Are You Doing Enough Genetic Screening? Meet Dr. Nidhee Sachdev
Welcome to another episode of The Egg Whisperer Show. I’m excited to have reproductive endocrinologist, Dr. Nidhee Sachdev, from Orange County on with us today. We are going to talk about one of the topics that I get so many questions about — genetics. Specifically, are patients doing enough genetic screening?
Dr. Aimee: You have a lot of background in this area, so tell our audience a little bit more about yourself, where you practice medicine, and where they can find you.
Dr. S: My name is Dr. Nidhee Sachdev. My patients call me Dr. S. I work here in Orange County, in a practice called OC fertility. We’re part of the CCRM Orange County Network here in Newport Beach. I am a California native and grew up in the Bay Area, not far from where you are, Dr. Aimee. Then through school, I came to Southern California and went to the Midwest at the University of Chicago for residency. I went to New York at NYU to do my fellowship, and then made my way back here to sunny Southern California.
Dr. Aimee: So we both did a lot of traveling. I went to UCLA, then went to Michigan, Boston, and back here. So it’s a fun thing to do because we get to learn how people practice medicine in different parts of the country and then take what we like and apply it to our practice.
Dr. S: And having that network is super helpful because when patients have questions, you can cast your net and ask and relate to different specialties all across the country.
Dr. Aimee: Tell us a little bit about why you went into medicine and then, more specifically, fertility medicine.
Dr. S: When I was younger, I honestly didn’t know exactly what I wanted to do other than I realized I liked science. I had only one family member who was in medicine, an older cousin of mine who was a gyn oncologist — a female cancer doctor. He suggested I get a job at a hospital. I actually got a job as a clerk at the hospital where he worked.
While I was there, I got to tag along with him and see him interact with his patients. I realized that I really liked the relationship he had with his patients. I liked the science and what he did. I decided that I was going to buck up, try hard in school, and try to get into med school. When I got to med school, I already had an interest in women’s health just through my exposure to him. So I decided to go into OB-GYN.
Once I got to residency, I realized that it wasn’t just the idea of taking care of pregnant women that I was interested in. It was the relationship I developed with them. I was hearing and meeting women in labor and delivery who had been on the other side of fertility. Talking to them and hearing about their journey was powerful. For some, it had been a really difficult journey. For some, it had been somewhat difficult. I realized that was the patient population I was drawn towards.
Part of being a doctor is the idea of feeling that I’m making a difference. I realized that with some people you have the ability to make a bigger difference than with others. And that’s what led me to it. I did some research in the field and I spent more time with different fertility clinics. The more I learned about it, the more impressive it was. The science was awesome, and things were changing. It was what I was meant to do.
Dr. Aimee: Your patients are clearly lucky to have you helping them. Let’s get into our show topic. We all know what the tushy method is:
T is for tubes
U is for uterus,
S is for sperm,
H for hormones,
Y is for your genetics.
So the first question I have for you, do genetics play a role in fertility?
Dr. S: Genetics do play a role. For that reason, the most important part of my new patient consultation in the history section is my patients’ family history. It’s important to understand: Are there any prior known developmental or genetic issues?
Were there any issues of fertility amongst a patient’s family? How old was her mom when she had them? Does my patient know what age her mom went through menopause? That’s also important information.
Dr. Aimee: What are the genetic causes of infertility in both men and women?
Dr. S: There are quite a few. A really important one is anything dealing with chromosomes. For one, age can be related to a genetic issue. As we get older, we have a harder time as women having eggs that have the right number of chromosomes. That is a big genetic issue when talking about fertility because as we get older, we’re less likely to make chromosomally normal embryos.
Another factor is endometriosis. Endometriosis has some familial causes. It’s not a directly linear relationship, but having a sibling or a mother who has endometriosis does put a patient at a slightly higher risk of having endometriosis themselves. There are other factors, such as inheritable diseases that we can pass on to our kids. Specifically, one called Fragile X that we can carry that could one be associated with having a lower amount of eggs, a lower ovarian reserve, passing onto our kids infertility issues, and possibly having kids born with developmental delays.
Dr. Aimee: And what kind of tests do you offer your patients routinely, whether they’re trying to get pregnant naturally, with IUI, or with IVF? What is your go-to set of genetic tests that make you feel like you’re doing a complete job for your patients?
