Transcription
[Music] So, uh, so I'll be talking about VTE risk assessment during pregnancy, and we'll be doing, um, a case-based review. So I do not have any disclosures, um, for this, uh, teaching activity. Objectives: So what I'll be doing is I'll be describing the hemostatic changes in pregnancy, um, that result in a thrombophilic predisposition and the duration of this risk. We will also go through some cases where we will discuss, um, VTE risk stratification for pregnancies when there is a prior history of VTE and presence of hereditary thrombophilias, um, if there are any other risk factors for thrombosis, and assisted reproductive techniques. Um, so just as an example, I'll be starting off with the case. So this is a 29-year-old, um, who comes in, first pregnancy, um, she's heterozygous for the Factor V Leiden mutation. She's presenting early pregnancy, and, um, it is very empowering to sort of see when patients are sort of asking about their risks of VTE during pregnancy and what options are available for prevention of risk. And she has got some knowledge about VTE because her father has got a history of an unprovoked PE.
So why is VTE prevention in pregnancy important? And we will start off with the Mother and Baby's Reducing Risk Audit and Confidentiality Inquiry across the UK. Um, and this was a report from 2021 looking at the maternal mortality between 2017 and 2019. And what we're seeing over here is that thrombosis and thromboembolism still is one of the leading causes of maternal mortality, and it is a direct cause for maternal mortality. Um, and the other thing that they also found during this, uh, confidential inquiry is that if two-thirds of the women who died because of the VTE actually had some risk factors. So if there were improvements in care, um, this, um, potentially devastating consequence could have been avoided.
So looking at, um, these inquiry confidential inquiries over the years, um, since 2003 to 2019, we see that there's definitely been a reduction in the direct and indirect maternal death rate. Um, but what we're seeing in terms of the direct maternal death rate, in which VTE is one of the leading causes, has sort of become static. Um, and why we think this has become static, it could be because, you know, we are definitely, um, seeing a lot more complicated, uh, pregnancies, um, women possibly having a lot more sort of medical comorbidities, um, obesity is on the rise. Um, so we're going to look at some cases, um, for this. Um, so when the EMBRACE inquiries actually looked into selected characteristics of women who died from direct or indirect causes, and what they found is that certainly we're looking at sort of pre-existing medical problems, and so that was a predominant cause over here, but also BMI greater than 30, maternal health problems as well, and some of the unfortunate circumstances whereas of women who are not receiving direct, um, recommended antenatal care or minimal level of antenatal care as well. Again, cesarean section, smoking are some of the other characteristics as well.
So going further, I mean, I've talked about maternal mortality, but it, maternal mortality is just, um, sort of the peak of this iceberg here. Um, what we're not seeing is the number of women who end up with sort of long-term consequences because of VTE. Um, and these are reminiscent of who have got chronic post-thrombotic syndrome, um, who have got, sort of, pulmonary hypertension because of chronic thromboembolic disease. Um, women who postpartum are supposed to be enjoying a good period of time with their children, um, or their newborn babies, actually have got an impaired quality of life because of venous thromboembolism, the pain, the limitations, the post-traumatic stress disorder. Um, so these are some things that we are not really, um, taking into account, but we should be definitely taking into account when we are assessing women for venous thromboembolic conditions.
Um, so when we are sort of looking at, um, what are the risk factors for pregnancy, and we can sort of look at the fertile triad, and there's definitely an increase in the coagulation factors. Um, there's an increase in APC resistance, reduction of natural anticoagulants such as protein C and protein S. There's reduction in fibrinolytic activity, but there's also venous stasis because of progesterone. There's dilatation, um, obviously the right, um, sort of common iliac arteries coming and compressing slightly on the left common iliac vein. Um, and this is, um, what most of the time, 85 percent of the time, that we're seeing left-sided DVT during pregnancy. Vessel injury, obviously, this is because of the endothelial, um, injury, but also trauma around the time of birth, um, because of normal delivery, but it can also happen before cesarean section or around the time of cesarean section.
