This podcast presents an in-depth exploration of fertility concerns and inquiries straight from those undergoing fertility treatment. Standing apart from the usual information found online, we dive headfirst into the real science and comprehensive research behind these challenges. Amidst all this, we never forget to honor our cherished tradition - celebrating the simple joys of Taco Tuesday!
Your first beta hCG is 100. Two days later, it rises to 150—but it didn’t double. Does that mean miscarriage? Could it be ectopic? Or could the pregnancy still be progressing normally?
Before Google diagnoses you with three different pregnancy complications, take a breath.
In this episode of Taco Bout Fertility Tuesday, Dr. Mark Amols explains why the familiar rule that hCG must double every 48 hours is outdated—and how that rule grew from a 1981 study involving only 20 patients.
You’ll learn:
• What hCG does during early pregnancy and which cells produce it • Why we call the test “beta hCG” • Where the 48-hour and 66% rise rules originated • How the expected rise changes based on the starting hCG level • Why IVF pregnancies may occasionally progress with much slower rises • Why a slow rise does not diagnose miscarriage or ectopic pregnancy • Why even a perfect rise cannot confirm that the pregnancy is inside the uterus • Which symptoms require urgent medical evaluation regardless of the latest beta
The bottom line: hCG is useful, but it is not a pregnancy report card, a crystal ball, or a GPS. It provides one piece of the story—followed by another beta, careful symptom monitoring, and eventually an ultrasound.
If you have severe or worsening abdominal or pelvic pain, shoulder pain, dizziness, fainting, weakness, or heavy bleeding, seek urgent medical evaluation. Do not wait for your next scheduled blood test.
Next week, we’ll continue the conversation by discussing pregnancy of unknown location, the hCG discriminatory level, and how clinicians evaluate the possibility of an ectopic pregnancy.
Thanks for tuning in to another episode of 'Taco Bout Fertility Tuesday' with Dr. Mark Amols. If you found this episode insightful, please share it with friends and family who might benefit from our discussion. Remember, your feedback is invaluable to us – leave us a review on Apple Podcasts, Spotify, or your preferred listening platform.
Stay connected with us for updates and fertility tips – follow us on Facebook. For more resources and information, visit our website at www.NewDirectionFertility.com.
Have a question or a topic you'd like us to cover? We'd love to hear from you! Reach out to us at TBFT@NewDirectionFertility.com.
Join us next Tuesday for more discussions on fertility, where we blend medical expertise with a touch of humor to make complex topics accessible and engaging. Until then, keep the conversation going and remember: understanding your fertility is a journey we're on together.
>> Dr. Mark Amols:
Today we talk about why your hCG may not double in two days. Why even a perfect rise cannot tell us where the pregnancy is and why the most famous number in early pregnancy came from a study of 20 patients, a study that admitted right in its own data that it would be wrong about one in seven healthy pregnancies. I'm Dr. Mark Amols, and this is Taco Bout Fertility Tuesday. You have your first pregnancy test after your fertility treatment. The hCG is 100. Two days later, it's 150. It went up by 50%. It did not double. So naturally, you do what every calm, rational patient does. You open Google and you type my hCG didn't double. Am I having a miscarriage? And within those five minutes, you have diagnosed yourself with a miscarriage, an ectopic pregnancy, and at least two conditions that have nothing even to do
with pregnancy. But the real question is:
Is a 50% rise actually abnormal? Well, not necessarily. And the question is, does it guarantee everything is fine? Well, no. Does it mean the pregnancy is ectopic, then? Well, also no. And that is what makes hCG so frustrating. It gives us real information. But patients, and honestly, sometimes even clinicians, ask it to answer questions it was never able to answer. In the earlier episode, we talked about whether one single hCG value drawn on a specific point after a transfer could predict the outcome. That episode was about the first number. Today's episode is about what happens next. Now, before we get into percentages and thresholds, I want to say the most important thing in this episode. I want to say it early, because if you stop listening after 10 minutes, this is the part you need to know. No hCG number protects you from symptoms. If you have severe or worsening abdominal pain, one-sided pelvic pain, pain in your shoulder, dizziness, weakness, fainting, or heavy bleeding, you need to be evaluated urgently today. Don't wait till your next scheduled blood draw. It does not matter that your beta looked reassuring on Monday. It does not matter that your number seems too low to be an ectopic. A low hCG is not a bulletproof vest. An ectopic pregnancy does not check your lab values before it decides to rupture your tube. The point is, symptoms outrank the spreadsheet every time. Call your clinic or go be seen at an ER. Now we can talk about the numbers. Well, what is hCG actually doing? Well, quick refresher, because the biology explains almost everything that confuses people. The body doesn't just create hCG so that we can find out that our pregnancy