The Federal Reserve has not had an operating loss since 1915. However, that more than a century-long streak came to an end this year.

Profits and losses aren’t usually thought of as a consideration for central banks, but rapidly mounting red ink at the Federal Reserve and many peers risks becoming more than just an accounting oddity.

The bond market is enduring its worst selloff in a generation, triggered by high inflation and the aggressive interest-rate hikes that central banks are implementing. Falling bond prices, in turn, mean paper losses on the massive holdings that the Fed and others accumulated during their rescue efforts in recent years.

As a central bank which can literally print money, this short-term loss of $20 Billion doesn't mean that much. This goes double for the central bank of the globe's reserve currency.
However, it is still significant in two ways:
1) It causes a significant short-fall in payments to the U.S. Treasury.

Instead of having to pay income taxes, the Fed sends all of its income to the Treasury Department. Since 2001, the Fed has remitted $1.36 trillion to the Treasury Department. In 2022, it remitted $76 billion.

This is now expected to drop to zero. What is going to happen instead is that the Fed will be sending a significant amount of money to Wall Street banks. This is to pay a nominal amount of interest on cash deposits that the Fed requires the banks to keep at the Fed.
The Fed never paid interest on these deposits until 2009.

hey @ewarren when will you talk about how the Fed is paying banks $650 million in interest EVERY DAY? Or is it easier to distract the masses with bitcoin and gas stoves? pic.twitter.com/zGzuF6ZpCB

— zerohedge (@zerohedge) January 13, 2023

2) The Federal Reserve is often on the bleeding edge of new and extreme trends in the financial system. The Fed losing money is a once-a-century event that most likely has even deeper meanings that aren't yet obvious.
If you want to understand how the Fed actually works you must ignore what they say and only pay attention to they do. Let me give a few examples.
In December of 2007 the Fed began buying mortgage-backed securities. It was later determined that the recession started the very same month. In February of 2008, Fed Chair Ben Bernanke declared "very slow growth in 2008, but no recession."
The Fed began loaning hundreds of billions of dollars to Europe very early in 2008, but Europe's currency crisis didn't strike until 2010.
The Fed injected $4.5 Trillion into the financial system late in 2019, but the general public wasn't aware there was a problem until March of 2020.

So what new and extreme trend in the financial system is happening now?
We may not be sure of the main event for months, but one trend that is happening right now is central banks losing money and needing bailouts.

Several central banks have already fallen into negative equity in the past without it causing big problems, including those in the Czech Republic, Sweden, Chile, Israel and Mexico.
...
Some central banks are also suffering losses on the large bond portfolios acquired over recent years. The Reserve Bank of Australia recently announced an A$37bn ($25bn) accounting loss on its pandemic bond purchase programme, leaving it with a negative equity position of A$12bn. 

The UK’s Office for Budget Responsibility estimated that the Bank of England would need to be paid £133bn by the government over the next five years to cover losses on its quantitative easing portfolio.
...An extreme example is the Swiss National Bank, which warned in October that it had already made a record loss of SFr142.4bn ($152bn) in the first nine months of this year, mostly from losses on its investments made with its foreign exchange reserves.

The Bank of England is a good example. The country with the world's reserve currency as recently as a century ago, is being forced to send taxes directly to the central bank to cover for their losses in order to prevent the British Pound from collapsing.