Dr. S: For all patients after the history, we talk about genetic carrier screening. This is a blood test in which we’re able to screen the patient’s blood for different inheritable diseases. There are lots of different ways that we can inherit diseases and pass them onto our kids. Some diseases are passed on only through the X chromosomes. As women, since we have two X chromosomes, those are ones that we can then pass on to our sons.
Males have only one X chromosome, so if they do inherit a disease from our X chromosome, they are more likely to manifest those diseases. As part of that, the genetic carrier screen is something that I offer all of my patients, regardless of how they’re trying to conceive. This gives them the ability to screen themselves and their partners for these inheritable diseases.
Patients will often say, ‘Does my partner have to have it done as well?’ So I typically suggest that we could start with the patient. If you test just the male and not the female, you’re not going to have that ability to determine if the female patient herself has any diseases she can pass on via the X chromosome.
I recommend that my patients have it done, and we can determine if they are predisposed for any sort of disease that can pass on through that. That’s where I usually start.
There are other tests that we can do — chromosomal tests where we can look at a patient’s karyotype to see if as a woman we are 46 XX and the male 46 XY. I don’t always, right off the bat, start with that. It kind of depends on what treatment course we’re doing and their history.
Dr. Aimee: That makes perfect sense. I just do both at the same time: both the chromosomes and the carrier screen. In the old days doing a chromosome analysis was thousands of dollars, and now it’s just hundreds, just like the carrier screen. So sometimes I do it from the beginning, and sometimes I don’t.
Dr. S: We do it for all of our IVF patients. If someone is going to undergo IVF, we want to know is there something abnormal to chromosomes, like a translocation or reciprocal rearrangement. If you’re going to go through that and have a much higher risk of having abnormal embryos.
Sometimes patients will determine, ‘OK, we can’t do anything to change our own chromosomes.’ So some patients will say, ‘OK, if I have a higher risk of having all of my embryos being abnormal, let me try it and see what happens.’ Or they’ll say, ‘Instead of going down that route, maybe I’ll use a donor, whether it’s a donor egg or donor sperm.’ I’ve had patients make that decision.
Dr. Aimee: What about women who are freezing their eggs? Do you think that they should do carrier screening upfront first?
Dr. S: I recommend it to all of my patients. Especially if we’re concerned that there might be something that they can pass on to their male offspring — the X. What I do tell them, though, is that it’s important they have it done. But by the time they come back to use their eggs, the carrier screens might be more expanded, so there might be more diseases that they can test for. Then, when their partner gets tested (or whether they use donor sperm), they might have an expanded carrier screening panel, so there might be diseases they are tested for that you weren’t. I do recommend that they get it but some patients say, ‘I’ll wait until I want to use my eggs.’ and have it done prior to making embryos or trying to conceive on their own.
Dr. Aimee: What if someone says to you: ‘Dr. S, I understand you want me to do this test, but I’m not going to do anything with the results. Even if my partner and I are both carriers for the same disease.’ How do you answer?
Dr. S: That’s a fair question. I say that’s totally fine. You can look at information in two ways. You can look at it as information for which you don’t necessarily have to act on, but it’s information for which you can be more prepared in the future. Or, some people view information as anxiety-provoking. If it’s a recessive disease — which are the most common ones — if you and your partner are both carriers for it, there’s still a 25% chance that you could have a baby affected by that.
Now you can look at that and say, ‘Wow, there’s a one in four chance.’ Or you can look at it and say, ‘Hey, there’s a three in four chance that I’m going to be fine.’ So it depends on the individual and I respect everyone’s decision. I just educate them that if they do test, they can be prepared. They can maybe identify and tell their doctors so they can diagnose their baby sooner. But if they don’t want to do anything, that’s okay.
Dr. Aimee: It’s not required, but certainly I think when we talk to patients — just like you’re counseling — I think they sometimes see it as a different thing. They don’t see it as: ‘Oh, if I do it, it means that I’m going to have to potentially end a pregnancy that has a disease or something like that.’
You are very well published in this field. That’s why I wanted you for this show topic. And one particular question that I want you to answer for our audience is: How are genetics important when choosing a donor egg and/or donor sperm?
