Another gene-edited embryo in China?

December 4, 2018

A new twist has emerged in the gene-editing controversy created by Chinese scientist He Jiankui. PLUS: Would a minimum-volume standard improve hysterectomy outcomes? ALSO: Can lidocaine reduce pain during IUD insertion?

A new twist has emerged in the gene-editing controversy created by Chinese scientist He Jiankui. South China Morning Post has posted a video of He, made during a conference in Hong Kong, in which he says that a second woman may be pregnant with an embryo that he genetically modified using CRISPR-Cas9.

The revelation is the latest development in a saga that has caused an uproar in the scientific community worldwide and led to statements from the American Society for Reproductive Medicine (ASRM)and the American Society of Human Genetics (ASHG), among others, denouncing He’s work. 

He’s first announcement, made on November 26 and reported by Nature, was the revelation that twin girls had been born earlier in the month following his alteration of their genes to disable the CCR5gene, which plays a key role in HIV infection of cells. Editing of the embryos was done with CRISPR-Cas9, a system that can be programmed to target specific stretches of genetic code and to edit DNA at precise locations. 

He, a scientist at Southern University of Science and Technology in Shenzhen, China, claimed that the twins are healthy and that he only edited the target gene. But his work has not been verified or published.

The university is investigating He’s claims and in a statement published online, said the work “has seriously violated academic ethics and codes of conduct” and called the event “deeply shocking.” According to a November 29 report by NBCNews, the Chinese government has ordered a temporary halt to research on humans involving the editing of human genes. The rationale given by He for his editing-paternal HIV positivity-has been called into question because of negligible risk of fetal of HIV transmission from father to child.

In its statement on the report about He’s work, ASRM said that gene editing “should only be used clinically after careful study done with vigorous oversight.” The organization encouraged leaders around the world to “implement a sound regulatory system that allows for responsible investigation and innovation to improve human health.”

ASHG said that the report by He “would be at odds with field consensus that germline editing is not ready for human use.” The organization reaffirmed the “cautious yet proactive approach” to the technology that was reflected in its 2017 position statement, which asserted the following positions:

  • At this time, given the nature and number of unanswered scientific, ethical, and policy questions, it is inappropriate to perform germline gene editing that culminates in human pregnancy.
  • Currently, there is no reason to prohibit in vitro germline genome editing on human embryos and gametes, with appropriate oversight and consent from donors, to facilitate research on the possible future clinical applications of gene editing. There should be no prohibition on making public funds available to support this research.
  • Future clinical application of human germline genome editing should not proceed unless, at a minimum, there is (a) a compelling medical rationale, (b) an evidence base that supports its clinical use, (c) an ethical justification, and (d) a transparent public process to solicit and incorporate stakeholder input.  

Would a minimum-volume standard improve hysterectomy outcomes?

 

Several studies have shown that patients who are operated on at higher-volume hospitals and by higher-volume surgeons have lower rates of morbidity and mortality compared to those operated on by lower-volume healthcare providers. To improve quality, proposals for minimum-volume standards have become more common, but the ripple effects of implementing those standards are not completely clear. A recent modeling analysis, published in Obstetrics & Gynecology, sheds light on how implementing minimum-volume standards for hysterectomy might affect patient outcomes and surgeon practice patterns.

For the retrospective study, the authors used data from the New York Statewide Planning and Research Cooperative system to identify patients who underwent abdominal, robotic-assisted, laparoscopic, or vaginal hysterectomy between 2010 and 2014. The researchers’ primary estimate of surgery volume relied on the given surgeon’s or hospital’s procedural volume in the prior calendar year. Patient demographics were also tracked. 

The primary outcome of the analysis was perioperative morbidity, defined as any of several common complications. The authors explored the association between volume and perioperative morbidity rate and prior year procedural volume. An observed/expected ratio of less than 1 indicated that a surgeon’s morbidity rate was lower than expected and an observed/expected ratio of 1 or greater indicated it was the same or higher than expected. 

Of the 127,202 procedures reflected in the study, 55,816 (43.9%) were abdominal, 43,198 (34.0%) laparoscopic, 14,057 (11.1%) robotic-assisted, and 14,131 (11.1%) vaginal. The most common indications for surgery were leiomyoma for abdominal, laparoscopic, and robotic-assisted hysterectomy and pelvic organ prolapse for vaginal hysterectomy. The overall morbidity rate was 15.9% for abdominal, 4.3% for laparoscopic, 6.8% for robotic-assisted, and 5.1% for vaginal hysterectomy. 

The abdominal procedures were performed by 7,198 surgeons, whose numbers decreased each year. In contrast, the number of surgeons performing both laparoscopic and robotic-assisted hysterectomy increased each year, though the median prior year case numbers remained constant. The number of surgeons performing vaginal hysterectomy declined though the median prior year case volume also remained constant. 

When surgeon volume was increased, abdominal hysterectomy was associated with a decreasing rate of complications. Overall, 17.5% (n=1260) of included surgeons had a prior year volume of just one abdominal hysterectomy. The mean observed/expected morbidity ratio of surgeons with a prior year abdominal hysterectomy volume of one was 1.47 (SD 2.71) and 31.4% of this group had an observed/expected ratio of 1 or greater, indicating a higher than expected complication rate. Conversely, 68.7% of these surgeons had an observed/expected ratio of less than 1, suggesting a lower than expected rate of complications. 

