Defining the rise of serum HCG in viable pregnancies achieved through use of IVF
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Human Reproduction Vol.21, No.3 pp. 823–828, 2006 doi:10.1093/humrep/dei389 Advance Access publication November 25, 2005. Defining the rise of serum HCG in viable pregnancies achieved through use of IVF Karine Chung1,2,5, Mary D.Sammel2, Christos Coutifaris1, Raffi Chalian1, Kathleen Lin1, Arthur J.Castelbaum3,4, Martin F.Freedman3,4 and Kurt T.Barnhart1,2 1 University of Pennsylvania, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, 3701 Market Street, Suite 800, Philadelphia, PA 19104, 2University of Pennsylvania, Center for Clinical Epidemiology and Biostatistics, Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, 3Northern Fertility and Reproductive Associates, 1650 Huntingdon Pk, Suite 154, Meadowbrook, PA 19046 and 4Temple University School of Medicine, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, 3401 N. Broad Street, Philadelphia, PA 19140, USA 5 To whom correspondence should be addressed. E-mail: karinech@usc.edu BACKGROUND: We aimed to characterize the rate of HCG rise associated with viable IVF pregnancies, and to evaluate the association between HCG rise and potentially influential factors. METHODS: We performed a retro- spective cohort analysis of all viable pregnancies achieved through IVF at two centres between January 1999 and March 2004. RESULTS: Of the 455 pregnancies resulting in live births, 391 met inclusion criteria and contributed a total of 1052 HCG values. Using random effects models, the best pattern to describe the rise of log HCG was quad- ratic with the rate of increase slowing at 24 days post-oocyte retrieval. Limiting the analysis to measurements below the discriminatory zone, the linear model adequately characterized the profile. The average slope was 0.403, yielding a predicted increase of 1.50 (50% increase) in 1 day and 2.24 (124%) in 2 days. In the final model, absolute HCG values, but not rate of rise, were significantly higher for twins and triplets and significantly lower for patients with BMI >30 kg/m2. CONCLUSIONS: The HCG profile of viable pregnancies conceived with IVF is quadratic with an earlier plateau than has been reported for non-IVF pregnancies. The average rate of rise is comparable to previous estimates in symptomatic spontaneous conceptions. Key words: body mass index/HCG rise/IVF/multiple pregnancies/viable pregnancies Introduction Whether a similar pattern of HCG rise should be expected in Serial measurements of serum HCG in early gestations repres- pregnancies conceived through IVF has not been confirmed. ent an invaluable aid in the differentiation of normal and abnor- Because there is an elevated risk of ectopic pregnancy among mal pregnancies. When ultrasonography is non-diagnostic, patients who conceive through assisted reproductive technolo- clinical practice relies upon established rates of HCG rise to gies such as IVF (Marcus and Brinsden, 1995), it is necessary estimate the likelihood of pregnancy viability and determine to determine whether clinical rules derived from populations of the need for intervention if an ectopic pregnancy is suspected. spontaneously conceived pregnancies are applicable to this Initial studies by Kadar et al. (1981) described the pattern of unique patient population. Previous studies attempting to char- HCG rise in normally developing pregnancies. These authors acterize the HCG curve associated with IVF pregnancies are reported that an increase of
K.Chung et al.
influential factors such as multiple gestations. The curves To optimize the clinical utility of these data, we then limited the
defined by our data will facilitate the interpretation of serial analysis to HCG measurements obtained prior to 39 days gestation (25
HCG values in early IVF pregnancies and aid in the differenti- days post-oocyte retrieval). This sub-group of early gestational ages
ation of normal and abnormal gestations in these patients at was selected because we were interested in describing the pattern of
rise that occurs during the period when monitoring of serial HCG levels
risk for ectopic pregnancy.
is clinically most appropriate, i.e. when ultrasound is non-diagnostic.
