Metformin Use During Conception and Pregnancy

The following recent query requested my opinion regarding the safety of metformin during the periconceptual period and throughout pregnancy. Although there are not many large or comprehensive studies addressing these concerns, the bulk of the data available to us is encouraging...

Dr. T,

Quick opinion if you don't mind. As you may recall, I miscarried on 9/12. I have since seen my PCP for a regular check-up. He prescribed me Metformin….he believes based on my history, weight, blood work and family history, my body may have issues with the breakdown of sugars (i.e., type 2 diabetes but I'm not diagnosed with that). He said that it also may have some positive side effects for me including weight loss and assistance in helping me to conceive (although that doesn't appear to be a problem since I WAS able to get pregnant even though I miscarried). He says it is completely safe.

I have read mixed things online about Metformin and potential effects on babies. Namely that no known birth defects have been caused from it but that there are not many studies either. Additionally, I have read some things about it potentially causing miscarriage.

Could you please give me your opinion on this? I would like to take it as I have for a week now, because I physically feel better. I'm very scared of the effect it may have of a pregnancy and if I were to stop taking it during my pregnancy (as my doctor said this is elective as he feels it would benefit me but is not imperative for me to take). Do you know of any potential miscarriage issues with this prescription?

Thanks again for EVERYTHING!

Christe


Women with insulin resistance are at increased risk for hyperinsulinemia, type 2 diabetes, polycystic ovary syndrome (PCOS), and hyperandrogenism (increased levels of ‘male hormones’). They also are at risk for reduced fertility secondary to ovulatory dysfunction and a suboptimal hormonal milieu that may impair conception, implantation, and placentation. Pregnancy complications include higher rates of miscarriage, gestational diabetes, hypertensive disorders, preterm delivery and operative deliveries, excessive maternal weight gain, fetal macrosomia as well as growth restriction, and admission of their babies to neonatal intensive care units for a variety of reasons (Boomsa, et al., Semin Reprod Med. 2008;26:72-84). In my own experience, they also appear to be at increased risk for complications related to cervical insufficiency.

Metformin is an oral hypoglycemic (blood sugar lowering) agent whose primary affect seems to be mediated through its ability to reduce insulin resistance, thereby leading to a reduction in blood glucose and insulin levels. Metformin has also been found to have other beneficial affects, some of which appear to be independent of its hypoglycemic activity. Included among these are its effects on lipids, inflammation, hemostasis, and endothelial cell and platelet function (Anfossi G, et al. Curr Vasc Pharmacol. 2010 Jan 1. [Epub ahead of print]; Matsumoto T, et al., Am J Physiol Heart Circ Physiol. 2008;295:H1165-H1176).

In women with PCOS, “reduction of hyperinsulinemia with metformin and diet is associated not only with improvement of the biochemical endocrinopathy, but, commonly, with restoration of menstrual cycles and fertility (Goldenberg, et al, Minerva Ginecol. 2008;60:63-75).” When used in infertile women with PCOS in combination with clomiphene citrate, an ovulation-inducing drug, metformin was shown to improve improve conception rates and, perhaps, live-birth rates compared to either drug alone (Legro, et al., N Engl J Med. 2007;356:551-66). In a recent small study of 66 women with PCOS who were clomiphene resistant and underwent in vitro fertilization, those who “received metformin (until conception) showed a significantly higher number of good quality embryos and implantation rate when compared with the placebo controls (Qublan, et al., J Obstet Gynaecol. 2009;29:651-5).” They were also found to undergo fewer spontaneous abortions in early pregnancy.

Very few studies have been done in which metformin therapy has been continued throughout the pregnancy, but in those that have, the results have been encouraging. Khattab and colleagues (Gynecol Endocrinol. 2006;22:680-4) studied 200 nondiabetic women who took metformin while undergoing assisted reproduction, of which 80 stopped the drug once they conceived and 120 continued it throughout pregnancy. Demographically, both groups were similar. Miscarriage rates “in the metformin group were 11.6% compared with 36.3% in the control group (p < 0.0001; odds ratio = 0.23, 95% confidence interval 0.11-0.42).” Similarly, Nawaz and colleagues (J Obstet Gynaecol Res. 2008;34:832-7), found that “In women with PCOS, continuous use of metformin during pregnancy significantly reduced the rate of miscarriage, gestational diabetes requiring insulin treatment and fetal growth restriction.” Furthermore, no significant congenital anomaly, intrauterine death or stillbirth in any of the woman who took metformin during in this study.