In terms of the hypercoagulability, this was a study, um, which was published by Chables in 2001, which is looking at the around 500 D-dimer values of her around 150 women during pregnancy. And what we're seeing is that there is an increase in the D-dimer levels as the pregnancy progresses. Um, and this is a study, um, which was again published in 2008, and it is looking at women who ended up having venous thromboembolism, um, but in the antepartum and postpartum period. Um, I think that it included around 600 women, 300 women had DVT during the antenatal period up to delivery, and around 300 women had VTE event in the postpartum period. Um, what we see here is that there is a kind of an equal distribution in the first and second trimester, so 10 and 10, and certainly a slightly increased risk in the third trimester. In the postpartum period, what we see from this study is that 49 percent of the VTE events are during the first six weeks, um, of the postpartum period. So these six weeks are certainly a high-risk period, and we say high-risk period again because the period is certainly shorter compared to the the nine months of, um, pregnancy here. And then after six months, I think the VTE rates were around 1.8 percent. Um, again, this was, um, a question, does the VTE risk extend beyond six weeks? Because the number of times we, uh, have this question that gets asked, how long should we continue anticoagulation for? Um, and this was a study in California, uh, looking at again postpartum, um, VTE rates. Um, so it wasn't just VTE, but sort of arterial and venous, um, thromboembolism, but again, um, it's the first three weeks which is the highest risk period for VTE, and as we progress, um, through the postpartum period, the risk, um, sort of gradually reduces. So first three weeks and, uh, definitely a very highest period, and I would still call the six weeks high risk of VTE.
So risk factors, um, for VTE in pregnancy and postpartum period, um, you can have pre-existing risk factors, for example, previous history of unprovoked venous thromboembolism, um, thrombophilias, family history, other medical conditions. There can be obstetric risk factors, for example, if they're admitted during pregnancy, dehydration, hyperemesis, um, preeclampsia, postpartum hemorrhage are some of the obstetric risk factors. And there can be transient risk factors. Some of these again, admissions during pregnancy, um, can be transient, um, if there have been vomiting, if they've been dehydrated, um, infection risk, recently, I mean, we're sort of recovering from the COVID-19 pandemic, so again, COVID-19 infections, um, and we've sort of definitely seen a lot of literature around COVID-19 infections. So there can be transient risk factors. Um, and therefore, the assessment of VTE risk in pregnancy should be, um, a dynamic process, because you know, the risk is evolving in these women. And women have to be assessed prenatal period. I do mention, and as we will go through this presentation, um, I think counseling women who are considered to be at risk of VTE during pregnancy is really important, and so they should be aware about that. And, uh, definitely sort of, um, early trimester repeat with any intercurrent illness and any admissions that women have. We will look at some of the cases that came out of EMBRACE and reflecting how recurrent assessment of women is really important, intrapartum assessment, and postpartum assessment.
Um, so, um, we've talked about the risk, um, of VTE during pregnancy, but what are the options available for thromboprophylaxis? And when we are sort of discussing about what medications that we can use, um, during pregnancy, we're obviously sort of thinking about placental circulation and, um, which medications can cross the placenta and affect the baby. And when you're discussing this in clinic, obviously, Mom, the first question Moms have always asked me is that, is this safe for my baby? So that is a priority for a lot of women. Is what is the safety profile of the medications used? So definitely yes, low molecular weight heparin is safe in pregnancy. Um, it is preferred over unfractionated heparin, um, which was used a long time ago, and sometimes it's still used in some rare cases, but definitely a better safety profile. Unfractionated heparin, yes, it can still be used, but, um, it has a short half-life, there is risk of osteoporosis, heparin-induced thrombocytopenia, um, from the paradox, and possibly, yes, um, it does cross the placenta to some extent. Um, and we do have limited clinical experience. Danaparoid, yes, definitely in women who unfortunately either are unable to tolerate, um, low molecular weight heparin for whatever reason, or happening to use thrombocytopenia, danaparoid has been used. It does not cross the placenta. The new oral anticoagulants, no, we don't have enough safety data in pregnancy, and some of these molecules which are small molecules can cross the placenta, and, um, I would say that limited safety data is available, although we do have an ISTH registry which is looking at, um, the use of new oral anticoagulants in women who are exposed to these, um, during early pregnancy and the outcome of these, um, pregnancies.
