Risk Factors Revisited

Now that we've discussed the Maternal-Fetal Conflict and seen the role of sFlt1 in the cascade of symptoms, let's take another look at risk factors. What leads to a placenta implanting poorly?

* a first pregnancy, or a first pregnancy with a new partner
While the risk of PE is around 5% for women as a whole, it's around 10% for first time mothers. Most women who get it once do not have it in subsequent pregnancies. Why?

One theory is that in a first pregnancy, a woman's body doesn't know how to react to the "foreign invasion" of the placenta, and so has a stronger immune response than needed. In subsequent pregnancies, Mom's body knows what to expect and doesn't attack as strongly. It's thought to be a similar process to desensitizing therapies done with allergies. This would fit with the increased risk in a pregnancy with a new partner. Mom was already "desensitized" to the previous father but reacts more strongly to the DNA of the new father.

Another theory is that the first placenta does a lot of work to remodel Mom's uterine arteries. Subsequent placentas can build on this work to make a deeper, better connection. One scientist describes it like a pair of pantyhose. Compare a brand new pair to one that has been worn: it's stretched out. It takes time to bounce back to normal. If Mom's immune response is just a little stronger than normal, if she had mild PE late in the pregnancy, it's a lot less likely she'll have it again, possibly due to this phenomenon.

* Age: teenagers and those over 40
Teenagers' bodies are still gearing up toward peak fertility. They aren't as prepared for pregnancy and are more likely to overreact in their immune response. On the other end, as we approach menopause, our bodies are gearing back down and are no longer as prepared to accept a placenta.

* Women who have chronic high blood pressure outside of pregnancy, including those with a predisposition for high blood pressure that has not yet shown up.
If you have high blood pressure outside of pregnancy, your risk of developing PE is 25%. If you have a predisposition for high blood pressure, the stress of pregnancy can bring it out, just like the stress of getting older or gaining weight. If your blood pressure goes up in the first trimester, it's generally assumed you have unmasked chronic hypertension rather than pregnancy-induced hypertension. The risk in this case is also 25%. It is thought, though, that the increased risk is less due to a poorly implanted placenta but rather to one that has been damaged by the higher blood pressure. This is called super-imposed preeclampsia. The cause is different, but the result is the same.

* Autoimmune disease such as lupus and rheumatoid arthritis
Having an autoimmune disease means your immune response is already more sensitive than it should be. It makes sense, then, that such women would also have a higher immune response to the placenta and would thus be more prone to PE.

* A blood clotting disorder such as Factor V Liden and MTHFR
Once again, it is thought that this risk factor might be due to super-imposed PE--the placenta may have implanted normally, but mini blood clots block off the artery connections, leading to poor nutrient transfer and the cascade of symptoms.

* A family history of PE, especially if either grandmother had it while pregnant with Mom or Dad
Research into the possibility of a genetic connection is in early stages and ongoing, but it seems very plausible that a mother with a strong limit-the-fetus gene or whose husband passes on a strong grow-a-big-fetus gene would be at greater risk.

* Carrying multiples
Do the math: more placentas=more chance of something going wrong. Also, more babies=greater demand for nutrients.

* Obesity
This may be less due to the obesity than to the tendency toward high blood pressure that often goes along with it, but improving BMI also seems to improve pregnancy outcomes as far as PE is concerned.

* personal history
After a mild case at term, the risk may be no higher than a first pregnancy (10%), but the earlier and more severely it struck, the greater the risk of recurrence. Having PE severe enough to require delivery before 36 weeks puts the risk of recurrence at 40%; before 28 weeks, 60%. Whatever issue caused PE the first time may still be in play in subsequent pregnancies. The good news is, in most cases, if PE does strike again it's likely to be milder and later.

A Nasty Little Protein

Once again, let's start with my disclaimer.

Yesterday, we explored the Maternal-Fetal Conflict, the idea that pregnancy complications result from mother and child having different needs for their survival. Dr. David Haig theorized that the fetus must be sending some signal to the mother that led to the cascade of symptoms in preelcampsia. This work was built on by Dr. Ananth Karumanchi, who discovered two proteins that can explain almost every symptom that comes up in PE.