Previous studies have shown that if gestational age is known and mul-
Materials and methods tiple pregnancy is a possibility, the discriminatory zone at which a
diagnosis can be achieved by transvaginal ultrasound is best defined
This study was approved by the Institutional Review Board of the
by gestational age ≥24 days post-conception (≥38 days from LMP)
University of Pennsylvania. The study population was comprised of
rather than by HCG concentration (Kadar et al., 1994).
patients from two local infertility practices, one university-based and
Population average values for slope, standard errors, and upper and
one community-based. All pregnancies which were conceived
lower confidence bounds on the rate of increase in log(HCG) were
through use of IVF procedures performed between January 1999 and
estimated from the multivariable linear regression model which
March 2004 were considered for inclusion. Those pregnancies which
assumed that log(HCG) was normally distributed. The final model
ultimately resulted in the live birth of one to three infants were eli-
was used to calculate expected values at clinically pertinent points in
gible. For patients who contributed more than one pregnancy during
time. Primary data management and analyses were conducted using
the study period, only the first pregnancy that met inclusion criteria
STATA version 8 (StataCorp, College Station, TX, USA). Random
was used in the analysis. We excluded all spontaneous abortions and
effects models were analysed using SAS statistical software (SAS
ectopic pregnancies, as well as gestations with more than three
Institute, Cary, NC, USA).
fetuses. Pregnancies resulting from alternative methods of assisted
reproduction treatment, such as gamete or zygote intra-Fallopian
transfer, cryopreservation and donor transfers, were also excluded. Results
Additional inclusion criteria required that patients had one or more
serum HCG level documented in the medical record and subsequently Of the 455 pregnancies which ultimately achieved live births
validated in each centre’s computerized database. Values which were during the study period, 409 had HCG determinations con-
measured at intervals of ≥24 h and ≤7 days were included in the ana- firmed in the appropriate centre’s computerized database. Values
lysis. Serum HCG concentrations were determined using the Abbot that were documented in the medical record, but could not be
Axsym total β immunoassay (Abbot Laboratories, Abbot Park, IL, confirmed in the computerized database, were assumed to be
USA) at the university-based centre and the DPC Immulite assay performed at outside laboratories and were therefore not
(Diagnostic Products Corporation, Los Angeles, CA, USA) at the included in the analysis. Of the 409 remaining pregnancies, 18
community-based centre. These two automated immunometric assays were identified as having more than one pregnancy which met
have been shown to yield comparable results and few errors when inclusion criteria. For these patients, only data from the first
compared to radioimmunoassay (Cole et al., 2001). Inter- and intra-
eligible pregnancy were included in the analysis, yielding a
assay variations wereRise in HCG in IVF pregnancies
slowing after 24 days post-oocyte retrieval (38 days from
LMP; Figure 1). Multivariable analyses revealed that abso-
lute values of log(HCG) were significantly influenced by
number of gestational sacs and maternal BMI. Interactions
between the slope and number of gestational sacs and
between the slope and BMI were not significant, indicating
that these factors did not affect the rate of rise over time. In
the final model, BMI was considered as a categorical variable
to facilitate clinical interpretation. Groups were defined as
BMI 30
(bmigrp3, n = 91).
Overall, the optimal model included a fixed quadratic effect
and a random linear effect for gestational age (number of days
from LMP) allowing for random slopes and random intercepts,
as well as fixed effects for number of gestational sacs and
groups of BMI. The population average profile for the rise in
log(HCG) per days of gestational age (days) was described by
the following equation:
log(HCG) = 0.842(days) – 0.007(days2) + 0.406(twin)
Figure 2. Generated curve of serial log(HCG) values in women who
+ 0.825(triplet) + 0.130(bmigrp1) achieved singleton, twin and triplet live births through use of IVF.
– 0.049(bmigrp2) – 0.266 (bmigrp3) – 13.74.
