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Successful treatment algorithm for evaluation of early pregnancy after in vitro fertilization
Successful treatment algorithm for evaluation of early pregnancy after in vitro fertilization Lisa Marii Cookingham, M.D., Rachel P. Goossen, B.A., Amy E. T. Sparks, Ph.D., Bradley J. Van Voorhis, M.D., and Eyup Hakan Duran, M.D. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Iowa College of Medicine, Iowa City, Iowa
Objective: To evaluate a prospectively implemented clinical algorithm for early identification of ectopic pregnancy (EP) and heterotopic pregnancy (HP) after assisted reproductive technology (ART). Design: Analysis of prospectively collected data. Setting: Academic medical center. Patient(s): All ART-conceived pregnancies between January 1995 and June 2013. Intervention(s): Early pregnancy monitoring via clinical algorithm with all pregnancies screened using human chorionic gonadotropin (hCG) levels and reported symptoms, with subsequent early ultrasound evaluation if hCG levels were abnormal or if the patient reported pain or vaginal bleeding. Main Outcome Measure(s): Algorithmic efficiency for diagnosis of EP and HP and their subsequent clinical outcomes using a binary forward stepwise logistic regression model built to determine predictors of early pregnancy failure. Result(s): Of the 3,904 pregnancies included, the incidence of EP and HP was 0.77% and 0.46%, respectively. The algorithm selected 96.7% and 83.3% of pregnancies diagnosed with EP and HP, respectively, for early ultrasound evaluation, leading to earlier treatment and resolution. Logistic regression revealed that first hCG, second hCG, hCG slope, age, pain, and vaginal bleeding were all independent predictors of early pregnancy failure after ART. Conclusion(s): Our clinical algorithm for early pregnancy evaluation after ART is effective for identification and prompt intervention of EP and HP without significant over- or misdiagnosis, Use your smartphone and avoids the potential catastrophic morbidity associated with delayed diagnosis. (Fertil SterilÒ to scan this QR code 2015;104:932–7. Ó2015 by American Society for Reproductive Medicine.) and connect to the Key Words: ART, algorithm, ectopic, heterotopic, IVF Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/cookinghaml-early-pregnancy-evaluation-ivf/
P
regnancies conceived by in vitro fertilization (IVF) are typically monitored by reproductive endocrinologists using both serial human chorionic gonadotropin (hCG) measurements and ultrasound examinations. The purpose is to determine the viability, location, and number of implanting embryos. Of particular concern are ectopic pregnancy (EP) and heterotopic pregnancy (HP)
because of the significant potential for morbidity if the diagnosis is delayed. There is compelling evidence that EPs behave differently than viable, singleton intrauterine pregnancies, having generally lower hCG levels at the same gestational age (1). Retrospective studies of IVF-conceived pregnancies have established that pregnancies with an initial hCG value below 50 IU/ L are at particularly high risk for mis-
Received April 6, 2015; revised June 11, 2015; accepted July 6, 2015; published online August 8, 2015. L.M.C. has nothing to disclose. R.P.G. has nothing to disclose. A.E.T.S. has nothing to disclose. B.J.V.V. has nothing to disclose. E.H.D. has nothing to disclose. Reprint requests: Lisa Marii Cookingham, M.D., Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, Iowa 52242 (E-mail: [email protected]). Fertility and Sterility® Vol. 104, No. 4, October 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2015.07.1133 932
discussion forum for this article now.*
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carrying or being an EP (2–4). In addition to the initial hCG level, it is common practice to obtain a second hCG approximately 48 hours later to determine the percentage of rise between the two values. This is performed to identify those cases that are more likely to be nonviable; for example, a decrease, plateau, or minimal rise in hCG (<66%) is likely indicative of a failing pregnancy (5). Multiple lines of evidence suggest that pregnancies conceived via assisted reproductive technologies (ART) with low initial hCG levels or an abnormal rise in hCG deserve special attention with early surveillance and close monitoring, as they are more commonly associated with adverse pregnancy VOL. 104 NO. 4 / OCTOBER 2015
Fertility and Sterility® outcomes (3, 6–8). Based on these retrospective data, we prospectively implemented a clinical algorithm for monitoring ART pregnancies that combined a strategy of initial and follow-up hCG monitoring as well as patient reporting of specific symptoms to time subsequent ultrasound examinations. The goal of this algorithm was to identify pregnancies at high risk for failing, particularly those that are an EP or HP, and target these pregnancies for an early ultrasound evaluation and hopefully an earlier diagnosis. Conversely, pregnancies at relatively low risk for complications were scheduled for a later ultrasound evaluation at a time when viability can be more reliably determined, thus limiting the number of visits and ultrasound examinations for these patients. Another important goal was avoiding premature intervention in these pregnancies, such as giving methotrexate to a pregnancy of unknown location that subsequently turns out to be a viable intrauterine pregnancy (IUP). The purpose of this study was to evaluate this clinical algorithm to determine its effectiveness in meeting these clinical goals. We also sought to identify and compare early predictors of all early pregnancy failures after an ART cycle, and to determine if our current algorithm resulted in early, safe and successful treatment of EP and HP.
MATERIALS AND METHODS
was instructed to call in and an ultrasound was performed immediately. For purposes of this analysis, an ‘‘early’’ ultrasound was defined as being performed <35 days and a ‘‘late’’ ultrasound as R35 days from the oocyte retrieval. This clinical algorithm is demonstrated in Figure 1. Biochemical pregnancies, characterized by hCG levels that dropped spontaneously and resolved without any treatment, were not included in this study as ultrasound examinations were not necessary. All cases of pregnancy of unknown location, where a gestational sac could not be visualized either inside or outside the uterus, were investigated with suction curettage. Diagnosis of EP was confirmed by the absence of chorionic villi in the specimen and lack of significant decrease in hCG level after the procedure. Methotrexate injection was avoided until the confirmation of EP diagnosis either as described earlier or by visualization of complex adnexal mass and/or ectopic gestational sac. Some patients elected to undergo hCG monitoring at their local laboratories for convenience; thus, there was some variability in the hCG assays used, due to the great distance that many of our patients travel for IVF treatment. However, all ultrasound examinations were performed at our center. This clinical algorithm of hCG and ultrasound monitoring has been in place at our institution for all the years included in the study.
Sample Selection
Data Analysis
This study was approved by the institutional review board of the University of Iowa (no. 201305736). Any pregnancy conceived via ART between January 1995 and June 2013 at the University of Iowa’s Center for Advanced Reproductive Care was included in this study, regardless of type of ART cycle, gamete source, type of embryo transfer, or embryo stage on transfer day. Additionally, we included patients who conceived more than one time in the designated time period.
