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NSAIDs, the fetal heart, and prostaglandins
By | September 26, 2011
I think this issue – which started out as a rather lengthy email – will be interesting to the perinatal interest group at large. Some midwives were having a discussion about NSAIDs, and they considered that you don’t take them during pregnancy because it’ll cause a bleed. But there’s more to it than that, so I wrote this discussion. Inflammatory cascades are a special interest of mine, and I prescribe NSAIDs for inflammatory pain daily (unless the patient is pregnant!), and I also treat folks for the ill effects of NSAIDs daily.
NSAIDs = non-steroidal (i.e., not prednisone) anti inflammatory drugs.
Examples: aspirin/Exedrin (and Alka-Seltzer!), naproxen/Aleve, ibuprofen/Advil, indomethacin/Indocin, meloxicam/Mobic, ketorolac/Toradol (injectable for migraine), diclofenac/Voltaren, and oh so many more.
They all basically work by reducing the amount of prostaglandin production in the body.
Prostaglandins are made from arachadonic acid (like Arachne, the first spider-woman) that is derived from recycling cell membrane phospholipids. They are made by all kinds of cells all over the place.
The enzymes that make the prostaglandins are called cox-1 and cox-2.
Cox-1 is “turned on” all the time (is “constitutional”) and is just always doing its work. It makes prostaglandins that you need all the time – for example, to make a protective mucus coating for the stomach wall, and to keep platelets sticky so they will clot properly.
Cox-2 is only turned on as needed (is “inducible”). It makes prostaglandins that create inflammation, the immune system’s most basic response.
You’ll note that blocking all prostaglandin synthesis, in order to quell fever, swelling, pain, etc., will also block the “good” PGs, like the ones that promote the stomach’s mucus lining (ibuprofen > stomach ulcers) and that keep platelets sticky (baby aspirin a day > blood thinner, for clot-risk patients). So if you could only block cox-2, you’d have it made, right?
Unfortunately, cox-2 blockers were found to cause heart attacks and were yanked from the market (cf. Vioxx). They caused *too much* cox-1 “good prostaglandin” effect, including too much platelet stickiness in the coronary arteries of older folk.
Those pointy blue-green things are monkey wrenches, representing
the activity of cox 1/2 enzymes. The yellow thing is a former chicken,
but even if you’re vegan, you’ll get it by recycling old cells
Another “good” PG, made via cox-1, keeps “the ductus” open. We love “the ductus”! You used to have a ductus, and it rocked. It’s gone now.
The ductus arteriosus allows fetal blood flow to bypass the lungs. The high pressure of the direct blood flow would be too much for the delicate fetal lung vessels. (The fetus doesn’t even need lungs, because s/he has the placenta.)
Where is it located? The ductus connects the pulmonary artery (remember, all arteries travel away from the heart, so the pulmonary [lung] artery carries blood from the gentle right heart into the delicate lungs) to the aorta (connects to this giant artery from the strong left heart to the rest of the body – as big as a garden hose!).
The ductus is just a little shunt – some of the blood does trickle out to the lungs, but most bypasses them and goes directly to the rest of the body via the aorta.
After birth, you need the ductus to close, so that ALL the blood from the right heart can go to the lung capillaries, and be oxygenated by the air in the air sacs.
But before birth, you need the ductus to take some of the pressure off those delicate lungs.
The process of closing the ductus is part of the newborn’s “transition” to terrestrial life, and it can take hours or days. Almost all close in the first 4 days, roughly corresponding to full milk production by the mom, interestingly (to me).
VERY nice, if somewhat wordy (have your dictionary nearby, when you read it) summary of these changes, in outline form, at this link.
[Note another major heart specialization for aquatic life, the foramen ovale, a hole between the right and left heart. This also takes a lot of the pressure off the lungs, reducing the amount of blood flow from the right heart to the lungs, and shooting it directly to the muscular left ventricle, instead. The foramen ("for-AY-mun") can take 3 months post-birth to close, and in a lot of adults it still isn't all the way closed, and doesn't really cause any problems most of the time. The third fetal shunt is the ductus venosus, which protects the liver from too much placental blood flow. Wikipedia has a good entry on that one.You'll like it if you are especially captivated by placental circulation - I know I am...]
So there are two things that can go wrong with the ductus.
1. It can fail to close, causing a “patent ductus arteriosus.” This creates a noisy heart murmur and a poorly oxygenated baby. Watch for it in Downs kids (about 40% of them can have it).
2. It can close too soon, subjecting the lung vessels to too much pressure in utero, so they get kind of scarred up and don’t work very well after birth. These newborns have respiratory distress from prolonged high blood pressure in the lung vessels. On an x-ray, the chest has “clear lung hypertension” as opposed to meconium aspiration syndrome, which shows as a cloudy white x-ray. (Meconium aspiration can cause high blood pressure in the lung vessels, a.k.a pulmonary hypertension.)
What keeps the ductus open? Prostaglandins. You can give prostaglandins if you need to keep the ductus open (for example, if the infant will need chest surgery, and they need the blood supply to bypass the lungs).
What closes it? Lowered sensitivity to prostaglandins (normal), or less prostaglandins overall (not normal).
Earlier in fetal life, the ductus is more sensitive to prostaglandins; near birth, is less sensitive. Which makes sense, because these PGs are produced constitutively, i.e., all the time, not as needed. They are also produced by ductus cells themselves. So the only way to control their effect is to control sensitivity to them (by changing the number of prostaglandin receptors that are able to respond to prostaglandins).
We all start out as water babies
…remember?
If your lady takes enough NSAIDs to stop inflammation (stop a fever, stop inflammatory pain e.g. arthritis, etc.), then she might be taking significant enough doses to affect the ductus. This has been shown by some studies – not many – but it’s more than a theoretical risk. Some folks say it’s okay to take them til the 3rd trimester, or until week 35, or such. The ductus may be more strongly affected as maturity and birth approach. I tell folks just not to take them during pregnancy. They can take acetaminophen or whatever instead.
Bonus question: Why are NSAIDs specifically called nonsteroidal? Answer: Because steroids, i.e. cortico-steroids (made in the cort-ex of the adrenal glands from chole-ster-ol) also block prostaglandin synthesis, but at an earlier stage. They have a lot of side effects, for other reasons. So the development of NSAIDs was a big advance over steroid antiinflammatory drugs.
Bonus question #2: Why are they called prostaglandins? And why does intercourse with a man make my menstrual cramps better at first, then worse later? Answer: Ha ha! Prostaglandins were first discovered in semen and got their name from prostatic fluid. Playtime amuses you, but later prostaglandins make your uterus and cervix cramp. NSAIDs are #1 for uterine and cervical muscle pain – shame you can’t use em for labor.
Bonus question #3: Dr Leigh, what do you give pregnant ladies for pain? Answer: topicals, acetaminophen (which is not an NSAID), selected PO herbal remedies, or narcotics. You have to look closely at what the woman’s individual issues are, but for the most part, these are safer than NSAIDs.
Bonus question #4: Does this mean NSAIDs don’t present a hemorrhage risk? Answer: See paragraphs 3 & 4 above!
Thanks for playing!
Gratuitous photo of me and my
camera-shy boy-pren
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