A graphic representation of predicted values from the model is Table I. Predicted mean HCG values (mIU/ml) over time by number of
shown in Figure 2. Predicted absolute HCG values by number gestational sacs and maternal body mass indexa
of gestational sacs and BMI are listed in Table I. Data pre- Body mass Day 14 post-ET Day 16 post-ET Day 21 post-ET
sented in the Table I are meant to provide a reference for index (30 days (32 days (37 days
patients who conceive through IVF and ultimately achieve live (kg/m2) from LMP) from LMP) from LMP)
births. Singleton
When the analysis was limited to measurements obtained prior 30 141.74 320.54 1929.47
Twin
30 212.72 481.06 2895.75
Triplet
30 323.44 731.43 4402.82
a
Derived from final equation: log(HCG) = 0.842(days) – 0.007(days2)
+ 0.406(twin) + 0.825(triplet) + 0.130(bmigrp1) – 0.049(bmigrp2)
– 0.266(bmigrp3) – 13.74.
LMP = last menstual period; ET = embryo transfer.
the profile of log(HCG). The equation which defines this line
is as follows:
log(HCG) = 0.403(days) + 0.414(twin) + 0.812(triplet)
+ 0.119(bmigrp1) – 0.07(bmigrp2)
– 0.289(bmigrp3) – 6.76.
In the final model, absolute HCG values, but not rate of rise,
were significantly higher for twins (P < 0.0001) and triplets
Figure 1. Curve generated from serial log(HCG) concentrations of (P < 0.0001). Patients with BMI > 30 had significantly lower
women who conceived through IVF and ultimately achieved live HCG values (P = 0.009) than patients with normal BMI, but
births (391 patients, 1052 observations). CI = confidence interval. rates of rise were similar.
825K.Chung et al.
Table II. Predicted relative increase in HCG over time
Slope of HCG rise 1 days later 2 days later 7 days later
1st percentile 0.161 1.17 1.38 3.09
5th percentile 0.265 1.30 1.70 6.40
Mean 0.403 (0.391–0.415) 1.50 (1.50–1.52) 2.24 (2.19–2.30) 16.79 (15.46–18.32)
95th percentile 0.510 1.67 2.78 35.63
Values in parentheses are 99% confidence intervals.
Using this model, expected rates of increase in HCG values were effects models account for variability or error associated with
derived and are shown in Table II. On average, patients experi- individual observations, they assume that the error terms have
enced a relative increase of 1.50 (50% increase, 99% CI 1.50– independent and identical distributions. Because repeated
1.52) in 1 day and 2.24 (124%, 99% CI 2.19–2.30) in 2 days. measurements within subjects over time cannot be considered
Due to the large sample size, this estimated rate of rise is quite independent, such models are not appropriate. Random effects
precise as is reflected in the 99% confidence intervals. Of the models are ideal for evaluating repeated measurements because
actual values observed, the slowest confirmed rise was 1.14 they account for variability that occurs with each observation
(14%) in 1 day and 1.30 (30%) in 2 days. Relative rates of at each time interval within a subject as well as the between-
increase observed in the 1st percentile were 1.17 (17%) in 1 subject variability (Laird and Ware, 1982).
day and 1.38 (38%) in 2 days, and in the 5th percentile were The quadratic curve described by these data indicates that
1.30 (30%) in 1 day and 1.70 (70%) in 2 days. These data can the rate of increase slows at ∼24 days post-oocyte retrieval,
be used by clinicians for comparison when monitoring serial corresponding to a gestational age of 38 days (5 weeks and 3
HCG levels before a definitive diagnosis can be achieved with days) and an approximate HCG concentration of 3000 mIU/ml.
ultrasound. This relatively early plateau in HCG production may reflect
differential rates of implantation and resorption of non-viable
embryos in pregnancies resulting from IVF. Alternatively, it is
Discussion possible that the administration of exogenous progesterone,
Using sophisticated modelling and a large sample size, we which is common practice in IVF treatment, leads to a dimin-
precisely describe the HCG profiles of pregnancies which were ished need for the HCG-induced steroidogenesis of the corpora
conceived through IVF and ultimately achieved live births. lutea (Kohen et al., 2003).