Simple statistics were used to describe the outcomes of the clinical algorithm. For testing predictors of early pregnancy
FIGURE 1
Study Design We prospectively collected data for incorporation into an institutional database on every patient undergoing ART. Data were collected on patient characteristics, cycle characteristics, clinical pregnancy details, as well as details of all pregnancy outcomes. Specific treatment details for EP and HP were extracted from a review of the medical records when needed, with data subsequently incorporated into our preexisting ART database. All patients were scheduled for an initial serum hCG level 15 days after oocyte retrieval (first hCG), followed by a repeat hCG level (second hCG) 48 hours later. Every attempt was made to be consistent on the day of first hCG; however, scheduling difficulties permitted some variability in the timing of this blood draw. Regardless, if the first hCG measurement was <50 IU/L, or if the percentage rise after 48 hours was <70%, an ultrasound was performed 25 days after oocyte retrieval to evaluate for pregnancy location. Alternatively, if the first hCG was R50 IU/L and the percentage rise in hCG was R70%, an ultrasound was performed 35 days after oocyte retrieval. If a patient developed pelvic pain or vaginal bleeding in the interim before the ultrasound on day 35, she VOL. 104 NO. 4 / OCTOBER 2015
Flow diagram of clinical algorithm for early pregnancy evaluation after assisted reproduction technology. Monitoring of human chorionic gonadotropin (hCG) levels and evaluation by ultrasound was performed according to the clinical algorithm as pictorially represented. Cookingham. Early pregnancy evaluation after IVF. Fertil Steril 2015.
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ORIGINAL ARTICLE: EARLY PREGNANCY failures (including EP, HP, and miscarriage), a binary forward stepwise logistic regression model was built. Variables in the analysis included first hCG, second hCG, hCG slope, pain, vaginal bleeding, age, day of embryo transfer, and fresh versus cryopreserved embryos. To determine the variation in the timing of first hCG level, a histogram was created. Statistical analysis was performed using SPSS software (version 22; SPSS, Inc.).
RESULTS The demographic and clinical data for all patients who had a clinical pregnancy from ART at our center from January 1995 through June 2013 are listed in Table 1. Of the 3,904 clinical pregnancies included in our study, the incidence of EP and HP was 0.77% and 0.46%, respectively.
Clinical Outcomes Evaluated by Prospective Algorithm Using the clinical algorithm previously described, 1,640 of 3,897 (42.1%) clinical pregnancies were evaluated with an
early ultrasound (there were missing data on the timing of the ultrasound in seven pregnancies). Overall, the algorithm selected 29 (96.7%) of 30 women whose EP was eventually diagnosed and 15 (83.3%) of 18 women whose HP was eventually diagnosed for early ultrasound screening. The first criterion for early ultrasound screening was an initial hCG value of <50 IU/L, of which a total of 277 cases were identified. The majority of patients who started with low hCG levels had IUPs, with most ending as a live birth (56.2%); however, the miscarriage rates were high (Table 2). Ectopic pregnancies were most frequently identified by a first hCG <50 IU/L, with 18 (62.1%) of 29 EPs selected for early ultrasound by this criterion alone. By comparison, only 1 (6.7%) of 15 HPs had a low initial hCG level as the criterion for early ultrasound evaluation. The second criterion for early ultrasound evaluation was an hCG rise of <70% approximately 2 days after the initial hCG level. After censoring for the first criterion (hCG <50 IU/L), we identified 277 additional pregnancies that had an early ultrasound based on a second hCG level with <70% rise. Again, a majority of these cases were IUPs, with 68.6%
TABLE 1 Demographic and clinical data for all patients with a clinical pregnancy (January 1995 to June 2013). Pregnancy type Patient characteristics No. of cases Age range (y) Mean age Primary infertility diagnosis Tubal factor infertility Male factor infertility Anovulatory Endometriosis Unexplained AMA/DOR/POF Uterine factor RPL Cervical factor Other Missing data (unknown) Type of ART cycle IVF Autologous oocyte Donor oocyte Donor embryo ZIFT Autologous oocyte Donor oocyte Donor embryo Other Type of ART transfer Fresh Cryopreserved Combined (fresh þ cryopreserved) Embryo stage on transfer day Day 0 (GIFT) Day 1 (ZIFT) Day 2 (IVF) Day 3 (IVF) Day 5 (IVF)
All
Ectopic
Heterotopic
3,904 22–50 34.0
30 (0.77) 24–43 33.9
18 (0.46) 24–39 32.7
715 (18.3) 711 (18.2) 657 (16.8) 499 (12.8) 425 (10.9) 412 (10.6) 97 (2.5) 21 (0.5) 13 (0.3) 99 (2.5) 255 (6.5)
15 (50.0) 3 (10.0) 1 (3.3) 2 (6.7) 3 (10.0) 3 (10.0) 1 (3.3) 2 (6.7) 0 (0) 0 (0) 0 (0)
9 (50.0) 1 (5.6) 3 (16.7) 2 (11.1) 1 (5.6) 0 (0) 0 (0) 0 (0) 0 (0) 2 (11.1) 0 (0)
3,666 (93.9) 3,334 (90.9) 273 (7.4) 59 (1.6) 231 (5.9) 195 (84.4) 31 (13.4) 5 (2.2) 7 (0.2)
29 (96.7) 24 (82.8) 3 (10.3) 2 (6.9) 1 (3.3) 1 (100) 0 (0) 0 (0) 0 (0)
14 (77.8) 14 (100) 0 (0) 0 (0) 4 (22.2) 3 (75.0) 0 (0) 1 (25.0) 0 (0)
2,672 (68.4) 1,222 (31.3) 10 (0.3)
18 (60.0) 12 (40.0) 0 (0)
11 (61.1) 7 (38.9) 0 (0)
1 (0) 145 (3.7) 12 (0.3) 1,685 (43.2) 2,061 (52.8)
0 (0) 1 (3.3) 0 (0) 16 (53.3) 13 (43.3)
0 (0) 4 (22.2) 0 (0) 9 (50.0) 5 (27.8)
Note: Values presented as n (%), unless stated otherwise. AMA ¼ advanced maternal age; ART ¼ assisted reproduction technology; DOR ¼ diminished ovarian reserve; IVF ¼ in vitro fertilization; GIFT ¼ gamete intrafallopian transfer; POF ¼ premature ovarian failure; RPL ¼ recurrent pregnancy loss; ZIFT ¼ zygote intrafallopian transfer. Cookingham. Early pregnancy evaluation after IVF. Fertil Steril 2015.