To support the observations in humans and, perhaps, to provide a mechanism of action, Luchetti and colleagues (J Steroid Biochem Mol Biol. 2008;111:200-7) found in mouse studies that hyperandrogenization, such as that which occurs in PCOS, induces embryo resorption in early pregnancy and that this is correlated with reduced production of progesterone-induced blocking factor (PIBF) and increased production of cyclooxygenase-2 (COX-2) - the overall effect of these changes creating a pro-inflammatory environment. Coincident treatment with metformin is able to reverse such changes and prevent early pregnancy loss in this animal model. To further support the overall beneficial effect of metformin in human pregnancy being the result of its overall anti-inflammatory properties, Orio and colleagues (Eur J Endocrinol. 2007;157:69-73) found in nonpregnant PCOS women that metformin treatment significantly reduced WBC count and C-reactive protein (CRP), reduced androgens, reduced low density lipids, and increased high-density lipids – all contributing to a reduction in the “proinflammatory” status of those PCOS women receiving metformin.

Finally, to answer our reader’s final concerns, in all the studies we have reviewed, in no instance did taking metformin, either during conception or throughout any time frame of pregnancy, appear to have a serious deleterious affect on the babies. Although the studies have been small, there does not appear to be a greater risk for spontaneous abortion, later pregnancy loss, or congenital anomalies (Goldenberg, et al., Minerva Ginecol. 2008;60:63-75; Nawaz, et al., J Obstet Gynaecol Res. 2008;34:832-7; Qublan, et al., J Obstet Gynaecol. 2009;29:651-5; Elizur, et al., Fertil Steril. 2008;89:1595-602; Bolton, et al., Eur J Pediatr. 2009;168:203-6; Ekpebegh, et al., Diabet Med. 2007;24:253-8). Furthermore, Bolton and colleagues (Eur J Pediatr. 2009;168:203-6) have reported that metformin is actually associated with beneficial effects of fewer growth restricted (< 10th percentile) and macrosomic (> 90th percentile babies) and fewer cases of neonatal hypoglycemia requiring glucose infusion.

Labels: diabetes, insulin resistance, metformin

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Absence of Fetal Nasal Bone in Midtrimester as a Marker for Down Syndrome

Tamsen has left a new comment on your post "Amniocentesis is Not Without Risk":

I am 29 years old and am 21 weeks along. I just had an ultrasound a couple of days ago and was told that the nasal bone is not showing up which puts me at higher risk for a baby with Down Syndrome. I have yet to have someone tell me how much of an increased risk. I did not have the 1st trimester screenings as I've always said that it wouldn't make any difference but now that it's staring me in the face I am seriously considering an amniocentesis. I just wonder if I can go through the next 19 weeks wondering. Can you tell me what my risk is for a Down Syndrome baby? Thank you.
Posted by Tamsen to Fruit of the Womb at Wed Sep 02, 04:48:00 AM 2009

Previously we published a post that discussed the role of assessment of the fetal nasal bone in first trimester screening for fetal chromosomal abnormalities and, in particular, screening for Down syndrome (trisomy 21). Confirmed absence of the fetal nasal bone in first trimester has been correlated with a detection rate for Down syndrome in the range of 70% (with false positive rates dependent on maternal ethnicity – 2.2% in causcasians; 5% in Asians; and 9% in Afro-Carribeans) (Cicero, et al. Ultrasound Obstet Gynecol. 2003;21:15–18; Prefumo, et al., BJOG 2004; 111:109–112). Although determining the presence or absence of the nasal bone can clearly contribute to the risk assessment in first trimester, unfortunately, the technical difficulty of reliably obtaining an image and accurately interpreting the findings have led to more restricted use here in the U.S., even at many major academic centers.

In contrast, in midtrimester genetic screening, often done at 18-20 weeks, the finding of an absent nasal bone and to a lesser degree a hypoplastic nasal bone, is becoming more widely recognized as a major ‘marker’ for trisomy 21. In midtrimester, complete absence of the fetal nasal bone occurs in about one-third of Down syndrome babies. If a ‘short’ nasal bone (nasal bone hypoplasia), is included in the evaluation, 60% or more fetuses with Down syndrome may be detected, again with false-positive rates depending on ethnicity and the variable cut-off values for defining a “short nasal bone” in different studies (Bromley; et al., J Ultrasound Med 2002; 21:1387–1394; Bunduki; et al., Ultrasound Obstet Gynecol 2003; 21:156–160; Lee, et al., J Ultrasound Med 2003; 22:55–60; Gamez, et al., Ultrasound Obstet Gynecol 2004; 23:152–153).

