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Monday, September 28, 2020

How COVID-19 can damage the brain

 How COVID-19 can damage the brain

Some people who become ill with the coronavirus develop neurological symptoms. Scientists are struggling to understand why.




The woman had seen lions and monkeys in her house. She was becoming disoriented and aggressive towards others, and was convinced that her husband was an impostor. She was in her mid-50s — decades older than the age at which psychosis typically develops — and had no psychiatric history. What she did have, however, was COVID-19. Hers was one of the first known cases of someone developing psychosis after contracting the disease

In the early months of the COVID-19 pandemic, doctors struggled to keep patients breathing, and focused mainly on treating damage to the lungs and circulatory system. But even then, evidence for neurological effects was accumulating. Some people hospitalized with COVID-19 were experiencing delirium: they were confused, disorientated and agitated. In April, a group in Japan published the first report of someone with COVID-19 who had swelling and inflammation in brain tissues. Another report described a patient with deterioration of myelin, a fatty coating that protects neurons and is irreversibly damaged in neurodegenerative diseases such as multiple sclerosis.

“The neurological symptoms are only becoming more and more scary,” says Alysson Muotri, a neuroscientist at the University of California, San Diego, in La Jolla.

The list now includes stroke, brain haemorrhage and memory loss. It is not unheard of for serious diseases to cause such effects, but the scale of the COVID-19 pandemic means that thousands or even tens of thousands of people could already have these symptoms, and some might be facing lifelong problems as a result.

Yet researchers are struggling to answer key questions — including basic ones, such as how many people have these conditions, and who is at risk. Most importantly, they want to know why these particular symptoms are showing up.

Although viruses can invade and infect the brain, it is not clear whether SARS-CoV-2 does so to a significant extent. The neurological symptoms might instead be a result of overstimulation of the immune system. It is crucial to find out, because these two scenarios require entirely different treatments. “That’s why the disease mechanisms are so important,” says Benedict Michael, a neurologist at the University of Liverpool, UK.


Affected brains.

As the pandemic ramped up, Michael and his colleagues were among many scientists who began compiling case reports of neurological complications linked to COVID-19.

In a June paper5, he and his team analysed clinical details for 125 people in the United Kingdom with COVID-19 who had neurological or psychiatric effects. Of these, 62% had experienced damage to the brain’s blood supply, such as strokes and haemorrhages, and 31% had altered mental states, such as confusion or prolonged unconsciousness — sometimes accompanied by encephalitis, the swelling of brain tissue. Ten people who had altered mental states developed psychosis

Not all people with neurological symptoms have been seriously ill in intensive-care units, either. “We’ve seen this group of younger people without conventional risk factors who are having strokes, and patients having acute changes in mental status that are not otherwise explained,” says Michael.

A similar study1 published in July compiled detailed case reports of 43 people with neurological complications from COVID-19. Some patterns are becoming clear, says Michael Zandi, a neurologist at University College London and a lead author on the study. The most common neurological effects are stroke and encephalitis. The latter can escalate to a severe form called acute disseminated encephalomyelitis, in which both the brain and spinal cord become inflamed and neurons lose their myelin coatings — leading to symptoms resembling those of multiple sclerosis. Some of the worst-affected patients had only mild respiratory symptoms. “This was the brain being hit as their main disease,” says Zandi.

Less common complications include peripheral nerve damage, typical of Guillain–BarrĂ© syndrome, and what Zandi calls “a hodgepodge of things”, such as anxiety and post-traumatic stress disorder. Similar symptoms have been seen in outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), also caused by coronaviruses. But fewer people were infected in those outbreaks, so less data are available.


How many people?

But a major problem in quantifying cases is that clinical studies have typically focused on people with COVID-19 who were hospitalized, often those who required intensive care. The prevalence of neurological symptoms in this group could be “more than 50%”, says neurobiologist Fernanda De Felice at the Federal University of Rio de Janeiro in Brazil. But there is much less information about those who had mild illness or no respiratory symptoms.

That scarcity of data means it is difficult to work out why some people have neurological symptoms and others do not. It is also unclear whether the effects will linger: COVID-19 can have other health impacts that last for months, and different coronaviruses have left some people with symptoms for years

Infection or inflammation?

The most pressing question for many neuroscientists, however, is why the brain is affected at all. Although the pattern of disorders is fairly consistent, the underlying mechanisms are not yet clear, says De Felice.

Finding an answer will help clinicians to choose the right treatments. “If this is direct viral infection of the central nervous system, these are the patients we should be targeting for remdesivir or another antiviral,” says Michael. “Whereas if the virus is not in the central nervous system, maybe the virus is clear of the body, then we need to treat with anti-inflammatory therapies.”

Getting it wrong would be harmful. “It’s pointless giving the antivirals to someone if the virus is gone, and it’s risky giving anti-inflammatories to someone who’s got a virus in their brain,” says Michael.

There is clear evidence that SARS-CoV-2 can infect neurons. Muotri’s team specializes in building ‘organoids’ — miniaturized clumps of brain tissue, made by coaxing human pluripotent stem cells to differentiate into neurons.