For robotic-assisted hysterectomy, there was a non-statistically significant decrease in complications with increasing prior year procedural volume. In laparoscopic cases, the complication rate increased slightly from a prior year volume of one case up to three cases but then declined. However, the mean observed/expected ratio was 0.86 (SD 3.55), suggesting a more favorable morbidity profile than predicted. 

For vaginal hysterectomy, the authors saw the mean observed/expected ratio decline from a volume of one procedure to a volume of four but then rise to 15 procedures before falling again. Based on their findings, the authors suggest that if a prior year volume standard of one were implemented, 17.5% of surgeons performing abdominal hysterectomy, 12.5% of those performing robotic assisted hysterectomy, 16.8% of those performing laparoscopic, and 27.6% of surgeons performing vaginal hysterectomy would be restricted. 

The authors believe that while minimum-volume standard may have appeal in regard to patient safety, implementation would come with several practical limitations. Because a large number of gynecologic surgeons perform a low volume of procedures annually, even the lowest volume cut points would limit the practice of a substantial number of surgeons. As a result, patient access may become limited and would directly affect minority and underserved patients and residents of rural areas. 

Also, because the improved outcomes of high-volume health care providers for hysterectomy are modest, restricting care by low-volume physicians may actually be unpopular among patients. Minimum-volume standards could also disproportionately affect younger physicians and the large number of physicians who have better-than-expected outcomes. As such, the authors believe that while low-volume hysterectomy surgeons clearly have inferior outcomes, implementing a minimum-volume standard would create more problems than it would solve and policymakers should instead turn towards a more nuanced approach when discussing measures to improve patient outcomes. 

Can lidocaine reduce pain during IUD insertion?

 

Intrauterine devices (IUDs) are a highly effective and safe method of contraception but they remain underutilized. One major barrier to adoption is discomfort associated with IUD insertion and patient fear about the procedure. A randomized, double-blind, placebo-controlled trial appearing in American Journal of Obstetrics and Gynecology examined whether self-administered lidocaine gel has promise as a method of pain control for IUD insertion.

The authors hypothesized that 20 mL of 2% lidocaine gel, self-administered vaginally and over 15 minutes, would decrease pain with IUD insertion. For their study, they randomized patients undergoing IUD insertion between July 2016 and April 2017 to either lidocaine or a placebo gel. The women were instructed to insert the full length of a Luer-Lok syringe vaginally and administer the gel in a manner similar to use of a tampon. No additional cervical anesthesia or narcotic analgesia was administered prior to the procedure. 

The authors collected information on the patients’ sociodemographic characteristics and obstetric and menstrual history via a pre-procedure questionnaire. The women were also asked to report their pain levels throughout the procedure using a 100-mm unmarked visual analog scale (VAS) with 0 mm being “no pain” and 100 mm being the “worst pain imaginable.” In a post-procedure questionnaire, participants reported their overall pain score, global satisfaction with the procedure, acceptability of vaginal gel, and the amount of IUD insertion pain they would be willing to tolerate to avoid waiting for pain medication. Study coordinators also recorded procedural data and rated ease of insertion on a 100-mm scale with 0 mm being “very easy” and 100 mm being “very difficult.” 

The primary outcome was pain at the time of IUD insertion, based on the VAS responses immediately after speculum removal. Secondary outcomes included anticipated pain (measured immediately after gel insertion), baseline pain (measured immediately prior to start of the procedure), pain with speculum insertion, and after tenaculum placement. 

The analysis included 215 women with similar baseline characteristics. Median time from gel insertion to speculum placement was 21 minutes for the lidocaine gel group and 20 minutes for the placebo gel group. Median procedure time, measured from speculum placement to speculum removal, was 4 minutes for both the lidocaine and placebo gel groups. 

Pain with IUD insertion was not statistically different between the groups (58.1±23.2 mm lidocaine vs 52.3±25.2 mm placebo, P= .08). However, pain with speculum insertion did vary between groups and the median pain score was 7 mm (8-81 mm) compared to 11 mm (0-80 mm) for the placebo group (P= 0.46). Baseline pain level, tenaculum placement pain, and overall pain experience scores did not differ between groups. 

In the post-procedure questionnaire, theoretical median pain scores did not differ significantly between the groups when participants were asked how much pain they would be willing to tolerate to avoid waiting for pain medication. The majority of women in both groups either agreed or strongly agreed that the amount of vaginal leakage following gel insertion was acceptable. Ninety-two percent of all participants stated that they would strongly prefer to wait 16 minutes before IUD placement for potential analgesic effect. In response to a question about whether they would recommend IUD insertion, median VAS scores reported by the women in the lidocaine and placebo groups were 87 mm (33-100 mm) and 83 (9-100 mm), respectively. 

A few strengths and limitations to the study were identified. Among the noted strengths was its double-blind, randomized, placebo-controlled design. Also mentioned was inclusion of both nulliparous and parous patients receiving all five types of currently-approved IUDs. Noted limitations include the study’s potential generalizability because the majority of enrolled patients were white, nulliparous, and highly educated. 

While the authors were incorrect in their hypothesis that lidocaine application would reduce IUD insertion pain, they noted that the significant difference in reported pain levels after speculum insertion between the lidocaine and placebo groups. They said, that while that finding may not be clinically important for a general population of IUD initiators, it may be relevant for women with a history of sexual trauma or anxiety around speculum insertion.