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Fertility and Sterility®
TABLE 2 Early versus late ultrasound evaluation based on algorithmic criteria. Pregnancy type Outcomes Early ultrasounds <35 d after oocyte retrieval First hCG <50 IU/L (n ¼ 277) Live birth Miscarriage <70% rise on second hCG (n ¼ 277) Live birth Miscarriage Pain or vaginal bleeding (n ¼ 1,042) Live birth Miscarriage Late ultrasounds R35 d after oocyte retrieval
Number (n [ 3,897)
Intrauterine (n [ 3,849)
Ectopic (n [ 30)
Heterotopic (n [ 18)
n ¼ 1,640
n ¼ 1,596 258 145 (56.2%) 113 (43.8%) 271 186 (68.6%) 85 (31.4%) 1,024 871 (85.1%) 153 (14.9%)
n ¼ 29 18
n ¼ 15 1
4
2
7
11
n ¼ 2,253
n¼1
n¼3
a
n ¼ 2,257b
Note: hCG ¼ human chorionic gonadotropin. a Missing data on timing of ultrasound in seven pregnancies. b No indication for early monitoring (normal first hCG and rise, no symptoms). Cookingham. Early pregnancy evaluation after IVF. Fertil Steril 2015.
ending in live birth and 31.4% ending in miscarriage. Ectopic and heterotopic pregnancies were identified for early evaluation by this criterion exclusively in only 4 (13.8%) and 2 (13.3%) cases, respectively. The third criterion for early ultrasound evaluation was a patient report of pain or vaginal bleeding before the regularly scheduled ultrasound on day 35. After censoring for the first two criteria, we identified 1,042 additional cases that were selected by the algorithm for early ultrasound evaluation based on symptoms. Most of the IUPs ended in live birth (85.1%), with relatively few ending in miscarriage (14.9%). Heterotopic pregnancies were most frequently identified by this criterion, with 11 (73.3%) of 15 cases selected for early ultrasound by symptoms alone. By comparison, 7 (24.1%) of 29 EPs had symptoms of pain or vaginal bleeding as the sole criterion for early ultrasound evaluation. There were 44 additional pregnancies that were screened by the clinical algorithm and underwent subsequent early evaluation without a clear indication. All these cases reported a normal first hCG, normal second hCG rise, and no symptoms of pain or vaginal bleeding upon extensive record review. It is presumed that these cases were selected for early ultrasound screening based on one of the criterion that was not adequately documented, or they were selected inadvertently due to human error. All these cases resulted in a clinical IUP with the exception of 1 (6.7%) HP. Almost all of the EPs (29 of 30, 96.7%) and a majority of the HPs (15 of 18, 83.3%) underwent an early ultrasound evaluation based on the clinical algorithm (Table 3). In contrast to this high rate seen for EP and HP, only 41% of the entire population (1,596 of 3,897) received the same early ultrasound evaluation based on the clinical algorithm. Early ultrasound evaluation allowed for early diagnosis and treatment for a majority of both EP and HP cases, with a mean time of treatment being 29.0 and 31.0 days after oocyte retrieval, respectively. When assessing only those cases that had an early ultrasound leading to early initiation of treatment, the mean VOL. 104 NO. 4 / OCTOBER 2015
time of treatment for EPs and HPs was 28.3 and 28.8 days after oocyte retrieval, respectively. In contrast to the cases that were diagnosed via an early ultrasound evaluation, those diagnosed via a late ultrasound had a mean time of treatment of 35.0 and 37.7 days after oocyte retrieval, respectively. Treatment outcomes for cases of EP and HP are also noted in Table 3. As expected, the majority of EP cases diagnosed early were treated medically, and the majority of HP cases were treated surgically. Of those cases that were ‘‘missed’’ by the clinical algorithm (1 of 30 EPs, 3 of 18 HPs), thus undergoing delayed treatment, deviations were due to the following: not offered early ultrasound despite two episodes of vaginal bleeding (one case of EP); not offered early ultrasound despite one episode of vaginal bleeding (two cases of HP); identified as normal by algorithm with initial hCG >50 IU/L, appropriate hCG rise, and no symptoms (one case of HP). Regardless of early versus delayed treatment, there were no cases of ruptured fallopian tubes, and no cases requiring blood product replacement in cases treated surgically. Additionally, there were no reported short- or long-term complications from either medical or surgical intervention of all cases. Of note, 14 of the 15 HP cases undergoing surgical intervention went on to deliver the IUP without complications.
Analysis of Predictors of all Early Pregnancy Failures (Ectopic and Heterotopic Pregnancies and Miscarriages) The logistic regression analysis included 3,809 (98%) of the total 3,904 pregnancies. The model identified the following independent predictors for all early pregnancy failures (Nagelkerke r2: 0.150, df: 6, P< .001): first hCG, second hCG, hCG-slope, age, pain, and vaginal bleeding.
Timing of First hCG Although the majority of cases followed the protocol for first hCG level on the 15th day after oocyte retrieval, there was 935
ORIGINAL ARTICLE: EARLY PREGNANCY
TABLE 3 Clinical outcomes of all ectopic and heterotopic pregnancies. Pregnancy type Outcome Early ultrasound evaluation by clinical algorithm Treatment initiated <35 d after oocyte retrieval Mean age (days after oocyte retrieval) at time of treatment Treatment delayed R35 d after oocyte retrieval Mean age (days after oocyte retrieval) at time of treatment Expectant management with resolution Treatment outcomes of cases evaluated with early ultrasound Mean age (days after oocyte retrieval) at time of treatment Treatment leading to resolution Medical intervention Surgical intervention Expectant management ‘‘Missed’’ by clinical algorithm Mean age (days after oocyte retrieval) at time of treatment Treatment leading to resolution Medical intervention Surgical intervention Expectant management a
Ectopic (n [ 30)
Heterotopic (n [ 18)
29/30 (96.7%) 27 28.3 2 38.0 – 29/30 (96.7%) 29.0
15/18 (83.3%) 9 28.8 4 36.0 2 15/18 (83.3%) 31.0a
16/29 (55.1%) 13/29 (44.9%) – 1/30 (3.3%) 35.0
1/15 (6.7%) 12/15 (80.0%) 2/15 (13.3%) 3/18 (16.7%) 37.7
1/1 (100%) – –
– 3/3 (100%) –
Excludes those treated by expectant management.
Cookingham. Early pregnancy evaluation after IVF. Fertil Steril 2015.
variation among all pregnancies with a range from the 10th to 20th postretrieval day (Supplemental Fig. 1, available online). The histogram plot determined the variation in the timing of the first hCG, with 63% of all cases performed on day 15, and 93% performed between days 14 and 16. Despite the slight variation demonstrated, the logistic regression model proved intact.