In a May preprint, the team showed that SARS-CoV-2 could infect neurons in these organoids, killing some and reducing the formation of synapses between them. Work by immunologist Akiko Iwasaki and her colleagues at Yale University School of Medicine in New Haven, Connecticut, seems to confirm this using human organoids, mouse brains and some post-mortem examinations, according to a preprint published on 8 September. But questions remain over how the virus might reach people’s brains.

Because loss of smell is a common symptom, neurologists wondered whether the olfactory nerve might provide a route of entry. “Everyone was concerned that this was a possibility,” says Michael. But the evidence points against it.

A team led by Mary Fowkes, a pathologist at the Icahn School of Medicine at Mount Sinai in New York City, posted a preprint in late May describing post mortems in 67 people who had died of COVID-19. “We have seen the virus in the brain itself,” says Fowkes: electron microscopes revealed its presence. But virus levels were low and were not consistently detectable. Furthermore, if the virus was invading through the olfactory nerve, the associated brain region should be the first to be affected. “We’re simply not seeing the virus involved in the olfactory bulb,” says Fowkes. Rather, she says, infections in the brain are small and tend to cluster around blood vessels.

Michael agrees that the virus is hard to find in the brain, compared with other organs. Tests using the polymerase chain reaction (PCR) often do not detect it there, despite their high sensitivity, and several studies have failed to find any virus particles in the cerebrospinal fluid that surrounds the brain and spinal cord. One reason might be that the ACE2 receptor, a protein on human cells that the virus uses to gain entry, is not expressed much in brain cells.

“It seems to be incredibly rare that you get viral central nervous system infection,” Michael says. That means many of the problems clinicians are seeing are probably a result of the body’s immune system fighting the virus.

Still, this might not be true in all cases, which means that researchers will need to identify biomarkers that can reliably distinguish between a viral brain infection and immune activity. That, for now, means more clinical research, post mortems and physiological studies.

De Felice says that she and her colleagues are planning to follow patients who have recovered after intensive care, and create a biobank of samples including cerebrospinal fluid. Zandi says that similar studies are beginning at University College London. Researchers will no doubt be sorting through such samples for years. Although the questions they’re addressing have come up during nearly every disease outbreak, COVID-19 presents new challenges and opportunities, says Michael. “What we haven’t had since 1918 is a pandemic on this scale.”

Saturday, July 25, 2020

Study identifies six different "types" of COVID-19




Study identifies six different "types" of COVID-19

A new study of COVID-19, based on data from a symptom tracker app, determined that there are six distinct "types" of the disease involving different clusters of symptoms. The discovery could potentially open new possibilities for how doctors can better treat individual patients and predict what level of hospital care they would need.

Researchers from King's College London studied data from approximately 1,600 U.K. and U.S. patients who regularly logged their symptoms in the COVID Symptom Tracker App in March and April.

Typically, doctors will look for key symptoms such as cough, fever and loss of the sense of smell to detect COVID-19. The study, which has not been peer-reviewed, says the six different "types" of COVID-19 can vary by severity and come with their own set of symptoms.

"I think it's very, very interesting," Dr. Bob Lahita, who is not affiliated with the study, told CBSN anchors Vladimir Duthiers and Anne-Marie Green. "Among the patients I see, those who recovered, many of them present different ways: some people with fever and some without fever, and some with nausea and vomiting, some people with diarrhea, etc."

The six clusters of symptoms outlined in the study are:


1)Flu-like with no fever
Headache, loss of smell, muscle pains, cough, sore throat, chest pain, no fever.

2)Flu-like with fever: 
Headache, loss of smell, cough, sore throat, hoarseness, fever, loss of appetite
.
3)Gastrointestinal:
 Headache, loss of smell, loss of appetite, diarrhea, sore throat, chest pain, no cough.

4)Severe level one, fatigue: 
Headache, loss of smell, cough, fever, hoarseness, chest pain, fatigue.

5)Severe level two, confusion:
 Headache, loss of smell, loss of appetite, cough, fever, hoarseness, sore throat, chest pain, fatigue, confusion, muscle pain.

6)Severe level three, abdominal and respiratory: 
Headache, loss of smell, loss of appetite, cough, fever, hoarseness, sore throat, chest pain, fatigue, confusion, muscle pain, shortness of breath, diarrhea, abdominal pain.

The first level, "flu-like with no fever," is associated with headaches, loss of smell, muscle pains, cough, sore throat and chest pain. Patients at this level have a 1.5% chance of needing breathing support such as oxygen or a ventilator.

The second type, "flu-like with fever," includes symptoms like loss of appetite, headache, loss of smell, cough, sore throat, hoarseness and fever. Researchers say about 4.4% of patients at this level needed breathing support.

Patients with the third type, simply described as "gastrointestinal," do not have a cough as part of their illness. Instead, they experience headache, diarrhea, loss of smell, loss of appetite, sore throat and chest pain, and about 3.3% needed breathing support.

