Management of recurrent implantation failure during the COVID-19 pandemic
22 Mar 2022
bởiDr. Ameet Patki, Dr. Prakash Mayandi
Recurrent implantation failure (RIF) refers to the failure to achieve a clinical pregnancy after three in vitro fertilization (IVF) attempts with at least four good-quality embryos. RIF leaves couples frustrated and desperate for answers and is challenging for clinicians to handle, compounded by the impact of the COVID-19 pandemic restrictions. Two experts, Dr Ameet Patki, Medical Director of Fertility Associates Mumbai and Hon Assoc Prof at KJ Somaiya Medical College & Hospital, India, and Dr Prakash Mayandi, Metro IVF Fertility Centre, Kuala Lumpur, Malaysia, weigh in with their views on managing RIF during the COVID-19 pandemic.
Prevalence of infertility and RIF
Globally, 15 percent of couples in their reproductive years suffer from infertility, defined as the failure to achieve pregnancy after a year of unprotected regular intercourse. [Aging (Albany NY) 2019;11:10952–10991] “The actual incidence is likely to be higher, up to 22 percent, as couples may not seek medical help, either due to lack of awareness, lack of access, or stigma,” said Ameet. “The incidence of infertility is rising as couples delay having children until later in life,” Prakash concurred.
There is scarce data available on the incidence or prevalence of RIF. “Of couples undergoing infertility treatment in India, about 10–15 percent would have RIF,” estimates Ameet. “There is no national registry on IVF in Malaysia, but based on reports on cumulative success rates of IVF from private centres, RIF affects between one-third and two-thirds of patients undergoing IVF,” said Prakash.
Investigations and management of RIF
Ameet investigates five main factors that contribute to RIF, namely, 1) genetic abnormalities, 2) structural abnormalities (eg, fibroids, polyps, inadequate endometrial lining at the time of transfer), 3) autoimmune causes (antiphospholipid syndrome, lupus, autoimmune antibodies), 4) infections (particularly tuberculosis for India), and 5) metabolic abnormalities (eg, thyroid, glucose, prolactin).
“Some investigations are conducted in all patients and are treated prior to the assisted reproductive technology (ART) programme, for example, checking for fibroids, endometriosis, and metabolic abnormalities. Other investigations, such as genetic karyotyping and testing for thrombophilia are only carried out after RIF. Based on the results, further tests would be conducted. RIF patients need personalized treatment,” Ameet clarified.
Prakash meanwhile explores three main factors in patients with RIF, which he describes as the ‘3 Es’: Endometrium, Embryo, and Experience and emotional component.
Endometrium: Tests include ultrasound, hysteroscopy, dilatation and curettage (to check for anomalies), and endometrial receptivity array (ERA) (to check if the embryo transfer is done at the correct window period), as well as checking for maternal immunological factors that may cause the endometrium to be less susceptible, such as antiphospholipid syndrome.
Embryo: Things to check include the stage of the embryo being transferred (D2, D3, D5), grade of the embryo, and whether assisted hatching or preimplantation genetic screening (PGS) was conducted. More practices are moving towards single embryo transfer with blastocyst which has undergone PGS. Studies have also shown that hyaluronan-enriched culture medium such as EmbryoGlue may be useful in patients with RIF. [J Hum Reprod Sci 2015;8:214-217] Oocyte donation is another possible intervention for selected patients with RIF.
Experience and emotional component: The patient’s experience and emotional state during the IVF process may play a role, for example, stress leads to elevated cortisol levels, which is associated with negative pregnancy outcomes. [Reprod Biol Endocrinol 2018;16:121] It is important for physicians to communicate openly with patients and work out how to better support them in the next round. “In Malaysia, even after one implantation failure, most doctors would investigate and implement all possible measures to improve success rates. For RIF patients who have already tried various interventions in previous embryo transfers, there is little room for improvement. That is why one of the main things is improving the patient’s experience and emotional component,” explained Prakash.
In terms of managing RIF, Ameet notes that interventions in India are similar to those described in Table 1, though “PGS may not be as important for RIF as it is for recurrent spontaneous miscarriages, and interleukins or IV immunoglobulins are not commonly used.”
Take-home messages
“RIF is a frustrating condition for both patients and doctors, and failure leads to disappointment on both ends. Clinicians should continuously encourage patients and build trust through open communication, explaining what has been done and the available options, and actively involving them in decision-making. The pandemic has placed financial constraints on many couples; further investigations, and additional rounds of IVF, would increase their financial burden. Thus, having empathy and strong rapport will go a long way in supporting patients through their journey,” said Prakash.