One small study using 3D ultrasound found an absent nasal bone in 9 of 26 babies with Down syndrome (34.6%) and only 1 of 27 (3.4%) chromosomally normal babies, but this also meant that 9 of the 10 (90%) babies in whom complete absence of the nasal bone was found had Down syndrome (Goncalves, et al., J Ultrasound Med 2004;23:1619-27). In a recent study of 4373 babies evaluated in midtrimester, complete absence of the nasal bone was found in about 30% of Down syndrome and only 1% of chromosomally normal fetuses . (Odibo; et al., Am J Obstet Gynecol 2008;199:281.e1-281.e5). Nasal bone hypoplasia, defined in this study as <0.75 MoM, identified 47% of Down syndrome pregnancies and occurred in 6% of normal pregnancies.

So, to our reader, I cannot give a precise estimate of increased risk based on the ultrasound findings you report. However, if the ultrasound was performed by an experienced examiner and adequate images were obtained for evaluation, the complete absence of a fetal nasal bone at 21 weeks, even as an isolated finding, is disconcerting. The risk for Down syndrome could be as high as 90% and the false positive rate 5% or less. And, if you really need to know whether or not your baby is affected, an amniocentesis would be the best way to get that information. Best wishes and please let us know what you find out.
Dr T

Labels: Down syndrome, nasal bone assessment, nasal bone hypoplasia

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Urinary Tract Infections with Group B Streptococcus (GBS) During Pregnancy

The following comment was recently left on my previous post "Misunderstanding Group B Streptococcus (GBS)":

Hi - I am getting a little confused about Group B Strep (GBS) and UTI (urinary tract infection) information. Hoping you can help me clarify. I am 7 weeks pregnant and was just diagnosed with a UTI with GBS (asymptomatic - it was done as part of my first visit screen). The nurse called and wants me to start ampicillin (5oo mg 4x/day for 7 days) immediately. I have currently taken no medication (not even a tylenol) during this pregnancy (my first). I keep reading that GBS does not require treatment but then saw that it may with a UTI - I did not know symptomless UTI's were possible. I am very much wanting to not take any medication - your thoughts on this are greatly appreciated.

One of my very first posts here at “Fruit of the Womb” addressed Group B Streptococcus (GBS) infections and pregnancy. This is a topic that is worth revisiting periodically and the questions from today’s reader raise concerns that are shared by many women during pregnancy.

GBS is a bacterium that colonizes the urogenital and lower gastrointestinal tracts in as many as one-third of all healthy reproductive age women. It is the leading cause of serious bacterial infection in newborns and is often transmitted to babies at the time of delivery. Indeed, 8,000-12,000 babies per year in the U.S. will develop complications related to GBS and approximately 2,000 infants will die from their infections. There are several well-known situations in which babies are at increased risk for developing a serious GBS infection including:

• Premature labor or rupture of membranes before 37 weeks
• Prolonged rupture of membranes (18 hr or longer) before delivery
• Fever in labor (100.4F or higher)
• History of GBS urinary tract infection during the pregnancy (4-fold risk)
• Previous baby affected by GBS disease (increases risk 10-fold!!!)

Today’s reader had an asymptomatic UTI with GBS detected at her first prenatal visit during routine screening. We do NOT know why some people carry GBS and others do not, and we are not entirely clear why far more women actually carry the bacterium than are at risk for having a baby with a serious complication related to it, although the maternal immune response to the bacterium probably plays a key role. However, we do know that GBS UTIs place women in one of the highest risk categories for pregnancy complications (preterm labor; premature rupture of membranes; subclinical premature cervical change in the continuum of ‘cervical incompetence’; chorioamnionitis) and for transmission of GBS to the baby at the time of delivery and even prior to the onset of labor (CDC, MMWR May 31, 1996;45:1-24 ). Interestingly, women with GBS UTIs are also at greater risk for hypertensive disorders in pregnancy, anemia, and for babies that are not only premature, but ‘small for gestational age’ (Schieve, et al., Am J Public Health 1994;84:405-410).