In type four, or "severe level one," patients experience fatigue along with headache, loss of smell, cough, fever, hoarseness and chest pain. Patients at this level needed breathing support at a rate of 8.6%

Type five, "severe level two," includes the symptoms of type four along with loss of appetite, sore throat and muscle pain, and is mainly distinguished by confusion.

"That means you don't know where you are or where you live, whether you are in or out of the hospital, who your relatives are," Lahita explained. "That is very scary." Almost 10% of patients at that level need breathing support.

"That means you don't know where you are or where you live, whether you are in or out of the hospital, who your relatives are," Lahita explained. "That is very scary." Almost 10% of patients at that level need breathing support.

The most severe type of COVID-19 is referred to as "severe level three, abdominal and respiratory," and has all the above symptoms along with abdominal pain, shortness of breath and diarrhea. Nearly 20% of these patients need breathing support.


"Those are the severe level threes who wind up on a ventilator, and then it is touch-and-go as to whether they survive the infection entirely," Lahita said.

The U.K. researchers also found that only 16% of patients with type one COVID-19 required hospitalization, compared with nearly half of the patients with type six.

Patients in the severe clusters also tended to be older or with pre-exisiting conditions and weakened immune systems, compared to those in the first three. 

Scientists hope the discovery, once further studied, could help predict what types of care patients with COVID-19 might need, and give doctors the ability to predict which patients would fall into which category. 





Sunday, June 21, 2020

3 COVID-19 treatment drugs available in India today

















Coronavirus pandemic has killed over 4.7 lakh people across the globe. In India, the death toll is over 13,000. The good news is that DGCI has given nod to 3 companies to roll out their COVID-19 treatment medicine in India. These companies are -- Cipla, Glenmark and Hetero. And the three medicines are called Cipremi, FabiFlu and Covifor.

The three have reportedly shown good results so far and will be now slowly put into use under strict medical observation.


Here is everything we know about these drugs.

CIPREMI
  • Cipla has launched its own remedesivir under the name of Cipremi. The medicine is lyophilized powder for injection 100mg. 
  • The drug will be marketed by both the government and market channels. 
  • The drug has been approved for adult and paediartric patients hospitalised due to COVID-19 infection. The drug is most affective on those who need oxygen support.
  • The drug is most affective on those who need oxygen support. 
  • Cipla is yet to disclose the pricing for the drug.

FABIFLU
  • Priced at Rs 3,500 for 34 tablets, the dosage is 200 mg X 9 tablets on day one and 200 mg X 4 tablets a day for 14 days.
  • Global trials show the efficacy of over 80-88%; Japan, Bangladesh and UAE already use the drug for COVID-19 treatment.
  • The drug will be available both through hospitals and the retail channel.
  • Reportedly, Strides Pharma, Brinton Pharmaceuticals, Lasa Supergenerics and Optimus Pharma among firms readying its launch
  • Glenmark had developed the active pharmaceutical ingredient (API) and the formulation for FabiFlu through in-house R&D.
  • Favipiravir is backed by strong clinical evidence, showing encouraging results in patients with mild to moderate Covid-19.
  • Patients from over 10 leading government and private hospitals were enrolled for the study.
  • It offers rapid reduction in viral load within four days and provides faster symptomatic and radiological improvement.                                                                                                                                                                                                                                                         
  COVIFOR
  • The drug will be available in 100 mg injectable form which has to be administered intravenously in a hospital setting under the supervision of a healthcare professional. It is not a drug you can take at home. 
  • The company is sure about enough stock to cater to the present needs of the medicine. 
  • Hetero has confirmed that Covifor would cost between 5,000 to 6,000 per dose. 
  • The COVID-19 treatment by Covifor will cost not more than 30,000 per patient. Six dozes of the medicine will be given in this timeframe. 







Monday, June 15, 2020

FSH Followed by HMG vs FSH Plus HMG in IVF



 FSH Followed by HMG vs FSH Plus HMG in IVF 

Brief description of study 

The aim of this study is to compare the clinical outcomes of sequential administration of FSH and HP-hMG FSH alone versus concomitant administration of FSH and HP-hMG during controlled ovarian stimulation in IVF cycles.


Detailed Study Description

Women who are planned to be subjected to IVF/ICSI through COS by long GnRHa protocol will be assessed for possibility of participation in our study. Eligible participants in our study will be those with regular menstrual cycle (21-35 days) and normal uterine anatomy (confirmed by transvaginal ultrasound examination and in some cases hysteronsalpingography and hysteroscopy).

 Women with any of the following criteria will be excluded from the study: 1) age < 20 or > 37 years; 2) body mass index (BMI) < 18 or > 25 kg/m2; 3) low ovarian reserve (AFC < 7 and/or AMH < 1.1 ng/ml); 4) presence of polycystic ovarian syndrome (PCOS), endometrioma or hydrosalpinx; 5) history of chemotherapy, radiotherapy or ovarian surgery; 6) the husband needs testicular biopsy to obtain sperm; or 7) previous implantation failure.