DISCUSSION The overall EP rate in our study was 0.77%, which is somewhat lower than the reported incidence of 1.7% in pregnancies conceived with ART procedures nationally (9). This lower rate may be due to patient population differences or our practice of confirming pregnancies of unknown location as EP by the absence of villi using suction curettage. The clinical algorithm used for evaluation of early IVF pregnancies proved effective for early identification and treatment of nearly all patients with EP, and this study reports on the real-life outcomes of the algorithm, where 29 of 30 EPs were identified for early ultrasound. The algorithm was effective despite some variation in the laboratories used and the day of hCG measurement, suggesting it is robust for clinical application generally. Most cases of EP were identified by an abnormally low first hCG level as compared with the other criteria in the algorithm. Chart review of the one case that was not identified early revealed that she had reported two episodes of vaginal bleeding yet was not scheduled for an early ultrasound due to human error. Despite this ‘‘missed’’ case, the patient was evaluated and subsequently treated on day 35 after oocyte retrieval with methotrexate, and the EP resolved without complication. The two cases of delayed treatment of EP were both evaluated with early ultrasound (due to vaginal bleeding); however, treatment was delayed until days 37 and 39 due to uncertainty about the actual diagnosis. 936
A large majority of EP cases were treated before 7 weeks’ gestational age (corresponding to 35 days after oocyte retrieval), and more than half were able to avoid invasive surgical treatment of their EP. Furthermore, those cases that required surgical intervention were found to have nonruptured fallopian tubes and no evidence of excessive blood loss requiring transfusion. Application of the clinical algorithm allowed us to make an accurate diagnosis in a timesensitive manner while avoiding the catastrophic outcomes associated with EP. We are not aware of any cases of inadvertent methotrexate injection with an IUP in our series, which supports the safety of our algorithm in a large-scale setting. The incidence of HP is reported as 1%–3% in patients treated with ART procedures (10). In the 3,904 pregnancies that we evaluated, the incidence of HP at our institution was only 0.46%. This discordance in incidence is likely due to an overestimation of the true incidence of HP with modern IVF practice. We abandoned gamete and zygote intrafallopian transfer (GIFT and ZIFT) shortly after the starting date of this study and have emphasized single-embryo transfer for many years. Most cases of HP were identified by the third criterion (symptoms of pain or vaginal bleeding) as compared with all other criteria in the algorithm. Because the initial hCG level and hCG rise are less predictive of HP, the importance of evaluating patient symptoms by skilled early ultrasound examination in IVF-conceived pregnancies is demonstrated. A majority of HPs (15 of 18) were evaluated by early ultrasound according to the clinical algorithm, with most treated before 7 weeks’ gestational age (35 days after oocyte retrieval). The remaining cases were still diagnosed and treated relatively early (mean age of 36 days after oocyte retrieval). Within this group, there was one case that was delayed due to the uncertainty of ultrasound findings, followed by a miscarriage of the IUP, and then methotrexate administration for the tubal VOL. 104 NO. 4 / OCTOBER 2015
Fertility and Sterility® pregnancy. The final two cases were expectantly managed for nonviable IUPs, with the secondary pregnancy implanted as an interstitial mass; both cases resolved without complication or further intervention. When considering all the HPs that had early ultrasound evaluation, the mean gestational age for treatment initiation was only 2 days later than what we observed for EPs undergoing early ultrasound evaluation, allowing us to treat these cases in a time-sensitive manner and avoid a catastrophic outcome. This supports the use of our clinical algorithm even in the case of HP. There were a higher percentage of HP cases (16.7%) that evaded detection from the clinical algorithm as compared with EP, which may be expected due to the known difficulties in making this diagnosis. The three cases that evaded detection were still treated relatively early at a mean gestational age of 37.7 days after oocyte retrieval. Two of these cases should have been flagged according to the algorithm and evaluated by early ultrasound, as they both demonstrated symptoms of vaginal bleeding. The final case demonstrated normal hCG parameters and no symptoms of vaginal bleeding or pain; this was the only case that was truly missed by the clinical algorithm. The difficulty in diagnosis of HPs was also reflected in the later gestational age for diagnosis and initiation of treatment. It should be noted, however, that even with a delay in treatment, 14 of the 15 HPs treated surgically went on to have a live birth of the remaining IUP. The remaining case was found to have an anembryonic pregnancy, which subsequently ended in miscarriage. There are some inherent limitations to our clinical algorithm. Nearly half of our patients (42.1%) had an early ultrasound due to our algorithm, and yet a large majority had ongoing IUPs. One disadvantage of an early ultrasound before 7 weeks’ gestational age is the frequent need for repeat ultrasound evaluation to detect fetal cardiac activity. Thus, this algorithm has high sensitivity but low specificity for identifying early pregnancy failures, which is an appropriate strategy to minimize serious complications from delayed diagnosis of EP and HP, in our opinion. In addition, the diagnosis of EP and HP cannot always be certain with one early ultrasound. Of the 30 cases of EP at our institution, a majority (63.3%) required only the initial early ultrasound to confirm the diagnosis and proceed with treatment. The remaining cases required two (26.7%) and three (10%) ultrasound examinations to initiate treatment. In the 18 cases of HP, only 33.3% were able to be diagnosed and treated after a single ultrasound. The remaining HP cases required two (44.4%), three (16.7%), or four (16.7%) ultrasound examinations to establish a diagnosis. Our retrospective analyses of predictors of early pregnancy failure in our population support prior studies of IVF-conceived pregnancies and also support inclusion of the chosen parameters that make up this clinical algorithm. As indicated by the logistic regression, the first hCG measurement, second hCG measurement, and/or symptoms of pain or vaginal bleeding are highly and independently predictive of EP and other early pregnancy failures. One characteristic that was identified as a statistically significant predictor of EP and other early pregnancy failures
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was the presence of advancing age; however, this characteristic was not included as part of the original clinical algorithm. Additionally, we did not include infertility diagnosis into the logistic regression analysis because we had incomplete information about the presence/absence of tubal factor infertility in our ART database. It could be argued that a more comprehensive algorithm would integrate the infertility diagnosis as well as age, highlighting the strong association of both tubal factor infertility and advancing age with incidence of EP and other early pregnancy failures. Overall, we support that keen clinical judgment should trump any clinical algorithm: women with a history of tubal factor infertility and/ or advanced maternal age who present with worrisome symptoms after IVF should be evaluated early and closely, regardless of the hCG parameters.
CONCLUSION Ours is the first study of its kind to analyze a prospectively implemented clinical algorithm for identification of EP and HP. Of the parameters included in this algorithm, our data show that an abnormally low first hCG is the most common initial criterion by which EP are identified, and that symptoms of pain or vaginal bleeding are the most common initial criteria by which HP are identified. At this time, there is no consensus on how to evaluate IVF pregnancies in their early stages. We have demonstrated a clinical algorithm using hCG levels, clinical symptoms, and selective early ultrasound evaluation that is safe and effective in screening for EP and HP in this population.
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Confino E, Demir RH, Friberg J, Gleicher N. The predictive value of hCG b subunit levels in pregnancies achieved by in vitro fertilization and embryo transfer: an international collaborative study. Fertil Steril 1986;45:526–31. €stalo P, Stenman UH. Ectopic pregKorhonen J, Tiitinen A, Alfthan H, Ylo nancy after in-vitro fertilization is characterized by delayed implantation but a normal increase of serum human chorionic gonadotrophin and its subunits. Hum Reprod 1996;11:2750–7. Bjercke S, Tanbo T, Dale PO, Mørkrid L, Abyholm T. Human chorionic gonadotrophin concentrations in early pregnancy after in-vitro fertilization. Hum Reprod 1999;14:1642–6. Urbancsek J, Hauzman E, Fedorcsak P, Halmos A, Devenyi N, Papp Z. Serum human chorionic gonadotropin measurements may predict pregnancy outcome and multiple gestation after in vitro fertilization. Fertil Steril 2002;78:540–2. Kadar N, Caldwell BV, Romero R. A method of screening for ectopic pregnancy and its indications. Obstet Gynecol 1981;58:162–6. Glatstein IZ, Hornstein MD, Kahana MJ, Jackson KV, Friedman AJ. The predictive value of discriminatory human chorionic gonadotropin levels in the diagnosis of implantation outcome in in vitro fertilization cycles. Fertil Steril 1995;63:350–6. Poikkeus P, Hiilesmaa V, Tiitinen A. Serum HCG 12 days after embryo transfer in predicting pregnancy outcome. Hum Reprod 2002;17:1901–5. Seeber BE. What serial hCG can tell you, and cannot tell you, about an early pregnancy. Fertil Steril 2012;98:1074–7. Perkins KM, Boulet SL, Kissin DM, Jamieson DJ. Risk of ectopic pregnancy associated with assisted reproductive technology (ART), United States, 2001–2011. Fertil Steril 2014;102:e38–9. Fernandez H, Gervaise A. Ectopic pregnancies after infertility treatment: modern diagnosis and therapeutic strategy. Hum Reprod Update 2004; 10:503–13.