is going well. It's made by the trophoblastic cells, and these are the cells that go on to form the placenta. As they invade the uterine lining during implantation, they differentiate, and the syncytiotrophoblast becomes the main source of the hCG we measure in the blood. Its most important early job is rescuing the corpus luteum. The corpus luteum is what's left over in the ovary after ovulation. The sac that had the egg now becomes a progesterone production factory. And progesterone is what supports the endometrial lining, where the pregnancy will be. Now, without a pregnancy, it kind of winds down. Progesterone levels fall, and the period starts. However, when there's a pregnancy, it makes hCG from the syncytiotrophoblast and tells the corpus luteum, hey, hold on. Don't shut everything down. We still need progesterone because we got a baby here. And as you expect, the corpus luteum keeps producing progesterone until the placenta gradually takes over, usually somewhere around eight to 10 weeks. Have you ever wondered, well, why do we call it beta hCG, not just hCG? Well, because hCG is built from two subunits, an alpha and a beta subunit. Here's the part that usually gets softened, and it shouldn't be. The alpha subunit is not merely similar to the alpha subunits of LH, FSH, and TSH. It's identical. Same protein, same gene. All four hormones share it. So everything that makes hCG hCG lives in the beta subunit. That's why the blood test is called a beta. The assay is aimed at the part that isn't shared with three other hormones you don't want to accidentally measure. And the beta subunit has one more feature. It matters enormously, and that is the tail. hCG's beta subunit is nearly identical to LH's beta subunit, except hCG has an extra tail at the end of it. These approximately 24 additional amino acids are called the C-terminal peptide. It's decorated with these sugar chains. And here's the elegant part. Your liver clears glycoproteins out of the bloodstream using a receptor that grabs onto the specific sugars called galactose. If you expose galactose, the liver pulls the molecule out of circulation almost immediately. Except the sugar chains on hCG are capped with sialic acid, and that sialic acid sits directly on top of the galactose, covering it. So by disguising the tail, hCG can live longer. If you remove the sialic acid from it, hCG is cleared in minutes. And this is why LH has a half-life of roughly 20 to 30 minutes, while hCG has a half-life of roughly 24 hours to 36 hours. Same receptor, same basic signal, but wildly different persistence because of that chain. And by putting sialic acid on the end of it, it disguises the chain and doesn't get pulled from the blood. And it is because of this persistence that we can check hCG levels and look for this supposed doubling. So then the next question should be, but why 48 hours? Why not just check the hCG the next day? Well, the answer is older than you think. And this is a common question from patients. And it's a fair question. If you're worried about having a miscarriage, why do you need to wait two days? Why can't you just wait another day? Well, you may not like the answer, but it's actually quite interesting. The 48-hour interval comes from the same 1981 paper that we're going to talk about. And the reasoning was specific. Kadar calculated that at 24 hours, the difference between how a normal pregnancy rises and how an ectopic pregnancy rises was only about a 20% difference. And the problem with that is that a 20% difference was smaller than twice the error of the lab test itself. So the problem was, in 1981, those assays ran a coefficient of variation of up to 15%. That means you couldn't tell whether the difference was a change or just the variation that's noted between the tests? So the recommendation was then wait two days, let the biology outrun the noise. And that was very reasonable. But here's the thing. Modern assays run a coefficient of variation of about 5% or less. That means the noisy floor is not there anymore. Which is why some authors even argue that a 24-hour repeat is perfectly interpretable in current practice. Now, I'm not telling you to demand the next day blood draw from your doctor. Forty-eight hours is the standard, and that's what most of the data we have is based on. I'm just pointing out something worth discussing. The two-day rule and the 66% rule came from the same 20-patient paper. And both of them outlived the equipment they were built on. And one very practical point while we're here, different assays have different values, meaning if you use a different lab, you're not going to always get the same result. This is why it's important to always stay with the same lab when you're checking these hCG levels if you can. Unfortunately, this can sometimes cause worry or even hope when there's a rise or decrease, and it's between two different labs. So the question at hand, does your hCG need to double? The answer is simple. No. It is probably one of the most persistent myths in early pregnancy, hCG does not have to double every 48 hours. Now, doubling may be common early on, especially when starting with low values, but it's not a requirement. As we talked about, that rule comes from Kadar's 1981 paper. Fifty-three charts were reviewed, and of those, 20 viable pregnancies were found. And the 66% figure is the 85% confidence bound of that group. That 85% is important. It wasn't 90%, 95%, 99%. That