 A written informed consent will be taken from each women selected to participate before inclusion in the study. All women participating in the study will start GnRHa on day 21 of the preceding cycle and when down regulation occurs each woman will be randomly allocated into one of the two groups; group 1 and group 2. Women in group 1 will receive 225 IU FSH alone from day one of ovarian stimulation and when the follicular diameters reaches 10-12 mm, the 150 IU HP-hMG will substitute FSH and continued to the day of triggering. Women in group 2 will receive 150 IU FSH plus 75 IU HP-hMG from day one of ovarian stimulation and 150IU HP-HMG when the follicular diameters reaches 10-12 mm till day of triggering. The randomization will be simple and balanced (1:1) and will be carried out by a nurse through sealed, unlabeled, opaque envelopes containing computer-generated random numbers. The data assesor will be blinded to group assignment.

 In both groups, estradiol and LH will be measured on the third day of menstruation before start of stimulation and on day 6 of stimulation TVS will be performed. Progesterone and E2 will be measured and on day of triggering. The primary outcome measure of this study will be the ongoing pregnancy rate. The secondary outcomes measures will be cancellation rate, the number of oocytes retrieved, the number of embryos, the number of vitrified embryos, the clinical pregnancy rate, the implantation rate, OHSS rate, multiple pregnancy rate, and the miscarriage rate.

Saturday, June 13, 2020

Cost-effectiveness analysis of GnRH-agonist long-protocol and GnRH-antagonist protocol for in vitro fertilization






Cost-effectiveness analysis of GnRH-agonist long-protocol and GnRH-antagonist protocol for in vitro fertilization




Abstract

The gonadotropin releasing hormone agonist (GnRH-a) long-protocols and the GnRH-antagonist protocols are two commonly used protocols for in vitro fertilization (IVF), but their cost-effectiveness has not been studied, especially in China. A retrospective study involving 1638 individuals in GnRH-a long-protocol and 621 in GnRH-antagonist protocol were conducted and a decision tree model analysis was used to analyze the cost-effectiveness. Both direct and indirect costs were calculated. As a result, during the fresh embryo transplantation cycles, there was no significant difference in the rate of ongoing pregnancy between the two protocols, the average cost of per ongoing pregnancy in the GnRH-antagonist protocol was $ 16970.85, and that in the GnRH-agonist long-protocol was $19902.24. The probability of cumulative ongoing pregnancy per start cycle was estimated at 60.65% for the GnRH-antagonist protocol and 71.6% for the GnRH-agonist long-protocol (P < 0.01). Considering the cumulative ongoing pregnancy rate, the mean costs per ongoing pregnancy were estimated at $8176.76 and at $7595.28 with GnRH-antagonist protocol and GnRH-agonist long protocol, respectively. In conclusion, in fresh embryo transplantation cycle, the GnRH-antagonist protocol has economic advantage. However, the GnRH-agonist long protocol is more cost effective considering the cumulative ongoing pregnancy rate in the fresh embryo and frozen embryo transplantation cycles.

Introduction

According to a World Health Organization (WHO) report, about 48.5 million couples are affected by infertility worldwide in 2010. With the refinement and development of assisted reproductive technology (ART), increasing number of infertile couples seek ART. The European Society of Human Reproduction and Embryology (ESHRE) reported that the world-wide number of babies born as a result of ART has reached an estimated total of 8 million since the world’s first, Louise Brown, was born in July 1978. Up to now, ART is the most important method to treat infertility in the world.
Study has shown that cumulative live birth rates are increased with the number of oocytes obtained. Therefore, controlled ovarian hyperstimulation (COH) is an important process to obtain a set number of oocytes for IVF. The GnRH-agonists were introduced into IVF in the late 1980s and the GnRH-agonist long-protocol is still the most frequently used protocol in most centers worldwide4. The basic principle is to use gonadotropin-releasing hormone agonist (GnRH-a) to regulate pituitary and stimulate follicular growth with exogenous gonadotropin hormone, and avoid endogenous luteinizing hormone (LH) surge before oocyte retrieval. Since 1990s, GnRH antagonists were used in COH, this protocol competitively blocks pituitary GnRH receptors, inducing a rapid, reversible suppression of gonadotrophin secretion and preventing and interrupting LH surges. The GnRH-antagonist protocol have been widely adopted in IVF due to these advantages.
IVF is a protracted and costly process. In most developed countries, IVF is covered by insurance or subsidized. This is not the case in developing countries. In China, the cost of IVF is on patients. High costs discourage low-income infertility couples from seeking ART treatment.
While both protocols are commonly used today, little is known about their cost-effectiveness, especially in China. Studies have shown that hormonal stimulation covered the main part of the costs per cycle. Moolenaar et al. reported that most economic studies about ART were performed in countries from mainland Europe (38%) and the United States (34%). In China, there has been few economic researches on COH protocols. Herein, we performed a retrospective study on comparing the cost-effectiveness of the two protocols using a single center data in China. Choosing a cost-effective protocol, can not only ease the financial pressure on couples, but also provide reference for medical decision-making.