So this is taken from the RCOG Green-top Guideline, and again, it is important that the women are given the correct dose of low molecular weight heparin as per their body weight. Um, this is also important in women who have high BMI, and what doses of heparin, which may be slightly different from your medical and surgical patients. Um, so this, I always carry this chart with me, um, when I'm discussing about VTE prophylaxis and the doses of low molecular weight heparin, um, that should be, um, administered in women depending on the weight. Side effects of low molecular weight heparin, certainly the burden of injections, because we are looking at a good number of months of, um, treatment, and again, subjecting women, um, obviously in the UK, you, um, people don't have to sort of pay for these injections out of their pockets, but I know there are lots of countries where people would have to buy their own injections, and there's a substantial cost that is, um, attached with this. When we are offering this to women during pregnancy, um, bruising, um, is again, um, it may sound sort of trivial to us, but certainly for women who are administering these injections, bruising every day is a big nuisance for them. And then there is risk of skin reactions, delayed hypersensitivity reactions, which is sort of Type IV hypersensitivity reactions. Um, this may happen to one when women use one type of low molecular weight heparin, and you can change the brand. There is sometimes cross-reactivity, um, and again, it's a nuisance.
The other thing is about the use of regional epidural analgesia, um, and certainly if they're on low molecular weight heparin prophylaxis or prophylactic dose, um, then generally we tend to say avoid for at least 12 hours, avoid the epidural for at least 12 hours after the low molecular weight heparin dose. We don't necessarily need to have an elective induction of the pregnancy because they're on low molecular weight heparin thromboprophylaxis, but if they're on therapeutic, then there are certainly centers, um, who have to make sure that, um, women have elective or planned induction or planned labor if they want to have regional available for them. Um, there is a risk of bleeding. Um, again, there haven't been any randomized control trials which have sort of looked at, um, the bleeding risk in women who are on thromboprophylaxis. We're getting the data from sort of medical surgical patients, um, and some of the prospective or retrospective or case control studies that are available. Um, we, I tend to quote the antepartum bleeding risk is less than 1 percent, postpartum bleeding risk around, um, 2 percent or less than 2 percent. Um, sometimes I have also noted an increase in liver enzymes, um, which is of unknown clinical significance sometimes. So low molecular weight heparin, heparin-induced thrombocytopenia is again rare, but this is something we have to be aware of. Not so much in, um, thromboprophylaxis doses.
Um, so coming back to another case. So this is a 28-year-old, um, six weeks of gestational age for anticoagulation advice. She has a past history of a PE on combined oral contraceptive pill about four years ago, and she completed six months of anticoagulation. She is now, um, not on anticoagulation, and she would like some anticoagulant advice. So this is, um, a study which had looked at prior history of VTE, and when we're looking at sort of provoked VTE, the risk of VTE recurrence, so this VTE recurrence is not on anticoagulation and not on any thromboprophylaxis. So if this is a provoked VTE, and when we say provoked, it's obviously when provoking factors such as like in a plaster cast or a major surgery, um, antepartum risk is around 1.1 percent of VTE recurrence, whereas the postpartum risk is 7 percent. Unprovoked VTE, certainly the risk is, um, more or less around 3 percent antepartum and postpartum. Now, most of the guidelines, um, that we look at for VTE prevention, they tend to go for around risk of 3 percent, 3 to 5 percent or so antepartum period, postpartum 1 to 3 percent. The ASHRAE VTE guidelines say around 1 percent postpartum risk and 2 to 3 percent antepartum risk. Hormone-associated, and so combined contraceptive pill, which includes your estrogen, antepartum risk is around 6 percent, and postpartum is around 11 percent.
