Continuing the Conversation: Dr Nalini Mahajan on Women’s Fertility and IVF

Q) How does preimplantation genetic testing (PGT-A, PGT-M) affect IVF success rates?

A) Preimplantation genetic testing—so now, there are two types, as you’ve written: PGT-A and PGT-M.

PGT-A is for aneuploidies, which are numerical chromosomal abnormalities that happen with age. Normally, you have a certain number of chromosomes: 22 pairs plus either XX or XY. If there’s a break or error—for example, an extra chromosome—it’s called a trisomy. If there’s one missing, like XO, it’s a monosomy. These abnormalities often lead to miscarriages. Since age increases the risk of these aneuploidies, if an older woman is going for IVF, we do advise, if possible, to test the embryos for these abnormalities. If you find a normal embryo, it will give you a better chance at success.

PGT-M is for monogenic diseases. If there’s an inherited disorder in the family—say, a BRCA mutation—you can test for that using PGT-M. But for this, you must know the exact mutation—which gene, which chromosome, and what specific change—because you can’t test for everything. You have to pick exactly what mutation is to be tested. Then, that mutation is tested using the trophectoderm cells of the embryo, and whichever embryo is found to be normal, is considered for transfer.

Q) What is embryo culture and cryopreservation?
A) Embryo culture is what you do when you take the egg and the sperm and place them in a specially developed culture media that allows them to grow. This media provides the nutrients the egg and then the embryo need—such as glucose and other essential components. It also maintains the pH and temperature required for growth, all of which is managed within an incubator. The media is specifically prepared to support the embryo through the first five days of development. That is embryo culture.

Cryopreservation is the process of freezing the embryo for future use. What we currently use is a method called vitrification, where the temperature is drastically dropped. The embryo is placed in a special cryopreservation media that shrinks it, and then it’s rapidly frozen—put into an environment of around minus 190 to 195 degrees Celsius. When needed, the embryo is thawed, and put through opposite grades of concentration of media so that it can expand and return to its original state before being transferred.

Q) How does platelet-rich plasma (PRP) therapy work in improving endometrial lining and ovarian function?
A) Okay, so to begin with, this is still experimental, it is not standard, but it does work, and it works pretty well. Platelets have growth factors in them. When you talk about platelet-rich plasma, what you do is concentrate the platelets—suppose I take 20 ml of your blood, spin it, and separate out the platelets. Now those are concentrated.

Every platelet has a growth factor. For instance, when you get hurt and bleed, a clot forms and healing begins—that happens because the platelets are releasing growth factors, collagen, and other substances that start the healing process. When you concentrate these growth factors and put them into the endometrial lining, they enhance the ability of the endometrial basal cells (not so much the stem cells) to start growing. That’s how they enhance the lining.

It’s also being seen that they enhance implantation, by changing the immune profile, so the immune cells don’t attack the embryo and allow it to implant. So this is a work in progress, but it has shown a lot of good results.

As far as intra-ovarian platelets are concerned—it’s the same thing. You concentrate and put them in. What really happens is still a theory, because we don’t know exactly, but what is presumed and what you see is that dormant cells—primordial follicles—get activated. These follicles may not have sufficient growth factors to activate and grow.

Because everything is already there, we don’t exactly know what starts off the process of activating a group of eggs into a cycle—it’s pre-programmed, six months earlier. But some eggs, some primordial follicles, are lying dormant. When you put in the platelets, they enhance the ability of those dormant follicles to activate.

So you basically do it when the egg reserve is low, when the patient needs to go for IVF, and she wants to have more eggs—or when the only option is donor eggs because she doesn’t have any. So you try these kinds of experiments.

Q) How do different ovarian stimulation medications (e.g., GnRH agonists vs. antagonists) impact egg quality and retrieval success?
A) We started with GnRH agonists, which were used before antagonists were available. In this approach, you completely suppress the pituitary gland to prevent the LH surge, which can cause the follicles to rupture before retrieval. After suppressing the pituitary, you administer FSH externally to stimulate the growth of the eggs. Once the eggs reach the desired size and hormone levels align, you give an injection of hCG to simulate the LH surge, triggering the final maturation of the eggs.

With the agonist protocol, you generally get a more uniform group of follicles and slightly more eggs, but it requires a longer duration of injections and carries a higher risk of ovarian hyperstimulation syndrome (OHSS).