Dr. S: That’s a good question. So patients ask me that, and they say, ‘Well, what should I be looking for?’ And truthfully, you have to determine — either you or you and your partner — what’s important to you. When looking at a donor, especially for a donor egg, the criteria for a donor is to be of a certain age. To be typically in their twenties so that they have a high reproductive potential. When looking at a donor, helpful information is to say, have they donated before? How many eggs have they gotten, and what was the outcome of that? Truthfully, that’s the best marker of their fertility, and that’s the best marker of their genetic potential. Other aspects are: What’s important to that person? Is eye color important? Is hair color important? Is ethnicity important?
Those are genetic aspects that are important, and that oftentimes will manifest. Everybody is different. So when it comes to genetics, the key from a prognosis standpoint is age. And their ovarian reserve markers, which will be done by all agencies and clinics prior to them cycling.
Dr. Aimee: And what about paternal age? How does paternal age play a role in genetics?
Dr. S: That’s a good question. The blame always has been given to the egg. I did a study looking at paternal age to see if there was any association between paternal age and miscarriages. The study I did specifically looked at euploid or chromosomally normal embryos: If a 25-year-old has a normal embryo, but her partner is 50 — versus a 25-year-old with a 26-year-old partner. Does the one with the 50-year-old partner have a greater chance of having a miscarriage?
That study showed there really was no association between paternal age and chromosomally normal embryos miscarrying. That being said, that study was done after the embryos have already gone through the selection process. We selected them to be normal. It didn’t take into consideration that maybe that couple who had a higher paternal age had a higher percentage of abnormal embryos, or that the mechanism involved in creating the embryo was already selected.
So I definitely think that there is a possibility that paternal age plays a role. And now, we have the ability to do parental origin of aneuploidy in embryos diagnosed as abnormal,
in which we can determine if somebody has a higher percentage of aneuploid embryos, is that because of the egg or could it be the sperm as well?
And we’ve seen surprisingly that sometimes there’s a greater percentage due to the sperm rather than just the egg. So whereas traditionally, I would say 90% of the time the error was due to the egg. Now, instead of 10%, I see sometimes 15 to 20% of the time, the error can be due to this sperm.
Dr. Aimee: You just brought up something really important for people to hear. When you say embryos are genetically tested, what exactly does that mean? Can you test embryos for autism, hair color, height? What does genetically tested embryo mean?
Dr. S: Good Question. When talking about a genetically tested embryo, I’m talking about the process of preimplantation genetic testing or PGT. We take some cells out of the part of the embryo, which goes on to be the placenta, to determine the chromosomal makeup of those cells. That should be an accurate representation of the remainder of the embryo. Most commonly, when we do PGT-A (for aneuploidy), we’re looking to see: Does that embryo have the appropriate number of chromosomes? Does it have 46 like you and me? The 23 from sperm and 23 from the egg.
So the point of that test is to say, ‘Hey, do these embryos have the appropriate number of chromosomes?’ In the event that the carrier screening has shown that both the patient and their partner are carriers for the same disease, then we’re able to perform PGT-D (for diagnosis) or M for medical genetics.
In that case, prior to doing IVF, a specific probe needs to be made using the patient and their partner’s DNA to identify that specific mutation for that gene. So imagine you have Velcro? You have the sticky part, and you have the fuzzy part. So the probe is like the fuzzy part that finds a specific sequence of that gene to identify it. If that is the case, then you’re able to look for 1) the chromosomes. If you have five embryos, let’s say three are chromosomally normal, then you take those normal ones and say, ‘How many of these are actually affected with the disease?’ Or how many are carriers?
To answer your question. Autism, typically, no: Unless there has been a specific gene abnormality associated with that specific form of autism. We’re not able to screen the embryos for that, and we’re not able to screen for aesthetics like eye color or hair color. From my understanding, that’s not going to be something that’s done in the near future. Things change. So we’ll see.
Dr. Aimee: What about mosaicism? You’ve published on that too. Can you tell us what is a mosaic embryo? What should a fertility patient know about that?
Dr. S: Mosaicism is a really interesting topic that I’ve spent a lot of time researching. Mosaicism is when not all of the cells within the embryo have the exact same genetic makeup. If you have a hundred cells, maybe five of those cells have chromosomal abnormalities. Maybe those five cells have an extra chromosome — 47 — and the remainder of the 95 will have the appropriate 46.