Methods

Patients

Individuals who came to the Reproductive Center of Women’s Hospital, Zhejiang University School of Medicine for their first cycle of IVF treatment from 1 January 2015 to 31 December 2017 were included. Inclusion criteria were as follows: 20 < age ≤ 38 years, regular ovulatory cycles every 21–35 days, total antral follicle count (AFC) ≥ 5, first cycle of IVF treatment, COH planned using the GnRH-agonist long-protocol or the GnRH-antagonist protocol, IVF fertilization. Exclusion criteria were the use of donor oocytes or frozen-thawed oocytes for fertilization, other protocols for COH, ICSI fertilization. Patient demographics are presented in Table 1.



Table 1 Patient demographics and infertility treatment-related characteristics.

From: Cost-effectiveness analysis of GnRH-agonist long-protocol and GnRH-antagonist protocol for in vitro fertilization

CharacteristicsGnRH-agonist long-protocolGnRH-antagonist protocolP value
Age(year)29.26 ± 3.3629.54 ± 3.320.078
Duration of infertility (year)3.12 ± 2.343.28 ± 2.510.148
Height (cm)159.57 ± 6.02159.56 ± 4.600.964
Weight (kg)55.52 ± 7.5755.89 ± 7.260.305
BMI (kg/m2)21.76 ± 2.8121.95 ± 2.690.144
AFC (n)14.52 ± 4.0614.38 ± 4.300.463
bFSH (IU/L)6.22 ± 1.676.73 ± 1.79<0.01
bLH (IU/L)5.67 ± 3.185.58 ± 2.990.52
bE2 (pmol/l)116.67 ± 67.72115.40 ± 64.830.688
Duration of Gonadotropin stimulation (day)10.82 ± 1.789.53 ± 1.87<0.01
Gonadotropin used (IU)2021.09 ± 668.561823.78 ± 561.22<0.01
Number of oocytes obtained (n)13.90 ± 6.5811.89 ± 6.70<0.01
Number of embryos available (n)4.42 ± 3.433.98 ± 3.270.005
Number of frozen embryos (n)3.72 ± 3.743.20 ± 3.570.005
Average number of embryos transferred (n)1.810 ± 0.401.79 ± 0.420.349
Number of Frozen embryo transplantable cycle (n)2.051.78
Clinical pregnancy rate in the fresh embryo transplantation cycle47.26%49.44%0.487
Ongoing pregnancy rate of fresh embryo transplantation38.77%37.22%0.613
Cost in fresh embryo transplantation($)19902.2416970.85
Cumulative ongoing pregnancy rate71.6%60.65%<0.01
Cumulative multiple pregnancy rate17.6%18.4%0.667
OHSS rate4.9%2.0%0.001
Cumulative ectopic pregnancy rate2.9%4.0%0.26
  1. AFC: antral follicle count; bFSH: basal follicle stimulating hormone; bLH: basal luteinizing hormone; bE2: basal estrogen; OHSS: ovarian hyperstimulation syndrome.
COH protocols
GnRH-agonist long-protocol: A short-acting GnRH-a (Triptorelin, Ferring AG, Germany) was administrated daily in the mid luteal phase of the preceding cycle. 14 days later, follicular ultrasonography, serum LH, FSH and E2 were examined and 150–300IU recombination follicle stimulating hormone (r-FSH, Gonal-F, Merck Serono, Switzerland) was initiated daily when FSH and LH < 5 IU/L and E2 < 50 pg/ml. GnRH-a was continued until trigger. During the stimulation, according to ovarian response evaluated by transvaginal ultrasonography and serum hormone level, dose of r-FSH was adjusted as needed, human menopausal gonadotropin (HMG) or recombinant luteinizing hormone(r-LH) or growth hormone (GH) was added as needed.
GnRH-antagonist protocol: 150–300IU r-FSH was initiated on day 2 or 3 of the menstrual cycle until trigger. The dosage of r-FSH was adjusted and HMG or r-LH or GH was added according to the ovarian response evaluated by transvaginal ultrasonography and serum hormone level. 0.25 mg GnRH-A (Cetrorelix; Merck Serono, France) was used daily until trigger when the leading follicles reached a mean diameter of 14 mm.
For both protocols, if three follicles reached a mean diameter of 17 mm or two follicles reached a mean diameter of 18 mm, r-HCG (Ovidrel, Serono, Italy) was administered subcutaneously. Oocyte retrieval was performed 36 h after HCG injection by transvaginal ultrasound-guided single-lumen needle aspiration. Luteal phase support was initiated on day 1 after oocyte retrieval. Fresh embryo transplantation was carried out 72 h after oocyte retrieval. Fresh cycles were canceled if patients had endometrial thickness <7 mm, high risk of Ovarian hyperstimulation syndrome (OHSS) (E2 ≥ 5000 pg/ml on the trigger day, the number of oocytes obtained ≥20), no available embryos or other personal reasons. For those patients without fresh embryo transplantation or without ongoing pregnancy after fresh embryo transplantation, if excess frozen embryos were available and pregnancy test was negative, the frozen embryo transplantation (FET) was performed until no embryos remained or ongoing pregnancy was achieved. Clinical pregnancy was defined as a gestational sac observed by vaginal ultrasound. Ongoing pregnancy was defined as a pregnancy continuing 12 weeks without miscarriage.

