The population issue has always been a hot topic in recent years and is also a top priority of proposals at the Two Sessions not long ago. What economic laws are behind the continuous decline in population in recent years? Who is troubled by whether to have children or not?Mr. Mao Hua, Partner and Managing Director of Frost & Sullivan Greater China, was invited to appear on the Titanium Media program 'Helen's Financial Dinner'. Together with Mr. Sun Cheng, Content Director for East China at Titanium Media, and Mr. Jin Lun, Researcher at the Guangdong-Hong Kong-Macao Greater Bay Area Reform and Innovation Research Institute and financial columnist, they discussed this topic from two perspectives: the underlying reasons for the new low population and assisted reproductive methods.
Q: Since the birth of China's first 'test-tube baby' in 1988, human assisted reproductive technology has been widely applied and developed in our country for 30 years. It is believed that significant progress has been made over these years. Could you introduce some of the changes that have taken place over the years? And what are currently the more advanced medical methods of assisted reproduction?
Mr. Mao Hua introduced that assisted reproductive technology, abbreviated as ATR (Assisted Reproductive Technology), refers to the use of medical assistance to enable infertile couples to conceive. Since the successful birth of China's first 'test-tube baby' in 1988, more and more infertile couples in China have conceived through assisted reproductive technology, which has developed into a routine treatment method for tens of thousands of infertile couples. In 1999, Chinese scientists conducted the first preimplantation genetic diagnosis at the First Affiliated Hospital of Sun Yat-sen University, and the following year, the first preimplantation genetic diagnosis (PGD) baby was born. With innovations in technology and methods, improvements in in vitro culture conditions and environment, and the refinement of controlled ovarian stimulation protocols, the pregnancy rate and live birth rate of ART have significantly increased. Since 1989, China has continuously improved its laws and regulations related to assisted reproduction, with strict industry access threshold standards.
Although China's assisted reproductive technology started relatively late, it has developed rapidly. The level of its technology and derivative technologies is gradually aligning with the world standard and is gradually reaching international advanced levels.After more than 30 years of rapid development, China now has treated over 200,000 patients annually with assisted reproductive technology, becoming the world's leading country in this field. China's assisted reproductive technology is gradually maturing and has even reached a world-leading level in certain areas.On September 19, 2014, the world's first test-tube baby for single-gene genetic disease screening was born at Peking University Third Hospital using MALBAC genome amplification followed by high-throughput sequencing. Subsequent cord blood gene testing confirmed that the infant did not carry pathogenic loci.This marks that China's preimplantation genetic diagnosis technology has reached a world-leading level, and 'birth defects', as a major reproductive health challenge, have also been overcome.
In recent years, with technological advancements, new assisted reproductive technologies have been able to better assist doctors in clinical diagnosis and provide patients with more feasible and high-quality treatment options. For example,Research on DNA Fragmentation IndexClear indicators for male infertility can help doctors decide whether to use ICSI treatment or conventional IVF treatment.Endometrial receptivity array detection technologyThe success rate of implanting fertilized eggs can be evaluated by molecular analysis of endometrial tissue, which helps optimize the chances of successful transplantation after in vitro fertilization. Technological progress promotes the healthy development of the assisted reproductive services industry. In February 2020, China's first preimplantation genetic testing (PGT-A) product for non-homologous chromosome aberrations was approved for market release. By the end of 2020, medical institutions offering human assisted reproductive technology services were operating in all provinces and cities across the country, continuously improving accessibility. Various assisted reproductive technologies have developed rapidly, with technical levels gradually improving and service capabilities continuously enhancing, bringing good news to many infertile couples and making important contributions to family harmony and social stability.
Assisted reproductive technologies include two main categories: Artificial Insemination (AI) and In Vitro Fertilization and Embryo Transfer (IVF-ET) and their derivative techniques. In vitro fertilization with embryo transfer (IVF-ET) is the method used to produce babies through this technology. In addition, there are also some new technical approaches in experimental stages, such as whole-genome screening IVF-ET and stem cell babies.
Assisted reproductive services mainly consist of the following different projects: artificial insemination, gamete transfer, and in vitro fertilization (IVF). Artificial insemination can be further divided into husband sperm artificial insemination (AIH) and donor sperm artificial insemination (AID). Gamete transfer mainly includes intracytoplasmic sperm injection (ICSI) and intrauterine gamete transfer (IUT). IVF is divided into three generations, each suitable for different patients.