In a normal pregnancy, the placenta digs into the uterus, building new blood vessels and redirecting nutrients and oxygen to the growing baby. Early on, the baby doesn't need much, but the placenta is taking quite a bit to store up for later. As the baby gets bigger and bigger, it requires more and more nutrients.

During labor, the flow of blood to and through the placenta is significantly lessened during contractions. This isn't a problem, though, because the placenta has such a good store saved up. It dips into its supplies and keeps the baby well nourished and oxygenated during this process. As the saved oxygen is transferred to the baby, the placenta starts to release a protein called sFlt1. This protein binds to another protein found in the body, VEGF, which is the "repairman" of the circulatory system. Once sFlt1 has bound to VEGF, it can no longer repair the blood vessels.

When this process happens in a normal labor, the sFlt1 is limited to the placenta and only affects the repair of the blood vessels connecting the placenta to the uterus. This serves an important function in allowing the placenta to detach after delivery.

In PE, the placenta does not attach as well or as deeply to the uterus as it should. It simply cannot ferry the nutrients and oxygen in the amounts needed. Early on, this isn't a problem, but as the baby gets bigger and demands more, it can't keep up. It starts dipping into its savings long before labor has begun. This means sFlt1 is released earlier and in larger quantities and has a chance to move out of the placenta into the mother's blood stream. As it spreads throughout her body binding to her VEGF, the normal wear and tear on her blood vessels isn't repaired.

Fluid starts leaking out of the blood vessels into the surrounding tissue, leading to swelling. Mom's body reacts to this leaking by tightening down the blood vessels, which in turn raises the blood pressure. As the blood vessels in the kidney become leaky, protein in the blood slips through into the urine. And that right there is preeclampsia.

The higher blood pressure forces more blood to and through the placenta, leading to a temporary improvement in nutrient transfer to the baby, but it also causes damage to the blood vessels which weren't all that great to begin with. This leads to worse nutrient transfer, more dipping into reserves, more sFlt1, and a continuing cycle of more and more damage. The only way to stop it is to remove the placenta, aka deliver the baby.

Dr. Karumanchi found the levels of sFlt1 were elevated in women with PE, and that levels started to increase on average 5 weeks before symptoms appeared. However, the higher levels weren't much different between those women with mild PE and severe PE/HELLP. He reasoned there must be another chemical at play. It turned out to be endoglin, which is toxic to the liver and affects red blood cells and platelets.

These two proteins, sFlt1 and endoglin, can explain almost everything in PE. There may be other proteins involved as well. Research, as always, is ongoing.

The most exciting prospect from this research is the possiblity of a screening test. If women can know five weeks in advance that trouble is coming, they can be monitored more closely and their symptoms managed to give both mother and baby the best chance of survival.

The Maternal-Fetal Conflict

Before I begin this post, I want to reiterate my disclaimer: I am neither a doctor nor a research scientist. I am a woman who has experienced the devastating effects of preeclampsia three times. I write about preeclampsia as I understand it. Also keep in mind that research is ongoing. What we understand today may be adjusted, altered, or even thrown out entirely as new information is discovered.

One of the most exciting areas of research into pregnancy complications in recent years has to do with the Maternal-Fetal Conflict. First proposed by David Haig, it has to do with the idea that mother and child have different survival needs.

Picture taken from Wikipedia

Let's start at the beginning. Sperm meets egg, the fertilized egg starts multiplying and dividing, and the zygote moves down the fallopian tube to the uterus arriving about 5 days post conception (which, due to the bizarre way we count pregnancy, is around the end of the third week). At this stage, it's called a blastocyst. The blastocyst contains a clump of cells called the embryoblast, which will become the actual baby, surrounded by the trophoblast, which will become the placenta and amniotic sac. Interestingly, all of the maternal DNA in the trophoblast has been switched off and all of the paternal DNA has been switched on. This means the placenta is essentially all father.

From a purely biological perspective, the goal of reproduction is to pass on your genetic material. For the father, and therefore the placenta, the bigger the baby, the better the chances of survival. As far as the placenta is concerned, a 100 pound baby sounds awesome. Thus, the placenta digs deep into the uterus, shunting crucial nutrients and oxygen from the mother's blood supply to the baby.

