Wales duo Alisha Butchers and Donna Rose will miss the 2023 Women's Six Nations as they recover from long-term knee injuries.
Flanker Butchers and prop Rose both suffered anterior cruciate ligament (ACL) damage at last year's Rugby World Cup in New Zealand.
Head coach Ioan Cunningham is hopeful of having second rows Gwen Crabb and Natalia John fit for the campaign.
Wales begin the Six Nations by hosting Ireland on Saturday, 25 March.
Crabb and John were injured while playing for their Premier 15s clubs in December.
Crabb broke her fibula and displaced her foot after falling awkwardly in a tackle and spent four days in hospital, while John suffered a posterior cruciate ligament (PCL) injury during a warm-up.
All four have been attending rehabilitation sessions at Wales' National Centre of Excellence as part of their professional status.
"Our medical team has done a great job with everyone," Cunningham told BBC Sport Wales.
"But the way we're looking at it, we've got these players now who are at a very high level, but this will give opportunities for others."
Butchers is no stranger to injury setbacks, the latest a cruel blow in the first World Cup Pool game against Scotland.
But the 25-year-old said the support from her team-mates, coaches and family helped her deal with the disappointment.
"It's just a part of my journey, it's been a rollercoaster, but I've learned so much from it and these past five months since leaving the World Cup, I've had a great opportunity to get even stronger and even fitter," she said.
Butchers is targeting a return with Bristol Bears at the start of next season, and despite being on track, says: "I'm not putting too much stress on myself.
"I am trying to be as positive as I can about it and hopefully when I get back, I'll be back for a while."
Crabb has also spoken positively about her recovery after her horror injury.
"As soon as it happened I was obviously gutted because my first thought was we're not that far away from the Six Nations," she said.
"I was really enjoying my rugby, I was starting to find my flow and was probably in the best form that I'd been in.
"Once I got out of hospital and got my head around it, it was more about 'how can I get better?'.
"Being able to come in four days a week for rehab has been game-changing because it is constantly improving."
Crabb is now hopeful to be fit for selection for the Ireland game.
"I am trying to rein it in and not promise too much, but hopefully next week I'll return to non-contact training and then the week after that contact training.
"So everything is on track."
The Ireland game will most likely come a week too soon for John, who is set to return for the trip to Scotland on Saturday, 1 April.
WRU Interim CEO Nigel Walker and Wales head coach Ioan Cunningham are pictured with Alisha Butchers, Natalia John, Gwenn Crabb and Hannah Jones
Cunningham will name his squad to for the Six Nations next week.
It remains to be seen if wing Jasmine Joyce and full-back Kayleigh Powell will be available for selection as they left the 15s programme in December to play for Great Britain Sevens on the 2022-23 World Series.
The pair were regulars in Wales' backline last year and Cunningham has not ruled out their involvement.
"The discussions we have had with the GB coaches is that the programme possibly doesn't allow it with their training camps when we're in camp and things like that," he said.
"But it's definitely not a closed door, if there was an opportunity we would look at it for sure.
"We want to support Jaz, she's aiming for the 2024 Olympics and then obviously the World Cup after that for us, hopefully."