The currently more advanced assisted reproductive technology is the third-generation in vitro fertilization (IVF) technique.PGT (Preimplantation Genetic Testing), also known as third-generation in vitro fertilization technology, refers to the genetic testing and detection of chromosomal abnormalities before an embryo conceived through in vitro fertilization is implanted into the mother's uterus. PGT technology can be divided into preimplantation genetic diagnosis (abbreviated as PGD) and preimplantation genetic screening (abbreviated as PGS). Currently, PGT can block 263 single-gene genetic diseases such as thalassemia, deafness, and spinal muscular atrophy (SMA), preventing birth defects; at the same time, it can effectively eliminate embryos with chromosomal abnormalities for infertile couples due to chromosomal structural abnormalities (such as balanced translocation/Robertsonian translocation and microdeletions/repeats).This method can directly screen out problematic embryos, selecting those with normal genetic material for implantation into the uterus, thereby improving pregnancy rates, reducing miscarriage rates, and preventing the birth of children with single-gene diseases and chromosomal abnormalities.
Q: What are the upstream and downstream forms of assisted reproduction? Why is clinical testing, especially chromosome testing, receiving increasing attention, which is considered to have a significant impact on eugenics and healthy childbearing?
A: 'The upstream of the assisted reproductive technology industry chain mainly includes reagents used before surgery, medications and instruments used during the assisted reproductive cycle, etc. The midstream mainly consists of pharmaceuticals, equipment agents, as well as some mobile and internet platforms. The downstream mainly comprises institutions that provide various assisted reproductive services to patients.'
Mr. Mao Hua further explained that the upstream of the assisted reproductive industry includes suppliers of drugs, devices, and diagnostic reagents. The market scale for assisted reproductive medications is about one hundred billion yuan, including drugs for down-regulation, ovulation induction, ovulation stimulation, and luteal support. Among them, ovulation-stimulating drugs account for 60%, and luteal-supporting drugs account for 20%.
The midstream of the industrial chain consists of assisted reproductive service institutions. Relying on the advantages of internet channels, these institutions have launched an online consultation APP for peripheral services related to assisted reproduction. Offline, they achieve precise customer acquisition through medical service entities and then direct them to downstream assisted reproductive medical service institutions, realizing a deep integration of 'Internet + assisted reproduction'.
The downstream of the industry consists of assisted reproductive medical service institutions. The market concentration in the downstream is low, with a highly fragmented competitive landscape, and public medical institutions have a more obvious advantage.
Preimplantation genetic testing (PGT) refers to the screening of embryo chromosomes before embryo transfer to eliminate embryos carrying genetic diseases and chromosomal abnormalities, thereby improving pregnancy outcomes. PGT technology includes the screening of non-identical chromosome pairs and the detection of embryos carrying certain known pathogenic genes. Depending on the purpose, PGT technologies are divided into preimplantation genetic testing for aneuploidy (PGT-A), preimplantation genetic testing for monogenic (PGT-M), and preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR).
According to research, up to 50% of early miscarriages are associated with aneuploidy of the embryo. Aneuploid embryos are difficult to implant, and even a small number that do implant often develop poorly. The incidence of chromosomal aneuploidy in embryos is related to the age of the pregnant woman, increasing with age. Homozygous embryos are more likely to implant and have better pregnancy outcomes. Therefore, the focus of evaluation has shifted from embryo morphology to chromosome aneuploidy screening.PGT-A can effectively increase the success rate of pregnancy by performing aneuploid screening on embryos.PGT-M (Preimplantation Genetic Testing for Males), which prevents the birth of male patients with X-linked recessive genetic diseases by selecting female embryos, has gained widespread clinical recognition for preventing single-gene genetic disorders with high incidence and mortality rates. PGT-M can use fluorescence in situ hybridization (FISH) technology to screen for balanced embryos, thereby preventing the transmission of abnormal chromosomes between two generations.The ultimate goal of PGT is to identify embryos with normal chromosomes, allowing for the implantation of healthy embryos back into the mother's womb, thereby greatly increasing the chances of pregnancy. This is especially beneficial for older women who have experienced multiple failed in vitro fertilization attempts and are at high risk of miscarriage. It can effectively prevent the occurrence of genetic diseases, while also avoiding potential harm from elective abortions and multiple abortions. It prevents physical and psychological trauma to pregnant women and their families due to the need to terminate pregnancy.
Q: Apart from China, what are the characteristics of assisted reproductive technologies worldwide?
Mr. Mao Hua stated that the global assisted reproductive industry has shown a strong trend, mainly reflected in rapid technological updates, large-scale industry development, and rapid growth of cross-border assisted reproductive markets. Overseas assisted reproductive policies are mature with high penetration rates.