The mother, on the other hand, wants a baby big enough to survive BUT small enough to fit through the birth canal so that she, too, can survive to reproduce again. Our bodies are amazing and can expand to birth an 8, 10, even 12 pound baby. But let's face it--a 100 pound baby simply isn't going to fit. Thus, the mother must limit the placenta in some way to ensure her own survival. The mother's immune system attacks the placenta as a foreign invader, preventing it from attaching too well and from comandeering too many nutrients. 

It's a very delicate balance to grow a baby that is big enough but not too big. Dr. Haig suggests a normal pregnancy is like a tug of war: both sides are pulling on the rope, but the ribbon in the middle doesn't move if each side pulls equally. However, if one side starts to win the tug of war, if the survival of the other side is threatened, it will employ strategies to keep itself safe. He theorized that the fetus must be sending some signal to the mother that triggers the cascade of symptoms known as preeclampsia. This theory was confirmed by another doctor, kidney specialist Ananth Karumanchi, who discovered elevated levels of a protein called sFlt1 in women with preeclampsia.

Tomorrow I plan to explore the role of sFlt1 in preeclampsia.

Wishing Peace...

For all mothers missing babies...
For all babies missing mothers...
A moment of silence.




Please join me in ending this terrible condition.

Survivor Saturday: Kristy's Story

I had the pleasure of running 14 miles this morning in honor of Kristy and her children. Like me, Kristy is a three-time survivor. I'm so glad she shared her story with me. If you have a story to share, I would like to hear it.

Kristy's Story

I am a preeclampsia and HELLP Syndrome survivor.  I am the mother of 6 children, three of whom were born early due to complications from these diseases.

My first born was delivered at 36 weeks after a week in the military hospital on bed rest with preeclampsia. I started showing signs of pre-e late in my 2nd trimester and my blood pressure was handled using medication.  I had weekly trips to the OB, regular non-stress tests, regular ultrasounds to monitor growth, and periodic 24 hour urine tests. I went in to the OB's office for a blood pressure check and was admitted to the hospital at 35 weeks. 

When I was admitted, I was put on strict bed rest and had to lie on my left side whenever I wasn't eating a meal or using the rest room.  The night before I would have been 36 weeks, the doctor came in to see me and told me that my labs were elevated and my blood pressure was no longer being controlled by the medication.  He wanted to begin the induction immediately.  I was transferred to a labor room and given pitocin to start labor.  I was also put on a mag-sulfate drip to avoid seizures.  It wasn't run with dilution and it burned my arm so badly I think I was in more pain from that than the contractions.  I was given an epidural site (with no drugs) in case of an emergency c-section.  I labored for about 9 and a half hours and pushed for about 30 minutes and my son was born.  He was 5 lbs, 2 oz and healthy as he could be. 

I was transferred to the recovery room where I spent the next 16 hours.  (Most women stay in recovering about 2 hours; have a meal, use the bathroom, etc.)  I was on mag-sulfate for the entire time I was in recovery.  I wasn't allowed to eat or hold my son.  He was in a bassinet next my bed but I wasn't allowed up to touch him.  I ended up being in the hospital for a week after delivery while they tried to settle my blood pressure.  I have had high blood pressure ever since.  (This was 18 years ago next month.)

My third baby was born at 34 weeks due to preeclampsia.  I had been having blood pressure issues from pretty much the start of the 2nd trimester.  I was supposed to be on bed rest but who can pull off bed rest with a 5 year and a 3 year old?  At 34 weeks I went in to see my OB for a routine appointment and she sent me straight over to the hospital.  My husband asked his brother to watch our other children while we waited to see the perinatologist at the hospital.  He was pretty sure I would be coming home that night.  Instead, the perinatologist felt it was best to begin an immediate induction. 

Once again, I was started on mag-sulfate and pitocin was started.  This time, the mag-sulfate was diluted and didn't cause any pain.  It did cause my vision to be blurry and a headache, but there was no burning in my arm!  I labored for 12+ hours and consented to an epidural at about 12 hours spot on.  I was a 4.  It was 8 am.  At 8:20 am I informed the nurse of intense pressure.  She assured me it was nothing but she would humor me and check me.  I was at a 9+ and ready to push!  Twenty minutes later, a very tiny head emerged!  I remember thinking it didn't feel like it was big enough to be born.  My daughter was 4 lbs, 8 oz with a teeny tiny little head!  She was pink and screaming and rushed off to the NICU.  I was crushed to not get to hold her.  I ended up not seeing my newborn daughter for over 36 hours as they worked to get my blood pressure down using medication and keeping me on strict bed rest and mag-sulfate. 