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SUPPLEMENTAL FIGURE 1
Histogram plot of variation in the timing of first human chorionic gonadotropin (hCG). As demonstrated, the majority of cases followed the protocol for first hCG on the 15th day after oocyte retrieval. Cookingham. Early pregnancy evaluation after IVF. Fertil Steril 2015.
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Objective: To evaluate a prospectively implemented clinical algorithm for early identification of ectopic pregnancy (EP) and heterotopic pregnancy (HP) after assisted reproductive technology (ART). Design: Analysis of prospectively collected data. Setting: Academic medical center. Patient(s): All ART-conceived pregnancies between January 1995 and June 2013. Intervention(s): Early pregnancy monitoring via clinical algorithm with all pregnancies screened using human chorionic gonadotropin (hCG) levels and reported symptoms, with subsequent early ultrasound evaluation if hCG levels were abnormal or if the patient reported pain or vaginal bleeding. Main Outcome Measure(s): Algorithmic efficiency for diagnosis of EP and HP and their subsequent clinical outcomes using a binary forward stepwise logistic regression model built to determine predictors of early pregnancy failure. Result(s): Of the 3,904 pregnancies included, the incidence of EP and HP was 0.77% and 0.46%, respectively. The algorithm selected 96.7% and 83.3% of pregnancies diagnosed with EP and HP, respectively, for early ultrasound evaluation, leading to earlier treatment and resolution. Logistic regression revealed that first hCG, second hCG, hCG slope, age, pain, and vaginal bleeding were all independent predictors of early pregnancy failure after ART. Conclusion(s): Our clinical algorithm for early pregnancy evaluation after ART is effective for identification and prompt intervention of EP and HP without significant over- or misdiagnosis, Use your smartphone and avoids the potential catastrophic morbidity associated with delayed diagnosis. (Fertil SterilÒ to scan this QR code 2015;104:932–7. Ó2015 by American Society for Reproductive Medicine.) and connect to the Key Words: ART, algorithm, ectopic, heterotopic, IVF Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/cookinghaml-early-pregnancy-evaluation-ivf/
P
regnancies conceived by in vitro fertilization (IVF) are typically monitored by reproductive endocrinologists using both serial human chorionic gonadotropin (hCG) measurements and ultrasound examinations. The purpose is to determine the viability, location, and number of implanting embryos. Of particular concern are ectopic pregnancy (EP) and heterotopic pregnancy (HP)
because of the significant potential for morbidity if the diagnosis is delayed. There is compelling evidence that EPs behave differently than viable, singleton intrauterine pregnancies, having generally lower hCG levels at the same gestational age (1). Retrospective studies of IVF-conceived pregnancies have established that pregnancies with an initial hCG value below 50 IU/ L are at particularly high risk for mis-
Received April 6, 2015; revised June 11, 2015; accepted July 6, 2015; published online August 8, 2015. L.M.C. has nothing to disclose. R.P.G. has nothing to disclose. A.E.T.S. has nothing to disclose. B.J.V.V. has nothing to disclose. E.H.D. has nothing to disclose. Reprint requests: Lisa Marii Cookingham, M.D., Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, Iowa 52242 (E-mail: [email protected]). Fertility and Sterility® Vol. 104, No. 4, October 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2015.07.1133 932
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carrying or being an EP (2–4). In addition to the initial hCG level, it is common practice to obtain a second hCG approximately 48 hours later to determine the percentage of rise between the two values. This is performed to identify those cases that are more likely to be nonviable; for example, a decrease, plateau, or minimal rise in hCG (<66%) is likely indicative of a failing pregnancy (5). Multiple lines of evidence suggest that pregnancies conceived via assisted reproductive technologies (ART) with low initial hCG levels or an abnormal rise in hCG deserve special attention with early surveillance and close monitoring, as they are more commonly associated with adverse pregnancy VOL. 104 NO. 4 / OCTOBER 2015
Fertility and Sterility® outcomes (3, 6–8). Based on these retrospective data, we prospectively implemented a clinical algorithm for monitoring ART pregnancies that combined a strategy of initial and follow-up hCG monitoring as well as patient reporting of specific symptoms to time subsequent ultrasound examinations. The goal of this algorithm was to identify pregnancies at high risk for failing, particularly those that are an EP or HP, and target these pregnancies for an early ultrasound evaluation and hopefully an earlier diagnosis. Conversely, pregnancies at relatively low risk for complications were scheduled for a later ultrasound evaluation at a time when viability can be more reliably determined, thus limiting the number of visits and ultrasound examinations for these patients. Another important goal was avoiding premature intervention in these pregnancies, such as giving methotrexate to a pregnancy of unknown location that subsequently turns out to be a viable intrauterine pregnancy (IUP). The purpose of this study was to evaluate this clinical algorithm to determine its effectiveness in meeting these clinical goals. We also sought to identify and compare early predictors of all early pregnancy failures after an ART cycle, and to determine if our current algorithm resulted in early, safe and successful treatment of EP and HP.
MATERIALS AND METHODS
was instructed to call in and an ultrasound was performed immediately. For purposes of this analysis, an ‘‘early’’ ultrasound was defined as being performed <35 days and a ‘‘late’’ ultrasound as R35 days from the oocyte retrieval. This clinical algorithm is demonstrated in Figure 1. Biochemical pregnancies, characterized by hCG levels that dropped spontaneously and resolved without any treatment, were not included in this study as ultrasound examinations were not necessary. All cases of pregnancy of unknown location, where a gestational sac could not be visualized either inside or outside the uterus, were investigated with suction curettage. Diagnosis of EP was confirmed by the absence of chorionic villi in the specimen and lack of significant decrease in hCG level after the procedure. Methotrexate injection was avoided until the confirmation of EP diagnosis either as described earlier or by visualization of complex adnexal mass and/or ectopic gestational sac. Some patients elected to undergo hCG monitoring at their local laboratories for convenience; thus, there was some variability in the hCG assays used, due to the great distance that many of our patients travel for IVF treatment. However, all ultrasound examinations were performed at our center. This clinical algorithm of hCG and ultrasound monitoring has been in place at our institution for all the years included in the study.