1) Overseas assisted reproductive technology is leading
Compared with domestic services, most assisted reproductive technologies abroad have a leading edge. In terms of success rates, in vitro fertilization (IVF) in the United States is 1.6 times more effective than that in Thailand and 2.6 times more effective than IVF in China.According to the analysis report data from Frost & Sullivan, the average success rate of in vitro fertilization (IVF) at officially approved reproductive centers and infertility hospitals in China is 30%-40%, with a slightly higher success rate for younger individuals; whereas the average success rate of IVF in the United States is 70%-80%, ranking first in the world; in Thailand and Malaysia, the success rate is 60%-70%, second only to the United States.
From the perspective of technological generations, most domestic hospitals are still operating on the first and second-generation in vitro fertilization (IVF) technologies. In contrast, countries such as the United States, Thailand, and Malaysia have maturely adopted the third-generation IVF PGD technology, which is considered a global top-tier technique. The third-generation IVF PGD technology abroad has been clinically used for over 20 years and leads China by more than a decade. It has an advantage in screening genetic diseases and chromosomal issues, capable of detecting up to 250 different genetic disorders. IVF cycles can be divided into multiple phases (2 days or 28 days), with precise dosages of ovulation-stimulating drugs that cause almost no side effects. Embryo transfer using blastocysts increases success rates even further. High-end laboratories abroad and experienced IVF experts ensure the success rate of IVF, along with personalized medical service management that provides one-on-one services from doctors. Therefore, in terms of laboratory level, embryologist technology, and doctor clinical experience, foreign IVF has more advantages.
2) Improvement of overseas assisted reproductive policies
Foreign policies allow the commercialization of reproductive cells:In countries abroad such as the United States and the United Kingdom, assisted reproduction is mostly led by companies. In private clinics offering artificial insemination, commercial sperm are commonly used, and there are also cases where women sell their own eggs.
Proportion of Recipients from the Same Donor:Most sperm banks abroad are commercial ones, and different private clinics have varying regulations on this ratio. It can range from 1:10 to 1:25 or even higher. In cases where the ratio is high, it allows for the maximum utilization of physiologically 'excellent' genes, thereby providing a certain guarantee for embryo quality.
Foreign single women can adopt assisted reproduction:In countries such as the United States and the United Kingdom, single women and gay couples can also conceive children through assisted reproductive technology.
Surrogacy abroad is legal:In countries such as the United States, the United Kingdom, and Australia, surrogacy is recognized as legal in multiple states, with relatively complete legal regulations and professional surrogacy intermediary agencies. Hong Kong in China also recognizes the legality of childbearing through surrogacy.
Q: What are the current domestic companies related to assisted reproduction? What characteristics do they exhibit? What is our current level of technology?
A:1) Upstream enterprises:
Equipment consumables: Desheng Biotech, Beikang Medical, BGI Medical, Yingsheng Biotech, Berry Health, Bio-Ocean, Antu Biotech, Yikang Gene, Jiarong Renhe, Yahui Long Biotechnology
Drugs: Merck Sharp & Dohme, Xianju Pharmaceutical, Lizhu Medicine, Jinsai Pharmaceutical
2) Midstream and downstream enterprises:
Jinxin Reproductive Medicine, Aiview Medical, Med66 Medical, Tongce Medical
The upstream multinational pharmaceutical companies in the assisted reproductive industry, such as Merck Serono and Merck Sharp & Dohme, have a clear competitive advantage. With the improvement of domestic R&D innovation levels and the enhancement of generic drug consistency evaluation, domestic pharmaceutical companies like Lizhu Group and Xianju Pharmaceutical will accelerate their penetration into high-end markets and speed up the process of domestic substitution. The production of assisted reproductive devices is mainly by foreign manufacturers, who almost monopolize the device market, such as Vitrolife and ORIGIO. China mainly produces auxiliary devices and consumables such as egg retrieval needles, embryo transfer catheters, and culture dishes. In the future, with the support and improvement of domestic assisted reproductive policies, and under the impetus of an environment that encourages domestic substitution, companies like Deshi (a manufacturer of chromosome testing equipment and auxiliary devices and consumables) are continuously deploying in the field of domestic assisted reproduction, reducing import dependence, and achieving domestic substitution will be an inevitable trend.