Now, what to do with that information is kind of confusing. When we biopsy the embryos, we’re taking five to eight cells. When we get those results, sometimes it will be clear there are 46 chromosomes. But sometimes the results won’t be exactly clear that it has an extra copy, it’s missing a copy, or it has exactly two copies of each.
Sometimes the results will look like it’s in-between. That’s what we diagnose as mosaicism: It doesn’t appear that all of the cells in those samples have the same number of chromosomes. Some might have an extra. Some might have less. There has been a greater diagnosis since we switched the platform to Next Generation Sequencing, NGS, which happened around 2015. We started to see a higher degree of mosaicism.
Before it used to be black and white. Normal. Abnormal. Normal — yay! You put it in. Abnormal — don’t put it in. Then we have this gray area, and what do we do with it? For a long time, we just held them — too scared to put them in. Now we’re slowly learning a little bit more about it and, and we’re slowly, thoughtfully putting them back in.
We’re learning about these mosaic embryos. It depends on: Does it have extra copies? Does it have missing copies? Does it have extra copies of something that’s associated with a known abnormality? Something that’s mosaic for down syndrome is a chromosomal abnormality mosaic embryo we’re less likely to put in than something that has the mosaic for something not associated with a syndrome.
We’re learning that when we put in these embryos, they are less likely to implant and have a higher rate of miscarriage. But the few studies have shown that we put them in, they’ve actually had live births, and many of them have been healthy.
The key is talking to your doctor and genetic counselor about which mosaic embryos you have and trying to assess what percent of mosaic is it? Did it seem like 30% of the sample had an extra copy, or did it seem like 70% had an extra copy? That is a significant difference.
I did a study in fellowship that was recently published where I rebiopsied the embryos myself. I rebiopsied embryos that were normal and rebiopsied embryos that were abnormal.
And I rebiopsied embryos that were mosaic. And we found the normal embryos were normal. The abnormal embryos were abnormal. The mosaic embryos: Sometimes, they were mosaic, and sometimes they were abnormal. The key is that, if it was mosaic and associated with the abnormal chromosome, it was definitely abnormal.
So it gave some reassurance that: normal is normal. Abnormal is abnormal. Mosaic has potential. I think that’s important because some people are in a position where they only have a mosaic embryo, and they’re kind of scared as to what to do.
Dr. Aimee: I hope that everyone who goes through IVF listens to this show because I think it’s essential for you to know what questions to ask your doctor. Not all clinics will talk to their patients about mosaic embryos. They don’t have that setting turned on, for example, on the report for them even to get that data. So people don’t know that data is available to them. So if you think that all your embryos are abnormal, it’s possible that maybe one is mosaic.
I’ve actually seen it the other way around where a patient has had a report where all the embryos were normal. And then when she asked for the mosaic report, a couple of them actually came back mosaic.
Dr. S: It’s interesting. I did a study comparing mosaic rates based on the IVF labs. It was all done by the same genetics lab. These different IVF labs sent their biopsies to one location. We found that the mosaic rates do vary by the lab a little bit. To that degree, it probably varies a little bit by the lab doing the genetic testing.
That’s an important concept to talk to our patients about. You’re right about the settings. How does each clinic, how does each lab determine what’s normal, what’s not? I think some are more inclined to call ones abnormal than normal. Some are more inclined to say, ‘Hey, we don’t know. We don’t know. No results.’ That’s how our lab is. We are more inclined to say, ‘We can’t tell.’ We call it a no result, and then we’ll rebiopsy those.
Dr. Aimee: The example that I just gave you was not my patient. Obviously, I have that setting turned on, and I talk to my patients about it. I just want everyone to know that.
For patients out there, and I’m talking more specifically about women, is there a list of things that they should talk to their moms about if that’s possible? As far as things that run in the family. Do you have a go-to list of ‘Hey mom.’ I’ll give you a scenario: I had a patient who came to see me who was 33, and she was so upset that her mom had never told her that she had gone into menopause at age 35. If her mom had told her that perhaps she would have had an opportunity to secure options for herself that she, unfortunately, didn’t have by the time she saw me.
So is there a list? What are your golden rules as far as genetic diseases that you think every woman should know that about if they run in their family or not?