Sample Selection
Data Analysis
This study was approved by the institutional review board of the University of Iowa (no. 201305736). Any pregnancy conceived via ART between January 1995 and June 2013 at the University of Iowa’s Center for Advanced Reproductive Care was included in this study, regardless of type of ART cycle, gamete source, type of embryo transfer, or embryo stage on transfer day. Additionally, we included patients who conceived more than one time in the designated time period.
Simple statistics were used to describe the outcomes of the clinical algorithm. For testing predictors of early pregnancy
FIGURE 1
Study Design We prospectively collected data for incorporation into an institutional database on every patient undergoing ART. Data were collected on patient characteristics, cycle characteristics, clinical pregnancy details, as well as details of all pregnancy outcomes. Specific treatment details for EP and HP were extracted from a review of the medical records when needed, with data subsequently incorporated into our preexisting ART database. All patients were scheduled for an initial serum hCG level 15 days after oocyte retrieval (first hCG), followed by a repeat hCG level (second hCG) 48 hours later. Every attempt was made to be consistent on the day of first hCG; however, scheduling difficulties permitted some variability in the timing of this blood draw. Regardless, if the first hCG measurement was <50 IU/L, or if the percentage rise after 48 hours was <70%, an ultrasound was performed 25 days after oocyte retrieval to evaluate for pregnancy location. Alternatively, if the first hCG was R50 IU/L and the percentage rise in hCG was R70%, an ultrasound was performed 35 days after oocyte retrieval. If a patient developed pelvic pain or vaginal bleeding in the interim before the ultrasound on day 35, she VOL. 104 NO. 4 / OCTOBER 2015
Flow diagram of clinical algorithm for early pregnancy evaluation after assisted reproduction technology. Monitoring of human chorionic gonadotropin (hCG) levels and evaluation by ultrasound was performed according to the clinical algorithm as pictorially represented. Cookingham. Early pregnancy evaluation after IVF. Fertil Steril 2015.
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ORIGINAL ARTICLE: EARLY PREGNANCY failures (including EP, HP, and miscarriage), a binary forward stepwise logistic regression model was built. Variables in the analysis included first hCG, second hCG, hCG slope, pain, vaginal bleeding, age, day of embryo transfer, and fresh versus cryopreserved embryos. To determine the variation in the timing of first hCG level, a histogram was created. Statistical analysis was performed using SPSS software (version 22; SPSS, Inc.).
RESULTS The demographic and clinical data for all patients who had a clinical pregnancy from ART at our center from January 1995 through June 2013 are listed in Table 1. Of the 3,904 clinical pregnancies included in our study, the incidence of EP and HP was 0.77% and 0.46%, respectively.
Clinical Outcomes Evaluated by Prospective Algorithm Using the clinical algorithm previously described, 1,640 of 3,897 (42.1%) clinical pregnancies were evaluated with an
early ultrasound (there were missing data on the timing of the ultrasound in seven pregnancies). Overall, the algorithm selected 29 (96.7%) of 30 women whose EP was eventually diagnosed and 15 (83.3%) of 18 women whose HP was eventually diagnosed for early ultrasound screening. The first criterion for early ultrasound screening was an initial hCG value of <50 IU/L, of which a total of 277 cases were identified. The majority of patients who started with low hCG levels had IUPs, with most ending as a live birth (56.2%); however, the miscarriage rates were high (Table 2). Ectopic pregnancies were most frequently identified by a first hCG <50 IU/L, with 18 (62.1%) of 29 EPs selected for early ultrasound by this criterion alone. By comparison, only 1 (6.7%) of 15 HPs had a low initial hCG level as the criterion for early ultrasound evaluation. The second criterion for early ultrasound evaluation was an hCG rise of <70% approximately 2 days after the initial hCG level. After censoring for the first criterion (hCG <50 IU/L), we identified 277 additional pregnancies that had an early ultrasound based on a second hCG level with <70% rise. Again, a majority of these cases were IUPs, with 68.6%
TABLE 1 Demographic and clinical data for all patients with a clinical pregnancy (January 1995 to June 2013). Pregnancy type Patient characteristics No. of cases Age range (y) Mean age Primary infertility diagnosis Tubal factor infertility Male factor infertility Anovulatory Endometriosis Unexplained AMA/DOR/POF Uterine factor RPL Cervical factor Other Missing data (unknown) Type of ART cycle IVF Autologous oocyte Donor oocyte Donor embryo ZIFT Autologous oocyte Donor oocyte Donor embryo Other Type of ART transfer Fresh Cryopreserved Combined (fresh þ cryopreserved) Embryo stage on transfer day Day 0 (GIFT) Day 1 (ZIFT) Day 2 (IVF) Day 3 (IVF) Day 5 (IVF)
All
Ectopic
Heterotopic
3,904 22–50 34.0
30 (0.77) 24–43 33.9
18 (0.46) 24–39 32.7
715 (18.3) 711 (18.2) 657 (16.8) 499 (12.8) 425 (10.9) 412 (10.6) 97 (2.5) 21 (0.5) 13 (0.3) 99 (2.5) 255 (6.5)
15 (50.0) 3 (10.0) 1 (3.3) 2 (6.7) 3 (10.0) 3 (10.0) 1 (3.3) 2 (6.7) 0 (0) 0 (0) 0 (0)
9 (50.0) 1 (5.6) 3 (16.7) 2 (11.1) 1 (5.6) 0 (0) 0 (0) 0 (0) 0 (0) 2 (11.1) 0 (0)
3,666 (93.9) 3,334 (90.9) 273 (7.4) 59 (1.6) 231 (5.9) 195 (84.4) 31 (13.4) 5 (2.2) 7 (0.2)
29 (96.7) 24 (82.8) 3 (10.3) 2 (6.9) 1 (3.3) 1 (100) 0 (0) 0 (0) 0 (0)
14 (77.8) 14 (100) 0 (0) 0 (0) 4 (22.2) 3 (75.0) 0 (0) 1 (25.0) 0 (0)
2,672 (68.4) 1,222 (31.3) 10 (0.3)
18 (60.0) 12 (40.0) 0 (0)
11 (61.1) 7 (38.9) 0 (0)
1 (0) 145 (3.7) 12 (0.3) 1,685 (43.2) 2,061 (52.8)
0 (0) 1 (3.3) 0 (0) 16 (53.3) 13 (43.3)
0 (0) 4 (22.2) 0 (0) 9 (50.0) 5 (27.8)
Note: Values presented as n (%), unless stated otherwise. AMA ¼ advanced maternal age; ART ¼ assisted reproduction technology; DOR ¼ diminished ovarian reserve; IVF ¼ in vitro fertilization; GIFT ¼ gamete intrafallopian transfer; POF ¼ premature ovarian failure; RPL ¼ recurrent pregnancy loss; ZIFT ¼ zygote intrafallopian transfer. Cookingham. Early pregnancy evaluation after IVF. Fertil Steril 2015.