The following day after delivery, in the afternoon, I was finally wheeled to the NICU to see my baby girl.  I was released from the hospital after 4 days but my wee girl had to stay for 10 days.  I cried so hard when I left the hospital that day.  (This was 12 years ago come August.)

My fifth baby was born at 35 weeks due to Class I HELLP Syndrome.  I had been having a text book pregnancy.  As usual, I was on medication for my blood pressure, but everything was going beautifully.  I had had hyper-emesis gravidarum from about week 7 to about week 18, but my blood pressure was fantastic and I wasn't spilling any protein in my urine. 

In late March, the night of Easter Sunday, I woke up in the middle of the night with pain in my upper abdomen.  I thought is was severe heartburn and woke my husband up to rub my back and try patting it hard to make it go away.  I couldn't get the pain to go and I kept getting in the shower and bath tub to relieve the pain.  By the early morning, we were out of hot water and my husband was boiling water on the stove to add to the tub while I put in a call to the midwife/OB I was seeing.  A nurse from the office finally called me back and told me it sounded like my gall bladder was acting up.  I thought that was odd as I had never had any gall bladder issues, but Ok.  She had me come in and see the OB later in the day. 

The OB started me on Vicodin and sent me home with a follow-up appointment for later in the week.  I took the Vicodin around the clock and never felt well.  Later in the week when I saw her again, she admitted me to the hospital for 24 hours to put me on morphine while this gall bladder thing worked itself out.  Then she sent me home and told me to see her the following Monday.  Meanwhile, I was still on Vicodin around the clock.  On Monday, she had me set up an appointment with a surgeon about appendicitis.  I was sent for another ultrasound and a CT scan.  I saw the surgeon on Wednesday for the results and she said there was no appendicitis but I had a kidney stone.  I was sent again to the hospital to be put on morphine again to pass this kidney stone. 

The next morning, early, the OB came into my room and told me I had preeclampsia again.  I was so crushed.  I told her I was sure it wasn't and she should check again.  My husband went home to shower and while he was gone, she came back and said that it wasn't preeclampsia, but HELLP Syndrome.  I had only sort of heard of HELLP and didn't really know anything about it.  She said they would begin inducing immediately and that a c-section was out of the question.  (No worries there.  I sure didn't want one!)  I asked her to wait until my husband got back.  She said she would wait 45 minutes and in the meantime would start the mag-sulfate.  I was so sad.  When my husband came back, I cried and cried. 

Labor was shockingly hard and fast. My baby girl was born after 4 hours at 4 lbs and 9 oz.  She was so tiny she slipped out with no pushing!  I was allowed to kiss her sweet head and then she was whisked away to the NICU.  I was bleeding excessively.  I was kept on the ante-partum floor for recovery.  That evening, they brought my wee one up for me to see her and then took her away again.  I wasn't even allowed to hold her.  The nurse was cold and unkind.  I don't remember ever feeling so depressed. 

Then things get really fuzzy.  Most of what I know about what happened next has come from my husband telling me.  I started to lose consciousness, going in and out.  A foley catheter was put in.  Blood was drawn every hour to check my platelets.  They continued to crash.  My gums were bleeding.  My nose was bleeding.  I was vaguely aware of being afraid to sleep as I thought I wouldn't wake up again.  I remember people being in my room constantly, looking serious and sober and somber.  Finally, around 6:30 the following morning, my platelets started to slowly come up.  They had dropped down to 20,000.  (Normal is 150,000-400,00.) 

I stayed in the hospital on mag-sulfate for 4 more days before I was released.  The first time they tried to stop the mag, my platelets dropped and my blood pressure started rising.  It took a long time and during that whole time, I was never allowed out of bed or to see my precious baby.  She was in the hospital for 2 weeks before being released.  To this day, she has severe allergies and some other issues that I can't help but wonder if they are related to the HELLP Syndrome.  (This was 7 years ago last month.)

 

My Birth Burned Down

It's the middle of the night. You wake up from a dead sleep. You can't quite figure out where you are or what's going on. What woke you? There's this noise…is that the fire alarm?!?

