Researchers in a 2019 study compared pregnancy outcomes with different serum β-hCG levels that were measured on day 16 of the embryo’s age (13dp3dt/11dp5dt).
Human chorionic gonadotropin (hCG) is the pregnancy hormone. It’s secreted from the developing trophoblast of the placenta after embryo implantation. Ever wanted to see what hCG looks like? Behold!
This is actually the crystal structure of hCG, and for those of you who haven’t seen a protein structure before, this is the shape hCG forms when all of the amino acids that make up the protein fold together. You’ll notice there’s two parts, or subunits, in green and orange. These are called the alpha and beta (β) subunits. The bit that we’re interested in with hCG is the β subunit – this is the portion that is responsible for hCG’s biological activity.
Serum β-hCG is used to establish pregnancy and is done typically after about 10-12 days from transfer of a Day 5 embryos (or 12-14 days after a Day 3 transfer, although this timeline can vary). Once a positive pregnancy is established this needs to be confirmed by ultrasound after around 5 weeks. A pregnancy that is confirmed by ultrasound is called a clinical pregnancy. Sometimes, a pregnancy is lost between the β-hCG test and ultrasound. This is called a biochemical pregnancy loss or miscarriage because pregnancy was only identified through a biochemical test and not clinically by ultrasound.
The amount of β-hCG in serum can be used to predict whether or not a biochemical loss will occur. However there are some issues with the existing data.
Most studies on β-hCG in early pregnancy have been done after transferring 2 embryos. Since β-hCG is secreted by the trophoblast cells, multiple embryos implanting can affect the β-hCG level. One study got around this by examining only singleton pregnancies after ultrasound (Naredi et al. 2017), but this still doesn’t exclude the possibility that both embryos could have implanted and contributed to early β-hCG levels.
Additionally, the cut-off for predicting a biochemical loss by β-hCG has classically been 100 IU/L (or 100 mIU/ml), which was established over 30 years ago (Wilcox et al. 1988)! Technology and sensitivity of β-hCG measurements have changed since then. So it’s time for an update.
Mamari et al. (2019) wanted to conduct a study that used single embryo transfers. They performed a retrospective study at a single fertility center between 2013 and 2017 with 1076 pregnancies. β-hCG was measured on Day 16 (embryo’s age) and they examined both Day 3 and Day 5 embryo transfers. The Day 3 embryo transfers would have β-hCG measured 13 days post transfer (13dp3dt), and the Day 5 embryo transfers would have β-hCG measured 11 days post transfer (11dp5dt).
The 1076 pregnancies were divided into 10 groups from lowest to highest β-hCG measurements (like a percentile, but split into groups of ten – this is called a decile). All the women were around 35 years old and these were fresh transfers.
If you’re wondering how your levels compare and you had a transfer at a different time, remember that β-hCG levels double every 2-3 days!
🔗 Original studies are referenced in this post or within the linked Remembryo posts.
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Results
The chance of a clinical pregnancy and live birth increased as the β-hCG levels increased:
The chance of a biochemical pregnancy decreased as the β-hCG levels increased:
They also compared biochemical losses between Day 3 and Day 5 embryo transfers and found no differences. So once you’re pregnant with a Day 3 or Day 5 embryo with a certain β-hCG level, the chances of a biochemical loss are about the same.
Finally, they compared β-hCG measurements and live birth rates in women who had their pregnancy confirmed clinically by ultrasound (aka they had a clinical pregnancy). You can also see the miscarriage rate below (the % of clinical pregnancies that miscarried).
So what about the cut-off? At what point is there a good chance of a sustained pregnancy (with a low chance of biochemical loss)?
Classically, a cut-off of 100 IU/L β-hCG was used to estimate whether or not a pregnancy would progress to a clinical pregnancy. At 100 IU/L, this study predicts about half would have a loss and half would have a sustained pregnancy! So this isn’t really a good cut-off, because half of the women who are pregnant at 100 IU/L won’t have a clinical pregnancy (ie. a false positive).
So they used a statistical test called an ROC test which can define a good cut-off value to minimize false positives and negatives. Using this test on their data, they found that the best cut-off was 191 IU/L for clinical pregnancy (with a 14% chance of a biochemical loss).
Conclusions
The highest chance of a clinical pregnancy or live birth occurred with β-hCG levels of 253 IU/L (92.7% chance of clinical pregnancy and 74.5% chance of a live birth, at 13dp3dt or 11dp5dt). At this point there was about a 7% chance of a biochemical pregnancy loss.
Doing an ROC analysis, they determined that a good cut-off value for predicting clinical pregnancy was 191 IU/L (with a 14% chance of a biochemical loss).
This means that having a β-hCG value of 191 IU/L 13dp3dt or 11dp5dt is highly predictive for a clinical pregnancy. There’s always a chance of a biochemical loss, but at this value it’s minimized. Having a lower value will increase the chance of a loss, and a higher value will reduce the chance of a loss (according to the graphs shown above).
Reference
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About Embryoman
Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.
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