Overall, the curve was quadratic with an earlier plateau than Within the clinically pertinent range of gestational ages at
has previously been reported for pregnancies conceived spon- which ultrasound is not likely to be diagnostic, we deter-
taneously or through other methods of infertility treatment. mined that a log-linear pattern can be used to describe the
Multiple investigators have evaluated the rise of HCG in vari- increase in serum HCG. Our data indicate that the population
ous populations of fertile, infertile, symptomatic and asympto- of IVF pregnancies which achieved a live birth, on average,
matic women for the purposes of estimating curves to demonstrated a relative HCG increase of 50% in 1 day and
distinguish normal from abnormal pregnancies (Pittaway and 124% in 2 days (slope = 0.403). This rate of HCG rise is com-
Wentz, 1985; Fritz and Guo, 1987; Kadar and Romero, 1987; parable to previous estimates for spontaneous intrauterine
Kadar et al., 1990; Check et al., 1992). In past years, there pregnancies (IUP) (Table III) and is not different for multiple
was much controversy about whether the pattern that best gestations.
described the rise in HCG was log-linear or quadratic. Catego- While the lower bound of the 99% CI suggests that the slow-
rization of the existing literature based on the presence or est rise in pregnancies resulting from IVF may be faster than
absence of symptoms of pain or bleeding in the first trimester that reported for symptomatic spontaneous pregnancies, this
suggests that indeed, the quadratic curve represents HCG rise finding should not be interpreted as a clinical rule. Due to our
when the population is asymptomatic and the gestational age large sample size and the exact nature of estimated gestational
is certain (Table III). Previous studies have estimated rates of age in our study population, we have achieved a great degree
increase among infertile patients treated with various methods of precision, thus narrowing the confidence interval around the
of ovulation induction, but have not specifically investigated mean. The 99% confidence interval represents the degree of
pregnancies resulting from IVF. Additionally, these earlier assurance that the true mean slope of HCG rise in our popu-
studies were limited by their use of doubling time, a measure lation lies between 0.391 and 0.415. However, the more clin-
which is sensitive to variations in the interval of testing (DT = ically relevant data are presented in the range and percentiles
[(log 2)*(time interval in days)]/[log(HCG2)/(HCG1)]) (Pittaway of observed rates of rise. The 1st, 5th and 95th percentiles
and Wentz, 1985). represent the distribution of our study population, indicating
In our study, we restricted the sample to pregnancies that the actual rates of rise can be notably slower or faster
achieved through IVF and analysed our data using random than the average. Indeed, the slowest rate of rise in our popula-
effects methods which are flexible and adjust for varying tion of pregnancies known to result in a live birth was 14% in 1
numbers of evaluations and intervals of testing. While fixed day and 30% in 2 days. To avoid the inadvertent interruption of
826Rise in HCG in IVF pregnancies
Table III. Review of previous estimates for HCG rise among viable intrauterine pregnancies
Authors Symptoms of Study population n Slope Final model
pain or bleeding
Pittaway et al. (1985) Asymptomatic Infertile patients, known EGA 49 subjects, 1 observation 0.433a; 0.257a Quadratic
(BBT, LMP) per subject
Fritz and Guo (1987) Asymptomatic Spontaneous pregnancies, known 16 subjects, 15–19 0.309a Quadratic; 0–6500: linear
EGA (BBT) observations per subject
Kadar et al. (1990) Asymptomatic Infertile patients (HMG, CC, 59 subjects, 1 observation 0.366 ± 0.004 >10 000: quadratic; 60 0.152 ± 0.04 (85% CI Log-linear
observations lower bound 0.11)
Kadar et al. (1987) Symptomatic Spontaneous pregnancies 44 subjects 0.456 ± 0.13 Log-linear
Present study Asymptomatic IVF pregnancies 391 subjects, 1052 0.403 (0.394–0.413) Quadratic; log-linear up to 39
observations days gestation
a
Slopes were calculated from doubling time.
EGA = estimated gestational age; BBT = basal body temperature; CC = clomiphene citrate; OI = ovulation induction; CI = confidence interval.
viable pregnancies in an attempt to diagnose or treat abnor- values in early IVF pregnancies, allow for extrapolation of
mal pregnancies, conservative threshold values are essen- expected HCG levels, and facilitate the counselling of patients
tial. Prospective evaluation of critical values is needed to being monitored.
establish and validate a clinical rule. Moreover, it is import-
ant to acknowledge that observation of a ‘normal’ rise in
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