“As COVID-19 does not appear to be stopping so soon, we must take all due precautions by reducing clinic visits and encouraging online consultations. All patients undergoing ART are advised to be fully vaccinated to protect themselves and their unborn child. For RIF patients, physicians should not delay their treatment as their success depends on their age,” emphasized Ameet.
Prevalence of infertility and RIF
Globally, 15 percent of couples in their reproductive years suffer from infertility, defined as the failure to achieve pregnancy after a year of unprotected regular intercourse. [Aging (Albany NY) 2019;11:10952–10991] “The actual incidence is likely to be higher, up to 22 percent, as couples may not seek medical help, either due to lack of awareness, lack of access, or stigma,” said Ameet. “The incidence of infertility is rising as couples delay having children until later in life,” Prakash concurred.
There is scarce data available on the incidence or prevalence of RIF. “Of couples undergoing infertility treatment in India, about 10–15 percent would have RIF,” estimates Ameet. “There is no national registry on IVF in Malaysia, but based on reports on cumulative success rates of IVF from private centres, RIF affects between one-third and two-thirds of patients undergoing IVF,” said Prakash.
Investigations and management of RIF
Ameet investigates five main factors that contribute to RIF, namely, 1) genetic abnormalities, 2) structural abnormalities (eg, fibroids, polyps, inadequate endometrial lining at the time of transfer), 3) autoimmune causes (antiphospholipid syndrome, lupus, autoimmune antibodies), 4) infections (particularly tuberculosis for India), and 5) metabolic abnormalities (eg, thyroid, glucose, prolactin).
“Some investigations are conducted in all patients and are treated prior to the assisted reproductive technology (ART) programme, for example, checking for fibroids, endometriosis, and metabolic abnormalities. Other investigations, such as genetic karyotyping and testing for thrombophilia are only carried out after RIF. Based on the results, further tests would be conducted. RIF patients need personalized treatment,” Ameet clarified.
Prakash meanwhile explores three main factors in patients with RIF, which he describes as the ‘3 Es’: Endometrium, Embryo, and Experience and emotional component.
Endometrium: Tests include ultrasound, hysteroscopy, dilatation and curettage (to check for anomalies), and endometrial receptivity array (ERA) (to check if the embryo transfer is done at the correct window period), as well as checking for maternal immunological factors that may cause the endometrium to be less susceptible, such as antiphospholipid syndrome.
Embryo: Things to check include the stage of the embryo being transferred (D2, D3, D5), grade of the embryo, and whether assisted hatching or preimplantation genetic screening (PGS) was conducted. More practices are moving towards single embryo transfer with blastocyst which has undergone PGS. Studies have also shown that hyaluronan-enriched culture medium such as EmbryoGlue may be useful in patients with RIF. [J Hum Reprod Sci 2015;8:214-217] Oocyte donation is another possible intervention for selected patients with RIF.
Experience and emotional component: The patient’s experience and emotional state during the IVF process may play a role, for example, stress leads to elevated cortisol levels, which is associated with negative pregnancy outcomes. [Reprod Biol Endocrinol 2018;16:121] It is important for physicians to communicate openly with patients and work out how to better support them in the next round. “In Malaysia, even after one implantation failure, most doctors would investigate and implement all possible measures to improve success rates. For RIF patients who have already tried various interventions in previous embryo transfers, there is little room for improvement. That is why one of the main things is improving the patient’s experience and emotional component,” explained Prakash.
In terms of managing RIF, Ameet notes that interventions in India are similar to those described in Table 1, though “PGS may not be as important for RIF as it is for recurrent spontaneous miscarriages, and interleukins or IV immunoglobulins are not commonly used.”
Take-home messages
“RIF is a frustrating condition for both patients and doctors, and failure leads to disappointment on both ends. Clinicians should continuously encourage patients and build trust through open communication, explaining what has been done and the available options, and actively involving them in decision-making. The pandemic has placed financial constraints on many couples; further investigations, and additional rounds of IVF, would increase their financial burden. Thus, having empathy and strong rapport will go a long way in supporting patients through their journey,” said Prakash.
“As COVID-19 does not appear to be stopping so soon, we must take all due precautions by reducing clinic visits and encouraging online consultations. All patients undergoing ART are advised to be fully vaccinated to protect themselves and their unborn child. For RIF patients, physicians should not delay their treatment as their success depends on their age,” emphasized Ameet.