Structure of the model

We constructed a decision tree model to analyze the cost-effectiveness of the GnRH-agonist long-protocol and GnRH-antagonist protocol in the fresh embryo transplantation and frozen embryo transplantation cycle (Fig. 1 and Fig. 2). Each route in the diagram represents possible steps in IVF. Each intersection is followed by a possible situation. Since the cumulative ongoing pregnancy rate was calculated by following utilization of all fresh and frozen embryos after the first IVF cycle, the number of transplants was based on available embryos. The terminal nodes of the model were: “No oocytes”, “No embryos”, “Ongoing pregnancy”, “No ongoing pregnancy”. Since each patient may have different situations after entering the cycle, we made relevant assumptions for the model for the convenience of calculation as shown in Table 2.



Figure 1
Decision tree model for fresh embryo transplantation. Figure 1 shows the process of fresh embryo transplantation. The number under each node in the figure is the correlation probability of this Figure 2
Figure 1Decision tree model for frozen embryo transplantation. Figure 2 shows the frozen embryo transplantation process after fresh embryo transplantation. The number under each node in the figure is the correlation probability of this step.


Figure 2
Decision tree model for frozen embryo transplantation. Figure 2 shows the frozen embryo transplantation process after fresh embryo transplantation. The number under each node in the figure is the correlation probability of this step.



Table 2 Assumptions in the model.



Assumptions
1.r-LH and GH were added according to the development of follicles, not all patients used it, so their costs were not included in the total cost.
2. In GnRH-agonist long-protocol, there were an average of 5 blood tests and follicular ultrasonography examinations, while in the GnRH-antagonist protocol, there were 4 blood tests and follicular ultrasonography examinations.
3. Artificial cycle drug was unified as estradiol valerate tablets, with an average of 4 follicular ultrasound tests. There were 4 follicular ultrasound tests on average in the natural cycle.
4. The corpus luteum support drugs were unified as estradiol valerate + dydrogesterone tablets + progesterone vaginal sustained release gel in fresh cycle and estradiol valerate + dydrogesterone tablets + progesterone capsules in frozen cycle.
5. The cost of lost work were calculated based on the per capita disposable income of the three-year residents in 2015–2017.
6. The transportation fee was calculated according to the second-class fare of the trains from various cities in Zhejiang Province to Hangzhou.
7. The bed fee during hospitalization was calculated at a rate of ¥40 per day for a three-person room.
8. The number of frozen embryo transfer cycles is calculated based on the number of frozen embryos and the number of transplanted embryos.

Transition probabilities

The transition probabilities for the various health states in this decision tree model were derived from the clinical data of included infertility patients. The transition probability of each step is shown in Fig. 1 and Fig. 2.

Cost analysis

This study was performed from a patient’s perspective. Both direct and indirect costs were included in the analysis. Direct medical costs included drug, ultrasound, laboratory, surgery and care costs. Medications included those used in ovulation stimulation trigger and luteal support. The cost of the drug was equal to the unit cost of the drug multiplied by the total amount used. When calculating the cost of IVF, it is prudent to include the treatment costs for complications, primarily OHSS. Therefore, the cost of treatment for OHSS was also calculated in the total cost of the patient. In this study, transportation costs were included as direct non-medical expenses. These were calculated as the average fare from each city in Zhejiang province to Hangzhou. Indirect costs included the cost of lost work. The cost of lost work was calculated according to the per capita disposable income. Intangible economic burden generally refers to the decline in the quality of life or other costs caused by illness in this case, IVF, and also included other costs not reflected in the direct and indirect costs. Thus, considering the difficulty in calculating these intangible costs, such costs were not included in this study. Cycle costs were relatively stable during the study period, so discounting is not considered. The specific costs are shown in Table 3.
Table 3 The cost involved in IVF.



DrugsCosts ($)OperationCosts ($)Non-medical expensesCosts ($)
Triptorelin(0.1 mg)16.33Oocyte retrieval305.81Single transportation fee11.61
Gonal-F(450IU)230.26Anesthetic Fee96.02The daily cost of lost work10.02
HMG(75IU)3.18IVF305.81Daily nursing expenses during hospitalization3.67
Cetrorelix(0.25 mg)52.72Embryo transplantation244.65Bed fee per day during hospitalization6.12
Ovidrel(6500IU)29.5Embryo cryopreservation611.62
Estradiol valerate tablets(tablet)0.26Embryos thawing76.45
Dydrogesterone tablets(tablet)0.83Follicular ultrasonography6.42
Progesterone vaginal sustained release gel11.47Serum FSH,LH,E2,Ptest4.89
Progesterone capsules (capsule)0.43Serum HCG6.12

Statistical analyses

The statistical software package SPSS22 was used for data analysis. When the measurement data matched the homogeneity of variance, the independent sample t test was used; when the data didn’t match the homogeneity of variance, the Mann-Whitney test was used. The chi-square test or Fisher’s exact probability method were used for the comparison of the rates, and P < 0.05 was considered statistically significant. Cost-effectiveness analysis and incremental cost-effectiveness analysis were used to evaluate the costs and effects between the two protocols. Sensitivity analyses were then performed to assess the stability of the model.