UTIs caused by GBS occur in about 5% of women. Many women are asymptomatic or confuse symptoms of pregnancy with subtle symptoms of urinary tract infections (pressure; suprapubic discomfort; frequency; and urgency). However, asymptomatic UTIs can still subject the pregnancy to the risks of the complications mentioned above. Even after treatment, asymptomatic or symptomatic UTIs will recur in as many as one-third of all pregnant women. The source of the ‘reinfection’ is usually the patient’s own lower gastrointestinal tract in which antibiotic therapy of the UTI is ineffective at eradicating colonization. Women with GBS UTIs are usually considered to be more heavily colonized and are at greater risk for persistent and recurrent GBS infections (CDC, MMWR August 16, 2002;51:1-22). They are also at greater risk for developing significant bladder and kidney infections (pyelonephritis), the latter of which may occur in as many as 50% of women who begin with an untreated ‘asymptomatic’ UTI and can be life-threatening, leading to sepsis, adult respiratory distress syndrome (ARDS), and even death during pregnancy. It is the current recommendation that women with symptomatic or asymptomatic GBS UTIs detected during pregnancy should be treated at the time of diagnosis (CDC, MMWR May 31, 1996;45:1-24).


There are 5 major serotypes of GBS (Ia, Ib, II, III, and V). All are capable of causing both maternal and neonatal disease. Babies born to women who do not have antibodies to types II and III seem to be at greater risk for complications. Indeed, at some point, this may be one of the primary factors we can use to differentiate pregnancies at risk from those which are less so. A recent study has shown that serotypes V, Ia, and III are most often associated with asymptomatic and symptomatic UTIs (Ulett, et al., J Clin Microbiol. 2009;47:2055-60). About two-thirds of serious GBS infections are apparent at the time of delivery and 90% of babies who will develop complications do so within the first 48 hr after delivery. This is generally referred to as “early-onset” GBS infection and technically is used to define disease occurring in the first week of life. “Late-onset” disease, frequently associated with serotype III, affects another 10% of newborns, often presents as meningitis with septicemia, and rarely occurs after one month of age. Up to one-third of the survivors of GBS meningitis will develop long-term physical and/or neurological handicaps and in 1 of every 8 of these babies, the handicaps will be severe.

Unless you are in one of the high risk groups noted above, the goal of prophylactic antibiotic therapy during labor in those who are found to be colonized with GBS during their pregnancies is to deliver antibiotics to the mother early enough in the course of labor that sufficient drug can be transferred across the placenta to achieve protective levels in the baby prior to birth. That means, the antibiotic selected must not only be able to kill GBS, but it must also be able to cross the placenta. Fortunately, GBS has not yet been found to have developed resistance to the antibiotic of choice, penicillin G, and this drug also readily crosses the placenta. It also has a long and proven safety record for the baby. Ideally, antibiotic therapy is begun, intravenously, at least 4 hr prior to delivery so that at least one or two doses can be administered before the baby is born. If a woman has a serious allergy to penicillin, other options for therapy exist and the risks and benefits of these are discussed in our previous post on this subject.

The important things are that your doctors did the right thing by screening you, they have identified a potential problem, and there is a well-proven means of significantly reducing the risks from that problem for both you and your baby during your pregnancy and at the time of your labor and delivery. Thanks for reading and for the good questions. Best wishes for the rest of your pregnancy!
Dr T

Labels: GBS and pregnancy, Group B Strep, urinary tract infection, UTI

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Polyploidy as a Cause of Early Pregnancy Loss

Probably one of the most popular series I have written over the past few years is the one on recurrent early pregnancy loss. There is not a week that goes by that I still don’t get inquiries related to that subject, most accompanied by the pain, frustration, sense of loss, and feelings of hopelessness for future fertility. There are several points I always remind readers and patients about whenever I have the opportunity to discuss their concerns: 1) In most cases, the tincture of time alone offers the answer to their prayers; 2) If specific reasons for their losses are found or suspected, these can often be addressed medically and/or surgically; 3) If specific reasons cannot be identified, there are reasonable approaches to ‘empiric therapy’; and, 4) If these approaches fail, the science of assisted reproductive technology (ART) has advanced to the point that it can often overcome most obstacles that stand in the way of fertility.

The other points I always mention in response to the questions of “Why did this happen to me?”, “What did I do wrong to cause this?”, “What can I do to assure that it never happens to me again?, particularly to couples who have had their first or second miscarriage, or a sporadic miscarriage after successful pregnancies, are the following: 1) Miscarriages occur in 15-20% of all conceptions; 2) The MOST COMMON cause of early pregnancy losses are chromosomal abnormalities that occur by chance (except in the case of parental chromosomal rearrangements) and are not under any controllable influences; 3) It is unlikely that anything was “done” to cause the loss, although if there are such potential factors identified, the loss may provide an incentive to modify lifestyle prior to another pregnancy attempt to minimize their risks.