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Fertility and Sterility®
TABLE 2 Early versus late ultrasound evaluation based on algorithmic criteria. Pregnancy type Outcomes Early ultrasounds <35 d after oocyte retrieval First hCG <50 IU/L (n ¼ 277) Live birth Miscarriage <70% rise on second hCG (n ¼ 277) Live birth Miscarriage Pain or vaginal bleeding (n ¼ 1,042) Live birth Miscarriage Late ultrasounds R35 d after oocyte retrieval
Number (n [ 3,897)
Intrauterine (n [ 3,849)
Ectopic (n [ 30)
Heterotopic (n [ 18)
n ¼ 1,640
n ¼ 1,596 258 145 (56.2%) 113 (43.8%) 271 186 (68.6%) 85 (31.4%) 1,024 871 (85.1%) 153 (14.9%)
n ¼ 29 18
n ¼ 15 1
4
2
7
11
n ¼ 2,253
n¼1
n¼3
a
n ¼ 2,257b
Note: hCG ¼ human chorionic gonadotropin. a Missing data on timing of ultrasound in seven pregnancies. b No indication for early monitoring (normal first hCG and rise, no symptoms). Cookingham. Early pregnancy evaluation after IVF. Fertil Steril 2015.
ending in live birth and 31.4% ending in miscarriage. Ectopic and heterotopic pregnancies were identified for early evaluation by this criterion exclusively in only 4 (13.8%) and 2 (13.3%) cases, respectively. The third criterion for early ultrasound evaluation was a patient report of pain or vaginal bleeding before the regularly scheduled ultrasound on day 35. After censoring for the first two criteria, we identified 1,042 additional cases that were selected by the algorithm for early ultrasound evaluation based on symptoms. Most of the IUPs ended in live birth (85.1%), with relatively few ending in miscarriage (14.9%). Heterotopic pregnancies were most frequently identified by this criterion, with 11 (73.3%) of 15 cases selected for early ultrasound by symptoms alone. By comparison, 7 (24.1%) of 29 EPs had symptoms of pain or vaginal bleeding as the sole criterion for early ultrasound evaluation. There were 44 additional pregnancies that were screened by the clinical algorithm and underwent subsequent early evaluation without a clear indication. All these cases reported a normal first hCG, normal second hCG rise, and no symptoms of pain or vaginal bleeding upon extensive record review. It is presumed that these cases were selected for early ultrasound screening based on one of the criterion that was not adequately documented, or they were selected inadvertently due to human error. All these cases resulted in a clinical IUP with the exception of 1 (6.7%) HP. Almost all of the EPs (29 of 30, 96.7%) and a majority of the HPs (15 of 18, 83.3%) underwent an early ultrasound evaluation based on the clinical algorithm (Table 3). In contrast to this high rate seen for EP and HP, only 41% of the entire population (1,596 of 3,897) received the same early ultrasound evaluation based on the clinical algorithm. Early ultrasound evaluation allowed for early diagnosis and treatment for a majority of both EP and HP cases, with a mean time of treatment being 29.0 and 31.0 days after oocyte retrieval, respectively. When assessing only those cases that had an early ultrasound leading to early initiation of treatment, the mean VOL. 104 NO. 4 / OCTOBER 2015
time of treatment for EPs and HPs was 28.3 and 28.8 days after oocyte retrieval, respectively. In contrast to the cases that were diagnosed via an early ultrasound evaluation, those diagnosed via a late ultrasound had a mean time of treatment of 35.0 and 37.7 days after oocyte retrieval, respectively. Treatment outcomes for cases of EP and HP are also noted in Table 3. As expected, the majority of EP cases diagnosed early were treated medically, and the majority of HP cases were treated surgically. Of those cases that were ‘‘missed’’ by the clinical algorithm (1 of 30 EPs, 3 of 18 HPs), thus undergoing delayed treatment, deviations were due to the following: not offered early ultrasound despite two episodes of vaginal bleeding (one case of EP); not offered early ultrasound despite one episode of vaginal bleeding (two cases of HP); identified as normal by algorithm with initial hCG >50 IU/L, appropriate hCG rise, and no symptoms (one case of HP). Regardless of early versus delayed treatment, there were no cases of ruptured fallopian tubes, and no cases requiring blood product replacement in cases treated surgically. Additionally, there were no reported short- or long-term complications from either medical or surgical intervention of all cases. Of note, 14 of the 15 HP cases undergoing surgical intervention went on to deliver the IUP without complications.
Analysis of Predictors of all Early Pregnancy Failures (Ectopic and Heterotopic Pregnancies and Miscarriages) The logistic regression analysis included 3,809 (98%) of the total 3,904 pregnancies. The model identified the following independent predictors for all early pregnancy failures (Nagelkerke r2: 0.150, df: 6, P< .001): first hCG, second hCG, hCG-slope, age, pain, and vaginal bleeding.
Timing of First hCG Although the majority of cases followed the protocol for first hCG level on the 15th day after oocyte retrieval, there was 935
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TABLE 3 Clinical outcomes of all ectopic and heterotopic pregnancies. Pregnancy type Outcome Early ultrasound evaluation by clinical algorithm Treatment initiated <35 d after oocyte retrieval Mean age (days after oocyte retrieval) at time of treatment Treatment delayed R35 d after oocyte retrieval Mean age (days after oocyte retrieval) at time of treatment Expectant management with resolution Treatment outcomes of cases evaluated with early ultrasound Mean age (days after oocyte retrieval) at time of treatment Treatment leading to resolution Medical intervention Surgical intervention Expectant management ‘‘Missed’’ by clinical algorithm Mean age (days after oocyte retrieval) at time of treatment Treatment leading to resolution Medical intervention Surgical intervention Expectant management a
Ectopic (n [ 30)
Heterotopic (n [ 18)
29/30 (96.7%) 27 28.3 2 38.0 – 29/30 (96.7%) 29.0
15/18 (83.3%) 9 28.8 4 36.0 2 15/18 (83.3%) 31.0a
16/29 (55.1%) 13/29 (44.9%) – 1/30 (3.3%) 35.0
1/15 (6.7%) 12/15 (80.0%) 2/15 (13.3%) 3/18 (16.7%) 37.7
1/1 (100%) – –
– 3/3 (100%) –
Excludes those treated by expectant management.
Cookingham. Early pregnancy evaluation after IVF. Fertil Steril 2015.
variation among all pregnancies with a range from the 10th to 20th postretrieval day (Supplemental Fig. 1, available online). The histogram plot determined the variation in the timing of the first hCG, with 63% of all cases performed on day 15, and 93% performed between days 14 and 16. Despite the slight variation demonstrated, the logistic regression model proved intact.