Um, so the RCOG guidance sort of classifies this as a high risk, and therefore women who've had unprovoked VTE, which is, so anything that is not provoked will be a high risk, they should receive antenatal prophylaxis with low molecular weight heparin and six weeks of postpartum low molecular weight heparin prophylaxis. Um, I think it is important, as I've said, that we should offer pre-pregnancy counseling for these women. So when they're diagnosed with a hormone-associated OCP, they should be, um, given information about any future pregnancies, um, so that they're aware of the use of low molecular weight heparin during pregnancy. Um, they should have a prospective thromboprophylaxis, um, in pregnancy plan. Now, there is, um, a little bit of a gap between whether we should offer these women prophylaxis or intermediate dose of low molecular weight heparin. There's certainly a randomized control trial, which is the HIGH-LOW trial, which is looking at offering prophylaxis versus intermediate dose low molecular weight heparin for women who've had unprovoked VTE events, which are or which are associated with hormone-associated VTE as well.
So this is a case which, um, was, um, flagged up in the EMBRACE inquiries, and this is a woman in her first pregnancy who has a history of previous unprovoked DVT. Um, again, she was seen for a threatened miscarriage, although she reported shortness of breath on exertion and tachycardia, and I guess there are overlap of symptoms between pregnancy as well as PE as well. Um, and PE was not considered likely. She was referred to the early pregnancy unit where she was seen twice, and unfortunately, she had a massive PE. So again, it's important that, you know, um, the awareness about unprovoked DVT, um, and future pregnancies.
So, uh, next case is a 29-year-old, um, who's heterozygous for Factor V Leiden mutation in early pregnancy, discussion about risk of VTE and options for prevention of risk. Her father has history of unprovoked pulmonary embolism. So this is looking at the VTE risk, um, antepartum and postpartum period without family history and with family history of VTE. Um, so antithrombin deficiency is certainly considered high-risk thrombophilia for severe deficiency of antithrombin, again, levels which are less than 60 percent, it is around 2.9. So these are all absolute risks. I think previously, um, there were, um, studies which indicated odds ratio, but certainly the absolute risk is around 2.9, um, for with or without family history. Homozygous, um, Factor V and prothrombin gene mutation, the risk is around 2 percent in the antepartum period. With the family history, it is around 6.8 to 5.87 percent. Again, when there is a compound heterozygosity, although most of the studies that we get are from family studies, but certainly without a family history, it is around 2.8 to 3 percent. Family history, certainly it is higher. Um, and if we look at sort of heterozygous or carriers of Factor V and prothrombin gene mutation, the risk is less than 1 percent.
So what do the guidelines say? So, um, we've talked about the high-risk thrombophilia and no VTE. So the RCOG guideline would consider this an intermediate risk, which would make it consider antenatal prophylaxis with low molecular weight heparin. The low-risk thrombophilia, so with the low-risk thrombophilia, I think it's important to look at other risk factors that women might have, and if they have four or more risk factors, then we would offer thromboprophylaxis from the first trimester. If they have three risk factors, then you would offer from 28 weeks of gestational age. If they have less than three risk factors, then they're considered lower risk, which, um, sort of says mobilization and avoidance of dehydration. But again, down here you've got, um, transient risk factors, and therefore, um, if women are sort of coming in with a systemic infection or they're asking about long-distance travel, then that would be considered a transient risk factor, and they need to be risk assessed again at this point in time. Similarly, in the postpartum period, low risk of thrombophilia and family history, and it is important to note this is considered a high risk, and therefore at least six weeks of postnatal prophylaxis should be offered. And to women, this is slightly different because family history along with a low-risk thrombophilia would be considered, sort of, looking at at the risk factors, um, and if there are less than two risk factors, again, even in the postpartum period, you would call it as a lower risk of VTE.
