for current ART treatment with oocyte retrieval yesterday. Vitals: BP 100/60, HR 104, RR 22, 99.4 F. After initiating fluid resuscitation, a bedside FAST is positive for fluid in the Pouch of Douglas. Patient was noted to have a pelvic hematoma which was managed conservatively.

Hemorrhage s/p oocyte retrieval
As discussed in the timeline above, oocyte retrieval typically occurs 2 weeks after the start of a simulated cycle. This procedure is performed by needle aspiration utilizing transvaginal US and is the gold standard in IVF therapy. Intra-abdominal bleeding is a serious side effect of this procedure secondary to direct damage of pelvic vessels or trauma to pelvic organs. In rare cases, bleeding may occur in the retroperitoneum (due to injury of the mid sacral vein). In contrast to major bleeding, the most common complication of transvaginal oocyte retrieval is minor vaginal hemorrhage due to direct trauma to vaginal vessels. Hemostatic control by direct pressure usually suffices in these cases but suture repair may be necessary. Care should be taken to apply direct pressure without the use of the speculum (after first identifying the lesion) since overstretching of the vaginal walls prolongs bleeding time.

Case #4:
A 32-year-old hemodynamically stable female presents to the ED with CC of LLQ abdominal pain and spotting x 36h. Patient reports nausea with one episode of emesis. PMHx/Obstetrical history is significant for recent embryo transfer 3 wks ago. Patient has a low grade temperature, with a WBC 12,500 and HCG (+). Examination reveals LLQ TTP wi
th accompanying adnexal tenderness – no peritoneal signs. A bedside US reveals a hyperechoic ring around a gestation sac in the left adnexa (tubal ring sign). Patient was treated medically with methotrexate therapy.

Ectopic Pregnancy (EP)
As with any female presenting to the ED with a constellation of abdominal pain ± vaginal bleeding, EP must be considered as a priori in the differential diagnosis. The incidence of EP in natural pregnancy is 1.9% v. 2.1-9.4% in IVF. In addition to EP, women who undergo IVF are at an increased risk of heterotopic pregnancy – incidence of 1:100 (compared to 1:15,000-30,000 in natural pregnancy). This is due to the fact that more than one embryo may be implanted at the time of IVF-ET. Confirmation of an IUP alone will not suffice in patients who have more than one embryo implanted and the EP must be hypervigilant to exclude heterotopic pregnancy.

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What entry point in the time line is the patient presenting (e.g. endogenous suppression, follicle stimulation, post oocyte retrieval, post implantation)?

Is the cycle is a fresh or frozen transfer?

How many days following oocyte retrieval did the transfer occur?

Calculate the adjusted LMP – patients undergoing IVF treatment will not have the estimated gestational age calculated on their last menstrual period.

IVF-ET transfer in fresh cycle (at 3 days post oocyte retrieval) – reduction of 17 days from the date of embryo transfer.

IVF-ET transfer in frozen cycle (blastocyst) – reduction of 19 days from the date of embryo transfer.

Example: Embryo transfer (12/1/2010) – calculated LMP is 11/14/2010 for fresh transfer; 11/12/2010 for frozen cycle.

How many embryos were transferred?

Bibliography

1. Vloeberghs, V., K. Peeraer, et al. (2009). “Ovarian hyperstimulation syndrome and complications of ART.” Best Pract Res Clin Obstet Gynaecol 23(5): 691-709.
2. Levison, J. H., R. L. Barbieri, et al. “Clinical problem-solving. Hard to conceive.” N Engl J Med 363(10): 965-70.
3. The Management of Ovarian Hyperstimulation Syndrome Green Top Guideline No.5 (2006). Royal College of Obstetricians and Gynaecologists. Available at: http://www.rcog.org.uk/files/rcog-corp/uploaded-files/GT5ManagementOvarianHyperstimulation.pdf.  Accessed November 2010.
4. Chan, W. S. and M. E. Dixon (2008). “The “ART” of thromboembolism: a review of assisted reproductive technology and thromboembolic complications.” Thromb Res 121(6): 713-26.
5. Al-Shawaf, T., A. Zosmer, et al. (2005). “Safety of drugs used in assisted reproduction techniques.” Drug Saf 28(6): 513-28.
5. El-Shawarby, S., R. Margara, et al. (2004). “A review of complications following transvaginal oocyte retrieval for in-vitro fertilization.” Hum Fertil (Camb) 7(2): 127-33.
6. Ludwig, A. K., M. Glawatz, et al. (2006). “Perioperative and post-operative complications of transvaginal ultrasound-guided oocyte retrieval: prospective study of >1000 oocyte retrievals.” Hum Reprod 21(12): 3235-40.
7. Klemetti, R., T. Sevon, et al. (2005). “Complications of IVF and ovulation induction.” Hum Reprod 20(12): 3293-300.
8. IVF Complications. http://www.ivf-worldwide.com/Education/ivf-complications.html.  Accessed November 2010.
9. Revel, A., I. Ophir, et al. (2008). “Changing etiology of tubal pregnancy following IVF.” Hum Reprod 23(6): 1372-6.
10. CDC Assisted Reproductive Technology Surveillance – United States 2007. Available at: http://www.cdc.gov/art/ART2007/PDF/COMPLETE_2007_ART.pdf.  Accessed November 2010.