Dr. S: That’s a great one. 1) Mom, have you gone through menopause? When did you go through menopause? 2) Where there any issues conceiving my siblings or me? I think sometimes people don’t realize, ‘Oh, there was a 10-year gap between my brother and me.’ Was that because they had a hard time conceiving, or was that just because they wanted a 10-year gap?
A lot of times, that could have been some underlying infertility. Forty years ago, patients didn’t have fertility clinics as successful as we do. If you take the trajectory of infertility, people who keep trying and trying: Odds are they have a chance of conceiving on their own. The whole point of fertility treatments is to shorten that time to conception.
If you have a big gap between you and your siblings, if you don’t have a concept of why that gap was there, maybe gently probe about why that was. The other thing I always ask patients: Are there any genetic or developmental issues that you know of. Sometimes people will have an uncle or aunt or something that they’re not really sure of. That’s also important to know. Or if anybody has had a history of a lot of miscarriages. Patients may not know that before them, their parents had several miscarriages. That’s important to know as well.
Dr. Aimee: You and I would know all about our family because we know what questions to ask. But often I have patients in my office, and more often than not, they’re texting their moms when they’re here because they don’t know the answer to those questions.
And it’s really cute to see them talk back and forth and find out these answers that can sometimes be really helpful and powerful about miscarriage history, menopause and endometriosis, and all that stuff.
Dr. S: The best consults are when the mom is here with them.
Dr. Aimee: Exactly. We invite everybody. So if you are a fertility patient with everything that you know, what tests would you do before treatment?
Dr. S: I would do a genetic carrier screen, particularly one looking for Fragile X. Fragile X is a syndrome that’s associated with developmental delay. It’s a gene on our X chromosome that is made up of little repeats of the code. Depending upon the number of repeats we each have, there is the ability for that number of repeats to expand as our generations go on. Once it expands to a certain point, that can result in developmental delay.
It’s important for all women to have that tested because even if they don’t have a low ovarian reserve, they could have the ability to pass on a gene that results in a developmental delay to their sons. Not only that, even if they don’t carry it, they could be an intermediate carrier, which then could pass on having a low ovarian reserve or putting their daughters in a position where they then could have a son with developmental delays.
I would also do a broad expanded genetic carrier screen, and I would do a karyotype just to make sure that there are no abnormalities of my chromosomes, and I am 46 XX.
Dr. Aimee: One other thing, especially if you have a cancer history, maybe check that extra box for cancer genes too. I did one on everyone in my family and my in-laws. They don’t have a choice when you’re related to me.
What are your predictions for genetic testing in our future?
Dr. S: I think genetic testing is going to get more precise when it comes to evaluating embryos. We’re going to make a change. Next-generation sequencing is evolving and getting better. It’s going to get to a higher resolution in which we’re going to be able to see, not just whole chromosome abnormalities, but these subtle little deletions. When you do noninvasive prenatal testing now, it’s not only looking for an extra copy of chromosome 21, 18 or 13. A lot of them are looking for microdeletions, which are associated with different developmental issues or complications with kids.
We’re going to be able to look for not just large differences in chromosomes. We’re going to be able to look for smaller ones too. There are going to be some growing pains that come with it. Just like with NGS, we had the mosaic growing pains. I think there’s going to be a lot of diagnoses of things that we don’t know what to do with. Ultimately, in the long run, I think it’s a good thing.
Dr. Aimee: Thank you, Dr. S, for being a guest on our show and talking about all the genetic screening that fertility patients can do. We appreciate you. Can you tell our audience again where they can find you and more about your practice?
Dr. S: Thanks so much for having me. I’m in practice here in Orange County in Newport Beach, California. We’re at OC Fertility here in Newport Beach, and we’re part of the CCRM Network. We’re part of CCRM Orange County as well.
The website to go is www.ocfertility.com, and on Instagram, I’m Dr. Nidhee Sachdev if you’re looking for me.
Dr. Aimee: I want everyone to follow her, and certainly, if you’re in Orange County or anywhere else and you want to see her, please do. Well, thank you again for being on today’s show.
And be sure to subscribe to my YouTube channel and sign up for my IVF class, tushy class or my egg freezing class at https://the-egg-whisperer-school.teachable.com/.