The middle and lower reaches are assisted reproductive service institutions.The downstream market has a low concentration, highly fragmented competition, and public medical institutions have a clear advantage.Most assisted reproductive centers can provide basic assisted reproductive services, but there is a significant gap in high-end technology needs, indicating that there is room for substantial improvement in overall assisted reproductive center technology. Data from the National Health Commission show that as of June 30, 2020, there were 523 medical institutions approved to carry out human assisted reproduction, with private hospital assisted reproductive centers accounting for about 10%. According to statistics, 325 centers provide intrauterine insemination (IUI) with husband's sperm, 83 provide donor insemination, 398 provide conventional IVF-ET, 399 provide intracytoplasmic sperm injection (ICSI), and 71 provide preimplantation genetic diagnosis (PGD). Among these, 45 assisted reproductive medical institutions offer all five technologies, accounting for 8.6% of the total national number.
Q: We have noticed that companies related to assisted reproduction are particularly favored by capital in terms of financing. What is your view on these startups? What are their future development directions?
A: With the continuous development of the social economy and the accelerating pace of life and work, fertility issues have become one of the urgent problems that need to be addressed in China and around the world. In recent years, the number of infertile couples in China has been increasing year by year, reaching 49.9 million in 2019, with a compound annual growth rate of 3.2% from 2015 to 2019.According to Frost & Sullivan's forecast, by 2024, this number will steadily grow to 52.6 million, with a compound annual growth rate of 1.1% from 2019 to 2024. The continuous postponement of marriage and childbearing age, coupled with the increasing population of elderly pregnant women driven by the three-child policy, and the urgent need for improved birth outcomes due to neonatal defects, have made the assisted reproductive industry one of the potential markets with the fastest demand growth and expansion in China's healthcare services sector.
As an emerging market for assisted reproduction, China has maintained a high growth rate in recent years. The Chinese assisted reproductive service market has increased from 162 billion yuan in 2015 to 282 billion yuan in 2019, on par with the US market, with a compound annual growth rate of 14.9%. With the increasing demand for assisted reproductive services, the Chinese market will continue to expand rapidly, expected to reach 681 billion yuan by 2024, with a compound annual growth rate of 19.3%.In China, assisted reproduction has high barriers, strong premium pricing power, and huge potential for market penetration. These characteristics make it an important reason why the assisted reproduction sector attracts capital.
Currently, Beijing has taken the lead, ushering assisted reproductive technology services from an era of 'no medical coverage' into one where they are 'paid for by medical insurance'..With the gradual maturity of assisted reproductive technology and national policy support for the industry, the assisted reproductive sector is about to enter a strategic opportunity period. In any case, the assisted reproductive service market is an untapped blue ocean. Nowadays, with the capitalization of some leading enterprises and the entry of more capital providers, start-up private assisted reproductive institutions are expected to welcome a new spring, while large assisted reproductive medical groups will gradually form and stand out. This market, worth hundreds of billions, will also experience accelerated explosive growth.
China's assisted reproductive industry is in the growth phase, and future market demand is promising. The innovation of assisted reproductive technologies through multidisciplinary collaboration will become the core driving force for the development of the industry.
1) Development of private assisted reproductive institutions
At present, the assisted reproductive service industry in China is still dominated by public medical institutions. Policies encourage the utilization of social resources for the operation of medical institutions, such as the 'Implementation Opinions on Promoting the Accelerated Development of Private Medical Institutions,' and the opening up of relevant approval certificates will lead to rapid development of private assisted reproductive institutions. In addition, private assisted reproductive medical institutions have the advantages of high flexibility and high service quality. With the increasingly clear requirements from the Ministry of Health for assisted reproductive hospitals and the expansion of market space, private assisted reproductive hospitals are increasingly integrating with the capital side, and downstream ports of the industry are gradually opening up, highlighting investment value. In the near future, more patients will tend to choose private assisted reproductive centers for assisted reproductive treatment, which will promote the rapid development of private assisted reproductive centers.
2) Chain operation
In China, due to the reproducibility of assisted reproductive services and a streamlined professional structure, there is a greater preference for development towards medical chains. The chain operation of assisted reproductive centers can share medical resources, brand images, improve overall operational efficiency, and promote coordinated development among various assisted reproductive institutions.
3) Continuously advancing technological progress
With the acceleration of globalization, assisted reproductive centers will have more opportunities to learn advanced assisted reproductive technologies and cooperate with outstanding overseas medical institutions. In turn, this will also enhance the technical level of ART centers. At the same time, third-generation technologies such as PGD and PGS are becoming increasingly popular in China, helping couples achieve better birth outcomes. The continuous improvement in technical levels will promote the development of the assisted reproductive service industry.