Suddenly fully awake, you shake your husband. Honey! Wake up, the house is on fire! Now you can smell smoke and see flickering lights under the door. You and your husband carefully open the door: it's definitely a fire, and spreading fast.

You run to your children's bedrooms, scooping them up and running for the front door. Can't go that way, it's already engulfed! You head for the back door, but there's too much smoke! You can't get out!

There's a window, but it won't open! You grab a lamp and smash the glass. Finally, a path to safety. You quickly climb out, then reach back as your husband hands the children out one by one.

Your family then stands on the sidewalk in your pajamas and watch as your house goes up in flames along with all your possessions.

You're in shock. How did this happen? But you look around and realize, you all survived. There may be some minor smoke inhalation, a cut from the broken window, a small burn, but you will recover.

Are you grateful that everyone is okay? Of course you are! Are you also upset about the traumatic experience you just went through, not to mention that you're now homeless with nothing but the pajamas on your back? Of course you are!

It's possible to feel both positive and negative emotions about different aspects of the same event. Being sad, fearful, angry, depressed, worried, traumatized, does not negate how grateful you are that you're all okay. And being happy that everyone survived doesn't erase the sadness, fear, and anger. It takes time to recover from such a trauma. You have to feel what you feel and work through it to the other side.

My births "burned down." It wasn't supposed to be this way. I was supposed to go into labor on my own. I was supposed to move around, eat and drink, be supported by people I loved. It would be the hardest thing I ever did, but at the end I'd lift my beautiful baby to my chest and all would be well.

That's not the way it happened.

Yes, I was thrilled with my beautiful babies. I was grateful we all survived. But I was also sad, angry, fearful, traumatized. I had to feel what I felt and work through it to the other side.

My first birth was struck by lightning. It was an "act of God," a legitimate medical complication that required necessary intervention. I look back at the ashes of that birth nearly nine years on, and mostly I feel wistful for what should have been. It went as well as it could have gone, and it certainly could have been worse. I am at peace.

My second birth was arson. Okay, maybe arson is too strong a word. No one wanted my baby and me to be harmed. But it was definitely some punk kids playing with matches. I was given dangerous medications when there were safer ones available. I was treated with disrespect, bullied and screamed at. My right to informed consent was ignored. My baby and I were both harmed as a direct result of what was done to us by the very people I trusted with our care. I look back at the ashes of that birth five and a half years later, and I am MAD AS HELL! It didn't need to be that way. It shouldn't have been that way.

My Story Part 2

I consider myself both a preeclampsia awareness advocate and a natural birth advocate. My first story explains how I came to the first role, and this story explains the second.

Having had severe PE at 35 weeks put my risk of recurrence at 40%. I knew that going into the pregnancy, but I also knew that if it did happen it would likely be later and milder. I also knew what to look for and was ready to advocate for myself and my baby to get the care we needed.

I started out my third pregnancy with a different doctor, one who I was confident would listen to me and monitor me carefully. I had wanted a natural childbirth the first time, but that had not been possible due to how sick I was. I wanted this birth to be different, but of course I would accept any necessary intervention if medical issues arose.

I religiously logged my blood pressures with a home cuff. As I entered the third trimester, I was seen more often than the average mother-to-be. At 32 weeks, I started showing the same warning signs as before: episodes of racing heartbeat and shortness of breath along with swelling. I started doing weekly 24-hour urine tests and blood work, and we watched the protein levels slowly creep up. I had a few episodes of high blood pressure that sent me to L&D, but it came back down. Labile pressures like this are not unusual as PE progresses, and we knew it was a matter of time before it stayed up.

At 36 weeks 5 days, I crossed the "magic line" and officially became diagnostic for mild PE. I talked things over with my doctor, and we decided since I was so close to term, it was best to induce before I became as sick as before. I spent 24 hours on strict bedrest and headed to the hospital the evening of 36+6 for an overnight induction.

I have no regrets about the decision to induce when we did. I have a lot of regrets about what happened next. You see, I trusted my doctor and the hospital staff to do what was best for me and for my baby. While I had a general philosophy that "natural is best," I hadn't done much research into natural birth. That's what I was paying my doctor for.