Ethical approval

The study was approved by the Ethics Committee of Women’s Hospital School of Medicine Zhejiang University. All patients meeting the inclusion criteria signed the informed consent. And this study complied with declaration of Helsinki/relevant guidelines for the study on humans.

Results

About 2259 infertility patients met inclusion criteria (1638 in GnRH-agonist long-protocol and 621 in GnRH-antagonist protocol). There were no differences in patient ages, BMI, duration of infertility, cycle day 3 LH levels, cycle day 3 E2 levels and AFC. The duration of gonadotrophin stimulation and dose of gonadotropin used, number of oocytes obtained and number of available embryos in GnRH-agonist long-protocol were higher than that in GnRH-antagonist protocol. The clinical pregnancy rate and ongoing pregnancy rate for GnRH-agonist long-protocol and GnRH-antagonist protocol in the fresh embryo transplantation cycle were not different (47.26% vs. 49.44%, P = 0.487; 38.77% vs. 37.22%, P = 0.613). When all available embryos had been utilized, the rate of cumulative ongoing pregnancy per start cycle was 60.65% for GnRH-antagonist protocol and 71.6% for GnRH-agonist long-protocol (P < 0.01). The OHSS rate was lower in GnRH-antagonist protocol (2.0% vs 4.9%, P = 0.001). The cumulative multiple pregnancy (17.6% vs 18.4%, P = 0.667) rate and the cumulative ectopic pregnancy rate (2.9% vs 4.0%, P = 0.26) in GnRH-agonist long-protocol was not different from that of GnRH-antagonist protocol. Data on patients’ demographic and infertility treatment-related characteristics are represented in Table 1.
In fresh embryo cycles, there were less amount of gonadotropin and few days of OHSS for GnRH-antagonist protocols. Therefore, the total cost was lower in GnRH-antagonist protocols (average cost $16970.85) than in GnRH-agonist long-protocol (average cost $19902.24) in fresh embryo cycles. In fresh embryo transfer cycles, there was no statistical difference in the ongoing pregnancy rate between the two protocols, therefore, the minimum cost method was used for analysis. When the cumulative ongoing pregnancy rate was taken into account in the long protocol group, the number of frozen embryo transfer cycle was higher, leading to a higher cumulative ongoing pregnancy rate, and consequently a higher cost. Using cost-effectiveness analysis, the mean costs per ongoing pregnancy were estimated at $8176.76 and at $7595.28 with GnRH-antagonist protocols and GnRH-agonist long-protocols, respectively. The incremental cost-effectiveness ratio (ICER) is an evaluation index commonly used in economics research. It refers to the ratio of cost difference and effect difference between different protocols. In this study, the ICER for GnRH-agonist long-protocol versus GnRH-antagonist protocol was estimated at $4375.95 for one more ongoing pregnancy (Table 4).

Table 4 Cost-Effectiveness analysis of GnRH-antagonist protocol and GnRH-agonist long-protocol.



ProtocolsCosts ($)EffectiveC/E ($)ICER ($)
GnRH-antagonist protocol4958.790.60658176.76
GnRH-agonist long-protocol5438.120.7167595.284375.95
Sensitivity analysis is to change the value of some parameters and analyze the degree of influence on the results. The cost of ovarian stimulation protocols account for the majority of the total costs10. In this study, the cost of drugs accounted for the largest proportion of the total cost of ovulation stimulation protocols. The reliability of the results was assessed by sensitivity analysis with drug cost fluctuation. The results of sensitivity analysis were consistent with the results of cost-effectiveness analysis, the cost per ongoing pregnancy in the GnRH-agonist long-protocol was lower than that in the GnRH-antagonist protocol, which means the results are stable.