DISCUSSION The overall EP rate in our study was 0.77%, which is somewhat lower than the reported incidence of 1.7% in pregnancies conceived with ART procedures nationally (9). This lower rate may be due to patient population differences or our practice of confirming pregnancies of unknown location as EP by the absence of villi using suction curettage. The clinical algorithm used for evaluation of early IVF pregnancies proved effective for early identification and treatment of nearly all patients with EP, and this study reports on the real-life outcomes of the algorithm, where 29 of 30 EPs were identified for early ultrasound. The algorithm was effective despite some variation in the laboratories used and the day of hCG measurement, suggesting it is robust for clinical application generally. Most cases of EP were identified by an abnormally low first hCG level as compared with the other criteria in the algorithm. Chart review of the one case that was not identified early revealed that she had reported two episodes of vaginal bleeding yet was not scheduled for an early ultrasound due to human error. Despite this ‘‘missed’’ case, the patient was evaluated and subsequently treated on day 35 after oocyte retrieval with methotrexate, and the EP resolved without complication. The two cases of delayed treatment of EP were both evaluated with early ultrasound (due to vaginal bleeding); however, treatment was delayed until days 37 and 39 due to uncertainty about the actual diagnosis. 936
A large majority of EP cases were treated before 7 weeks’ gestational age (corresponding to 35 days after oocyte retrieval), and more than half were able to avoid invasive surgical treatment of their EP. Furthermore, those cases that required surgical intervention were found to have nonruptured fallopian tubes and no evidence of excessive blood loss requiring transfusion. Application of the clinical algorithm allowed us to make an accurate diagnosis in a timesensitive manner while avoiding the catastrophic outcomes associated with EP. We are not aware of any cases of inadvertent methotrexate injection with an IUP in our series, which supports the safety of our algorithm in a large-scale setting. The incidence of HP is reported as 1%–3% in patients treated with ART procedures (10). In the 3,904 pregnancies that we evaluated, the incidence of HP at our institution was only 0.46%. This discordance in incidence is likely due to an overestimation of the true incidence of HP with modern IVF practice. We abandoned gamete and zygote intrafallopian transfer (GIFT and ZIFT) shortly after the starting date of this study and have emphasized single-embryo transfer for many years. Most cases of HP were identified by the third criterion (symptoms of pain or vaginal bleeding) as compared with all other criteria in the algorithm. Because the initial hCG level and hCG rise are less predictive of HP, the importance of evaluating patient symptoms by skilled early ultrasound examination in IVF-conceived pregnancies is demonstrated. A majority of HPs (15 of 18) were evaluated by early ultrasound according to the clinical algorithm, with most treated before 7 weeks’ gestational age (35 days after oocyte retrieval). The remaining cases were still diagnosed and treated relatively early (mean age of 36 days after oocyte retrieval). Within this group, there was one case that was delayed due to the uncertainty of ultrasound findings, followed by a miscarriage of the IUP, and then methotrexate administration for the tubal VOL. 104 NO. 4 / OCTOBER 2015
Fertility and Sterility® pregnancy. The final two cases were expectantly managed for nonviable IUPs, with the secondary pregnancy implanted as an interstitial mass; both cases resolved without complication or further intervention. When considering all the HPs that had early ultrasound evaluation, the mean gestational age for treatment initiation was only 2 days later than what we observed for EPs undergoing early ultrasound evaluation, allowing us to treat these cases in a time-sensitive manner and avoid a catastrophic outcome. This supports the use of our clinical algorithm even in the case of HP. There were a higher percentage of HP cases (16.7%) that evaded detection from the clinical algorithm as compared with EP, which may be expected due to the known difficulties in making this diagnosis. The three cases that evaded detection were still treated relatively early at a mean gestational age of 37.7 days after oocyte retrieval. Two of these cases should have been flagged according to the algorithm and evaluated by early ultrasound, as they both demonstrated symptoms of vaginal bleeding. The final case demonstrated normal hCG parameters and no symptoms of vaginal bleeding or pain; this was the only case that was truly missed by the clinical algorithm. The difficulty in diagnosis of HPs was also reflected in the later gestational age for diagnosis and initiation of treatment. It should be noted, however, that even with a delay in treatment, 14 of the 15 HPs treated surgically went on to have a live birth of the remaining IUP. The remaining case was found to have an anembryonic pregnancy, which subsequently ended in miscarriage. There are some inherent limitations to our clinical algorithm. Nearly half of our patients (42.1%) had an early ultrasound due to our algorithm, and yet a large majority had ongoing IUPs. One disadvantage of an early ultrasound before 7 weeks’ gestational age is the frequent need for repeat ultrasound evaluation to detect fetal cardiac activity. Thus, this algorithm has high sensitivity but low specificity for identifying early pregnancy failures, which is an appropriate strategy to minimize serious complications from delayed diagnosis of EP and HP, in our opinion. In addition, the diagnosis of EP and HP cannot always be certain with one early ultrasound. Of the 30 cases of EP at our institution, a majority (63.3%) required only the initial early ultrasound to confirm the diagnosis and proceed with treatment. The remaining cases required two (26.7%) and three (10%) ultrasound examinations to initiate treatment. In the 18 cases of HP, only 33.3% were able to be diagnosed and treated after a single ultrasound. The remaining HP cases required two (44.4%), three (16.7%), or four (16.7%) ultrasound examinations to establish a diagnosis. Our retrospective analyses of predictors of early pregnancy failure in our population support prior studies of IVF-conceived pregnancies and also support inclusion of the chosen parameters that make up this clinical algorithm. As indicated by the logistic regression, the first hCG measurement, second hCG measurement, and/or symptoms of pain or vaginal bleeding are highly and independently predictive of EP and other early pregnancy failures. One characteristic that was identified as a statistically significant predictor of EP and other early pregnancy failures
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was the presence of advancing age; however, this characteristic was not included as part of the original clinical algorithm. Additionally, we did not include infertility diagnosis into the logistic regression analysis because we had incomplete information about the presence/absence of tubal factor infertility in our ART database. It could be argued that a more comprehensive algorithm would integrate the infertility diagnosis as well as age, highlighting the strong association of both tubal factor infertility and advancing age with incidence of EP and other early pregnancy failures. Overall, we support that keen clinical judgment should trump any clinical algorithm: women with a history of tubal factor infertility and/ or advanced maternal age who present with worrisome symptoms after IVF should be evaluated early and closely, regardless of the hCG parameters.
CONCLUSION Ours is the first study of its kind to analyze a prospectively implemented clinical algorithm for identification of EP and HP. Of the parameters included in this algorithm, our data show that an abnormally low first hCG is the most common initial criterion by which EP are identified, and that symptoms of pain or vaginal bleeding are the most common initial criteria by which HP are identified. At this time, there is no consensus on how to evaluate IVF pregnancies in their early stages. We have demonstrated a clinical algorithm using hCG levels, clinical symptoms, and selective early ultrasound evaluation that is safe and effective in screening for EP and HP in this population.
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SUPPLEMENTAL FIGURE 1
Histogram plot of variation in the timing of first human chorionic gonadotropin (hCG). As demonstrated, the majority of cases followed the protocol for first hCG on the 15th day after oocyte retrieval. Cookingham. Early pregnancy evaluation after IVF. Fertil Steril 2015.
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