Doctors are supposed to get informed consent before performing any test, treatment, or procedure, but I was never informed of the risks. I didn't know the medication she had selected for my induction, Cytotec, has a black box warning stating that it should never be used in pregnant women, and that the company that makes it has put out numerous warnings begging doctors to stop using it for inductions. I didn't know that an overdose could cause hypercontractions that could put my baby in distress or even cause my uterus to rupture. If I had known, I would have chosen a different method of induction.

Remember yesterday's post about observer's bias? My doctor thought it was acceptable to use this dangerous drug because lots of doctors use it, it's usually fine if managed correctly, and if the risks become reality she'll just do a c-section, so what's the big deal? It may not have been a big deal to her, but it was a HUGE deal to me.

The next factor in this disastrous birth was the nurse assigned to me. I didn't know it at the time, but she told me later she was a substitute nurse who did not feel comfortable working in L&D. She had specifically requested me as a patient because nothing exciting was supposed to happen on her shift: the plan had been Cytotec overnight, pitocin in the morning (after she left), and baby by afternoon.

I had the first dose of Cytotec at 6:00 and the second at 10:00. By midnight I was in labor. The nurse came in a few times to fiddle with the contraction monitor. I finally asked her what she was doing, and she said, "This monitor must be faulty. It's picking up random movements whenever you roll over or sit up."

I said, "Those aren't random movements, they're contractions. I've been in labor for a while."

She said, "Don't be ridiculous, you couldn't possibly be in labor. You haven't had any pitocin yet." Then she pointed at a new peak on the strip and said, "See, you're tensing your abs right now!"

I hissed, "No, it's a contraction!"

And she reset the monitor at the height of the contraction so no further peaks showed up. That right there? Observer's bias, and a very dangerous one, no less.

At 2:00, the nurse came in to give me my final dose of Cytotec. I asked if it was really necessary since I was already in labor. She said first, I wasn't in labor, I may be having contractions but they weren't even showing up on the monitor (which she had intentionally set wrong), and second, the doctor had ordered three doses so she had to give me three doses, and she wasn't going to call her at 2 in the morning to ask. And like a good little patient, I trusted she knew what she was doing and let her insert the pill.

By 4:30, my labor was way out of control. I called Papa Runner, who had gone home to get a good night's rest before the excitement started, and told him he had to get here NOW or he was going to miss it. He got to the hospital at 5:30, took one look at me, and ran out to get the nurse. This was the first time she realized I was actually in labor. At that point I was in pretty bad shape. You've heard of double peak contractions? I had a multi-peak contraction that lasted a full 45 minutes. I consider myself very lucky my uterus didn't rupture right there.

And her second occurence of observer's bias showed up here. You see, I hadn't had an epidural yet, and laboring women HAVE to have an epidural. So instead of calling my doctor like a rational person, she paged the anesthesiologist. It took him almost an hour to show up, and in the mean time she injected two doses of Nubain into my IV without my knowledge or consent. Now, I was woefully uninformed about birth interventions, but I did know that narcotics should NEVER be given if birth is imminent because they can cause breathing and sucking issues in the baby. If I had known what she was giving me, I would have violently refused it, but I was never given the opportunity to refuse.

I started pushing spontaneously at 6:30. The nurse had a full blown panic attack, screamed at me to stop, and ran from the room screaming for help.

The anesthesiologist showed up at 6:45 and said, "Ok, it's time for your epidural." I used some words I don't usually use and told him it was way too late since I was already pushing, and besides, I hadn't asked for an epidural anyway.

The nurse screamed at him that he had to make me take something, then screamed at Papa Runner that he had to make me take something. I finally agreed to a spinal just to shut her up. The spinal was in place at 7:00, and my doctor showed up at 7:01. No joke. Now I had to push without being able to feel anything.

My baby got stuck on my pelvis. I had a strong instinct to roll over onto my hands and knees, and I have no doubt she would have easily been born if I had been able to do so. Instead, the doctor cut an episiotomy that then tore. It still gives me trouble today nearly six years later.

And my baby had trouble breathing and sucking due to the contraindicated medication illegally given without my consent.

My first birth taught me to advocate for proper care in pregnancy. My second taught me to do the same in birth. While preeclampsia was what led to my induction, and it did cause this baby to be mildly growth restricted as well, ultimately it wasn't PE that put my baby and me in danger. It was the incompetence of the hospital staff and the three medications (Cytotec, Nubain, and a coerced spinal) given without informed consent.