Discussion

In this study, we used an economics research method to evaluate the cost-effectiveness of the GnRH-agonist long-protocol and the GnRH-antagonist protocol for IVF. We found that in the fresh embryo transplantation cycle, there was no significant difference in the ongoing pregnancy rate between the GnRH-agonist long-protocol and the GnRH-antagonist protocol, while the cost in the GnRH-antagonist protocol was lower, so GnRH-antagonist protocol has advantage according to the principle of cost-minimization analysis of pharmacoeconomics. When considering the cumulative ongoing pregnancy rate after each ovarian stimulation, the cumulative ongoing pregnancy rate and cost in the GnRH-agonist long-protocol were higher than the GnRH-antagonist protocol. Using the cost-effectiveness analysis method, it was found that the average cost of each ongoing pregnancy in the GnRH-agonist long-protocol was lower than the GnRH-antagonist protocol. Therefore, the GnRH-agonist long-protocol is more cost-effective.
Studies have shown that one of the primary reasons for dropout from infertility treatment is economic burdens . China’s medical system does not provide insurance coverage for infertility diagnosis and treatment. It can be an enormous economic burden to patients seeking ART. Therefore, no matter from the perspective of patients, or from the perspective of medical resource allocation, it is necessary to carry out economic analysis on IVF and consider the cost and effect of each step. Although GnRH-agonist long-protocols and GnRH-antagonist protocols have been widely used in IVF, there is still an ongoing debate about the results of the two protocols. Orvieto and Grow found the GnRH-agonist protocol has a superiority over the GnRH-antagonist protocol in live birth rate. Some studies also found no significant difference in the rates of live births or ongoing pregnancies between the two protocols. However, these studies are only from the perspective of clinical results, not from the perspective of economics. In our research, we hope to be able to focus more on evaluating the cost-effectiveness of both protocols, not just the clinical outcomes, which are just a link in the evaluation. After consulting the literature, we found that there have been little economic studies on the two different ovarian stimulation protocols used in IVF. Wei Pan et al. conducted a retrospective analysis of the cost-effectiveness of GnRH-a protocols, GnRH-ant protocols and GnRH-a ultra-long protocols. They used the live birth rate as one outcome of the study. However, it is difficult to calculate the cost throughout pregnancy. In order to ensure that the results are more reliable, we used the ongoing pregnancy rate as the end point of this economic study.
The cost of IVF treatment for infertility (the cost per ongoing pregnancy) in this study was higher than the average hospitalization cost for 30 diseases in 2018 according to the national bureau of statistics. IVF is a complex process involving ovarian stimulation, ovum retrieval, fertilization, embryo transfer and other processes. In addition to the cost of these processes, the total cycle costs of IVF should also include the transportation costs, lost wages and the cost of treating OHSS. However, it is difficult to accurately assess the transportation costs and lost wages and these indirect cost consisted a small percentage of the total costs, many studies did not include them in the total cycle cost analysis. But, from the perspective of patients, these costs are indirect medically, yet direct economically to patients, so they are also included in this study. OHSS is a serious complication of IVF, and the treatment is expensive, which directly affects the total cycle costs. Studies have shown that the incidence of OHSS in the GnRH-antagonist protocol is lower than that in the GnRH-agonist long-protocol. Accordingly, the cost of treating OHSS in the GnRH-antagonist protocol is lower, resulting in reduction in the total cycle cost. This may be one of the reasons why the cost in GnRH-antagonist protocol is lower than the GnRH-agonist long-protocol in the fresh embryo transfer cycle.
Economic analysis of IVF is still challenging, and there is no unified view on the result indicators of the analysis. Existing economic studies often used ongoing pregnancy, live birth rates or quality-adjusted life years (QALYs) as result of the study. However, it is worth considering that QALYs of both husband and wife or child is used when taking QALYs as a result of IVF. Toftager et al. found that quality of life and psychosocial and physical well-being of patients used the GnRH-antagonist protocol was better than that used the GnRH-agonist protocol. But these are hard to quantify in terms of costs. And it’s difficult to calculate the impact on families and society of obtaining a healthy baby by IVF. Considering the different incidence of related complications during pregnancy, the treatment costs and nursing costs vary greatly. Therefore, in this study, we used the cumulative ongoing pregnancy rate as the effect of the study.
There are many economic analysis methods, but among the existing studies on economics in ART, 84% are cost-effectiveness analysis and 48% are model-based studies11. Economic model carried out before a trial is particularly useful in reducing unnecessary waste of research resources in evaluating techniques and interventions and improving the quality and efficiency of the research. In our study, we developed a decision-tree model to evaluate the cost-effectiveness of the GnRH-agonist long-protocol and GnRH-antagonist protocol. The relevant transfer probability in the model was calculated using the data of infertile patients in the reproductive center of our hospital. In addition, we have made some reasonable assumptions for analysis, as shown in Table 2.
This is a retrospective study on the data available from infertility diagnosis and treatment in our reproductive center. The relevant probability and costs in the model are calculated based on the data of our single center. These results may differ from those of other centers, but can provide some guidance for patients and clinicians. In the future, large samples, multi-center prospective randomized controlled trials are needed to more thoroughly explore more economical and effective treatment protocols.
In conclusion, if fresh embryo transfers are considered, the pregnancy outcomes between GnRH-agonist long protocols and GnRH-antagonist protocols are similar, but GnRH-antagonist protocols have lower cost. Therefore, in the fresh embryo transfer cycle, the GnRH-antagonist protocol has economic advantage and is worth recommending. However, GnRH-agonist long-protocol have higher success rates and higher costs when cumulative ongoing pregnancy rates are taken into account. The cost per ongoing pregnancy in the GnRH-agonist long-protocol cycles was lower than that in the GnRH-antagonist protocol cycles. Thus, cost-effectiveness analysis shows that the GnRH-agonist long-protocol is more cost-effective than the GnRH-antagonist protocol and may represent a cost-effective option from the perspective of patients. However, further large sample sizes and multi-center randomized controlled trials are needed.


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