So our next case is a 39-year-old, um, who is a multipara, and she's coming with history of secondary infertility undergoing IVF treatment, and she would like to know the options for VTE prevention, and she doesn't have any personal or family history of VTE. And so here we are looking at sort of what are the risk factors for VTE, um, in women who are undergoing assisted reproductive therapy. So IVF and VTE risk. So this is a meta-analysis, um, published in 2017, looking at the VTE risk, um, associated with in-vitro fertilization, and we can see that there is an increased, um, risk of VTE with the odds of around two. If you're looking at the first trimester, then definitely the odds of 6.39, um, specifically in the first trimester, and this is because, um, there is a syndrome called ovarian hyperstimulation syndrome, which is associated, which can complicate, um, some of the IVF treatment. It varies between mild, moderate, and severe from hyperstimulation syndrome, and one per OHSS is associated with 1.7 risk of VTE in the first trimester compared with less than one, 0.17 percent background risk of VTE. Um, women with PCOS similarly had increased risk due to, um, the hyperstimulation syndrome. Interestingly, um, most times women who have severe OHSS have presented with upper extremity, um, DVTs. Um, and what the advice we get from RCOG is again, women who are undergoing IVF, um, or assisted reproductive technique, we need to assess for other risk factors and also take into account transient risk factors. Um, but if it is, um, ovarian hyperstimulation syndrome, then you would offer antenatal prophylaxis, but only for the first trimester, so the first three months.
So if I, um, had somebody referred to me inquiring about sort of undergoing in-vitro fertilization and the options for thromboprophylaxis, I think my discussion would be, what is the risk of developing OHSS in this woman? Um, and I would go to the gynecologist or the fertility clinic who are offering in-vitro fertilization, asking them what the risk is, and based on that, I would have a discussion, whether I would, um, want to offer thromboprophylaxis or not. Um, obviously, if they've got sort of previous history of VTE or if they are on therapeutic anticoagulation, then that's a different discussion that I would have.
So these are some of the cases again from the EMBRACE confidential inquiries. This is about an older woman who had extreme obesity and history of mental health problems, and I have sort of highlighted some of the red flag signs over here, again reflecting that some of these risk factors are present, and it is about providing the the care to these women and doing and regularly actually offering VTE risk assessment. And so she had admissions for inpatient mental health care, VTE assessment was performed. She did give birth at term and received thromboprophylaxis for seven days, but several admissions postnatally, we don't know what period of time, but she didn't receive any thromboprophylaxis, and unfortunately, um, another devastating consequence of that. A young woman had a booking BMI of 45 kilograms per meter squared. She had some chest pain, and I think she had recurrent presentations with chest pain many times. A PE was excluded. She did give birth at term, was discharged on low molecular weight heparin, however, where the dose was calculated based on her booking weight. And so most times when I am reviewing patients in the clinic or I'm questioned about VTE thromboprophylaxis, and I think it is important that we don't go based on the booking weight, but the current weight during pregnancy. Um, so we do recap weight at around 28 weeks, and postpartum period, to recalculate the dose of low molecular weight heparin and the appropriate prophylactic dose based on the weight gain during pregnancy. And hospitals should develop their VTE risk assessment tools for pregnant as well as postpartum women, which should be consistent with the national guidance.
So certainly there are challenges in VTE risk assessment. Um, we don't have randomized control trials in this patient population, and I think whatever randomized control trials are there, they have suffered from sort of lower recruitment of patient numbers, even though these trials have been ongoing for many years, and it just reflects the difficulty that people have in, you know, managing or recruiting pregnant women. So most of the data that we have in the literature comes from retrospective, um, case or case control studies or cohorts. Um, and again, there are small patient populations within these studies. Therefore, most of the recommendations that we have are based on expert opinion and consensus. For example, if we look at the American College of Obstetrics and Gynecology guidelines, whereas the RCOG guidelines, there's a five-fold difference in the number of women receiving thromboprophylaxis. So 37 percent of women would receive under the RCOG guidelines for a 7 percent into the American guidelines. But we also should be aware about patient values. There are very few studies out there looking at patient values and what women during pregnancy actually want to do.
But I'd like to end my talk by saying that I think creating awareness in women is really important. So, you know, these are some of the tools or information that is available from Thrombosis UK. Um, I do have to say that when I'm seeing these women, these women in pregnancy, um, I, I feel that, you know, it's really empowering to see when they're presenting themselves, asking questions. Women who've had previous history of VTE actually phone us up, phone up our clinic to find out if they should receive thromboprophylaxis during pregnancy or even what they should be doing during their pregnancy. So I think that's a great start, but we certainly need to do a lot more about awareness. [Music]