Now, things have changed with the introduction of GnRH antagonists, which also suppress the pituitary, but they work much faster—the suppression happens within 24 hours. This means you have to administer the injection daily. For the LH surge, instead of using hCG, you can use a single dose of a GnRH agonist as a trigger, which is safer in terms of reducing OHSS risk.

Additionally, current protocols avoid fresh embryo transfers. Instead, embryos are frozen, which eliminates the risk of late-onset OHSS caused by endogenous hCG if implantation occurs. Other protective measures, such as the use of cabergoline, are also used if hCG is administered, further minimizing risk.

In terms of success rates, pregnancy outcomes with both protocols are comparable. You might retrieve 1 or 2 more eggs with the agonist, but the antagonist protocol is much safer and more comfortable overall.

Q) What factors determine embryo grading, and how important is it for success?
A) Embryo quality is absolutely critical for IVF success—at the end of the day, it's all about the embryo. Several factors influence embryo grading. These include the number of cells, rate of cell division, and how evenly the blastomeres (the early cells) are dividing. Other morphological features, such as the amount of fragmentation or the development of the blastocyst, are also assessed.

However, good grading starts long before observation. It depends heavily on the quality of the lab. The culture media must provide the right nutrients, the incubators must be properly calibrated, and every care must be taken to avoid environmental toxins or VOCs (volatile organic compounds). If these conditions aren't optimized, embryo quality suffers, no matter how good the egg or sperm is.

So yes, grading gives us a useful indication, and while pregnancies can sometimes still happen with lower-grade embryos, the chances are significantly higher when you start with a well-graded, healthy embryo grown in an excellent lab environment.

Q) How does FSH receptor polymorphism affect ovarian response to stimulation?
A) Different individuals can respond very differently to ovarian stimulation medications, and one key reason behind this variation is FSH or LH receptor polymorphism. These polymorphisms refer to slight genetic variations that cause the hormone receptors—specifically those for follicle-stimulating hormone (FSH) or luteinizing hormone (LH)—to function suboptimally.

As a result, even when ovarian reserve looks good and the correct dosage is given, some patients may not respond as expected. Their bodies may simply require higher doses of stimulation because the receptors are not as efficient at binding and responding to the hormones.

These tests aren’t done routinely—especially in countries like India, where IVF treatment is often paid out of pocket—because they add to the cost. However, if a patient shows a poor or unexpected response to stimulation despite favorable baseline indicators, testing for FSH/LH receptor polymorphisms can help personalize the medication protocol, such as adjusting the doses of FSH or adding LH support to optimize results.

Q) Are there long-term developmental differences in IVF-conceived children, or is there a risk of birth defects?
A) Extensive follow-up studies have been conducted on IVF-conceived children, and so far, the findings have been largely reassuring. In terms of congenital abnormalities, the overall risk remains very close to that of naturally conceived children. The baseline risk for congenital anomalies in the general population is about 3.7%, while some studies suggest a slightly higher risk—around 5%—in IVF-conceived children, particularly in cases involving male-factor infertility.

However, this marginal increase is often believed to be related more to the underlying cause of infertility rather than the IVF procedure itself. As for long-term developmental milestones or physical and cognitive development, current research has not shown significant differences between IVF and naturally conceived children.

That said, studies are ongoing, and while the current data is reassuring, the field continues to monitor long-term outcomes to ensure safety and well-being.

Q) How do hormonal medications in IVF impact overall health in the long term?
A) In general, hormonal medications used in IVF do not have long-term physical health effects. The hormones—primarily estrogen—are elevated only for a short duration, usually a few days, which is why injections need to be given daily. Their effects are also temporary. 

However, the emotional impact of IVF can be profound. The process often feels like an emotional rollercoaster—with alternating phases of hope and disappointment. This psychological toll can be more significant than any physical side effect.

The number of cycles a person undergoes also plays a role. If a patient produces a good number of embryos and undergoes up to three embryo transfers, their cumulative chance of success is around 70%, depending on factors like age and uterine health. Some individuals may choose to continue beyond that, doing 5–6 cycles, but at some point, it becomes important to listen to your body, consider taking a break, or explore alternative options. Ultimately, it’s a deeply personal decision, and one that should be made with care and support.