meant that 15% of healthy ongoing pregnancies rose slower than the cutoff—about one in seven. And then, for some reason, the medical world just took that number, dropped the confidence interval, and said, okay, patients should be worried if it's not increasing this much. Now, I'm not mocking the study. It was careful work for 1981 and was genuinely useful. I'm pointing out how a small, honest observation calcifies into doctrine, and then that doctrine persists and unfortunately might become the most frightening moment of your life by someone who has no idea it came from only 20 patients. Because small numbers don't usually reproduce in studies, Larger studies are usually more reproducible. That's the concern. So did someone do bigger studies? Well, they did. And those larger works pushed the floor even further down. Barnhart and colleagues in 2004 and again in 2016 studied women presenting with pain or bleeding who turned out to have a viable pregnancy. Their minimum rise came in around 53% over two days. Now, their later work made the threshold dependent on the starting value. If you're below 1,500, then 49%. If you're between 1,500 and 3,000, then you need to rise 40%. And if you were above 3,000, you need to rise about 33%. The higher the starting number, the slower the expected climb. The higher the starting number, the slower the expected climb. That's not a warning sign. That's just what happens as the denominator gets bigger. Now, there are two important things from this. First, these are not averages. Most ongoing pregnancies are going to rise considerably faster. These are the floors—the lowest observed rises. Second, they are not biological cliffs. A pregnancy does not become healthy at 49% and doomed at 48%. These are there to help predict things, but they do not predict on their own. But here's the study nobody quotes, because everything I just described came from women who walked into an emergency room bleeding or in pain. And this is not most of you. Many of you are asymptomatic. You have a known transfer date, you have a known embryo, and you have a scheduled blood draw. You feel completely fine. So has anyone actually studied people like you? Yes. And almost nobody mentions it. Chung and Barnhart and colleagues looked at 391 women who conceived through IVF and went on to have viable intrauterine pregnancies. That means confirmed live births. They found two things. One, the hCG curve in IVF pregnancies is not a straight line. It's quadratic and it plateaus earlier than in spontaneous conceptions. So rises that flatten sooner than you expected are a described feature of IVF pregnancies, not automatically a red flag. Two, and this is the number I want you to hear. In that cohort of confirmed viable IVF pregnancies, the slowest two-day rise that still ended in a live birth was 30%. 30. Not 66, not 53. 30%. And if you're really looking for some hope, there's a 2021 case series in F&S Reports that documented IVF patients with rises even lower than that who delivered healthy babies. So when someone quotes you the 66% rule, understand what happened. You were being measured against a threshold derived from 20 symptomatic women in 1981, when the study that actually looked at 391 people exactly like you, found live births at less than half that rate of
rise. So let's make this concrete. Your first hCG:
100; the second one, 150. A 50% rise that didn't double sits comfortably above every published floor compatible with a normal pregnancy. Now, 100 to 130—a 30% rise. Five years ago, I would have called that concerning without much hesitation, but today, I have to be a little more honest with you. 30% is exactly the floor observed in confirmed viable IVF pregnancies. Now, does that still concern me? Well, yes, a little bit, because I was trained that way. So it's taking time to adapt to the newer data, but it means I'm going to watch and wait because I know that live births can come from that, because some numbers genuinely live in the gray area. Now, what about 100 to 210? Well, more than double. That's got to be reassuring. And it still does not prove the pregnancy is inside the uterus. And that's the central limitation. hCG only tells us how much hormone is being produced. It cannot tell us where it's being produced. Unfortunately, hCG is just a clue, not a GPS signal. So when you're evaluating an hCG level, there should be three questions. Question 1. Is the pregnancy tissue present? And we know that if there's hCG, then that means trophoblastic tissue is present. Now, it's important to remember if you took a trigger shot, there could be a low hCG, but otherwise, you have confirmed that you are pregnant if there's hCG in your blood. Question 2. Is the trajectory compatible with a progressing pregnancy? See, these serial values shift the probability. They make one outcome more likely or another less likely. But they don't actually render a verdict. They just tell us where we need
to be thinking:
ectopic pregnancy, abnormal pregnancy, or progressing pregnancy. And then there's the third question, where is the pregnancy? And unfortunately, hCG cannot answer this. There's not a value. There's not even a trajectory that can answer that. This is where location comes into play. We look with an ultrasound. That means even a beautiful rise in hCG can still be an ectopic, and an hCG that's going slow can still be a normal pregnancy. Only a falling hCG can tell you that the pregnancy is not progressing, but it doesn't tell you whether it was inside the uterus or outside it. So, as you can see, three questions, one test. Yet it only answers part of one of them, which is why when you have these numbers in the gray zone, it doesn't seem like your doctor has an answer. And that's because they can't have an absolute answer, because hCG doesn't completely answer it by itself. So the question is, if the rise is slow, what actually is most likely? And this is the part I wish every patient heard before they hit Google. When the beta rises slowly, patients go straight to ectopic because ectopic is the scariest possibility. And the most dangerous. But scary is not the same as likely. And among pregnancies where the location isn't yet clear, the most common outcome by a wide margin is going to be early pregnancy loss. The second most common is a normal intrauterine pregnancy that just hasn't declared itself yet. Ectopic pregnancy is the least common of the three. Now, I'm not saying to ignore it. That's why we take it very seriously, because we know that's the one that can hurt you the most. It is because of that asymmetry that we watch you so closely. But the point is, if you're sitting at home at two in the morning and you're doing math on a number that went up 35%, the most probable explanation is not the one you are most afraid of. See, most people believe that ectopic pregnancies produce slowly rising hCGs, and many do. But ectopic pregnancies are not considerate enough to follow just one pattern, unfortunately. Silva and colleagues studied 200 confirmed ectopic pregnancies. Roughly 60% initially had rising levels and 40% had falling levels. And 21% rose in a pattern that looked like a progressing intrauterine pregnancy. Eight percent of them fell in a pattern that looked like a miscarriage. This is important because essentially 3 in 10 initially mimicked a pattern that a doctor might otherwise find reassuring. So a normal rise cannot exclude an ectopic. A falling level cannot immediately exclude one either. Now, if it's plateauing, has a slow rise, or a slower-than-average decline, yes, be concerned. But none of those alone establishes the location of the pregnancy. And the absolute value does not reliably predict if it's going to rupture or not. Which brings us back to where we started. Symptoms outrank the number. This is where the term pregnancy of unknown location comes from. And in next week's podcast, I'm actually going to talk about this and what's called a discriminatory level, and how this level is used to know when to see a pregnancy in the uterus and when we should not potentially see a pregnancy in the uterus. But we'll talk about that more next week. But let's go back to our patient. Let's return to the woman whose hCG went from 100 to 150. Her beta didn't double. So is that okay? The long and short answer is that that rise is compatible with an ongoing intrauterine pregnancy. This is not a confirmed one. It doesn't even guarantee the pregnancy will continue. It just says that everything is possibly going fine. And you may not declare victory, but you also do not declare defeat. You continue to follow it. You watch her symptoms, and then eventually, at some point, you check with an ultrasound. Early pregnancy sometimes forces us to sit with uncertainty. And this is extremely hard when you have infertility because you already have a lot of stress. Unfortunately, a lab result isn't going to end the waiting game, because one number does not give certainty. This is why we have to follow the
values. So my take-home message: six things. One:
hCG does not have to double every 48 hours. That
is a myth. Two:
The 66% rule came from 20 charts in a study in 1981, and that was at an 85% confidence bound that was known to miss one in seven healthy pregnancies. That should reassure you that you don't have to follow the double every
48-hour rule or the 66% rule. Three:
In 391 confirmed viable IVF pregnancies, the slowest two-day rise
that still ended in a live birth was 30%. Four:
A slow rise raises concern, but it doesn't diagnose a miscarriage or an ectopic pregnancy. And a normal rise does not prove the pregnancy is in the
uterus. Five:
Symptoms always matter more than the
spreadsheet. Six:
If you ever have questions, always talk to your clinic and your doctor. The point is, hCG is genuinely a useful hormone and a genuinely useful test. It's not a report card, it's not a crystal ball. It gives us one piece of the story. And in early pregnancy, this takes time. That's one number, then another number and eventually an ultrasound. I know we wish that with the first test we could tell you what's happening, but unfortunately we can't. We have to follow the evidence carefully and we have to keep you safe and eventually the full picture will emerge. As always, if you found this helpful, tell your friends about it. Share it with someone who may be going through IVF or who's actually going through this right now and worried about their hCG level. And as I mentioned, if you're worried about your own results right now, talk to your care team because your number only makes sense in the context of your treatment timing, your symptoms, and your ultrasound. If you like this podcast, please share it with your friends. Give us a five-star review on your favorite medium. But most of all, keep coming back. I look forward to talking again next week on Taco Bout Fertility Tuesday.
.jpg)