Recently, I received the query below from a woman who has had early pregnancy losses related to documented chromosomal abnormalities. Despite the other problems that have been identified which might contribute to reduced fertility in her case, these probably had no influence on her babies’ chromosomal abnormalities. But, they do give us the opportunity to briefly discuss the well-known observations that certain seemingly “unusual” chromosomal abnormalities (“unusual” in that they rarely or never result in a live born baby) actually contribute to a relatively high percentage of early pregnancy losses.

At Fri Aug 07, 03:17:00 PM 2009, Anonymous said…
I've experienced my 2nd miscarriage in 4 months - my husband and I had undergone intrauterine insemination after over a year of unsuccessful pregnancy attempts. These were my first two pregnancies. I had a D&C both times to test the products of conception, and both times, the result was tetraploidy, 92, XXXX. After the first loss, I was tested for many of the miscarriage factors, and was found to have elevated anticardiolipins, so was on 2x daily heparin shots and baby aspirin for the second pregnancy. I'm 35, almost 36, and have been diagnosed with PCOS in the past year. I've been on 1500 mg metformin as well as my prenatals, folic acid supplement (and Vitamin D when I was on the Heparin). It looks like tetraploidy is a pretty unusual outcome; what could cause this, and what would be the next recommended steps for us? Is a normal pregnancy *ever* possible?

Thanks for your response.


To anonymous Aug 7:

Humans normally have 46 chromosomes (23 from each of their parents) in each of their cells, except in eggs and sperm (which end up with just 23). When we think of fetal chromosomal abnormalities, the ones that usually come to mind are those associated with one extra chromosome (trisomy) as in the case of Down syndrome (an extra chromosome 21 – or 47 +21) or one less chromosome (monosomy) as in the case of Turner syndrome (one less sex chromosome – 45XO). The most common factor leading to one extra or one less chromosome is an event called nondisjunction that results when a single chromosomal pair (not all 23 pairs) fails to separate during the formation of a gamete (egg or sperm). When a gamete with an abnormal chromosomal complement resulting from nondisjunction then gets together with a normal gamete containing 23 chromosomes, the resulting baby will end up with either 47 or 45 chromosomes and in the vast number of instances (even with Down and Turner syndromes) such pregnancies will not develop past an early stage and be lost as a ‘”blighted ovum” or “spontaneous abortion” (miscarriage) before the end of the first trimester. One of the most common trisomies found in 1 of every 12 to 15 first trimester losses, trisomy 16, never results in a live born baby.

Polyploidy on the other hand describes conditions in which there are additional whole sets of chromosomes. Triploidy has three complete sets (69 chromosomes) and tetraploidy has four complete sets (92 chromosomes). Triploidy occurs in 1 of every 12-15 early losses and teraploidy can actually be found in about 1 out of every 30 early miscarriages, so they are NOT that uncommon! Tetraploidy is believed to result when an unequal division of chromosomes in mitosis during early embryogenesis occurs and causes the cell to not complete the division into two separate cells, resulting in a single cell with 92 chromosomes rather than two cells each with 46 chromosomes.

Triploidy seems to occur by several mechanisms. At the risk of oversimplification, a triploid embryo can have either two set of chromosomes from the mother plus one set from the father or two sets from the father and one from the mother. In the former case, the mother contributes an abnormal gamete containing 46 chromosomes (rather than 23) and that gamete is fertilized by a male gamete containing the normal 23 chromosomes. This is termed digynic triploidy. When the father is the cause of the triploidy, this can result by two mechanisms: 1) fertilization of a normal egg by two sperm from the father (dispermy) or, 2) actual fertilization of a normal egg by a sperm containing two sets of chromosomes. When the father is the source of the extra set of chromosomes, this is termed diandric triploidy. The most common cause of triploidy appears to be the result of paternal dispermy. Whether of maternal or paternal origin, triploidy is associated with multiple fetal abnormalities and usually death of the baby in utero and in the few survivors to birth (usually those of maternal origin), death within the first year of life. Diandric triploidy is often associated with large placentas that have a "Swiss cheese” appearance (partial molar pregnancies) and digynic triploidy typically is accompanied by very small, noncystic, placentas and early fetal growth restriction.

With regard to the reader’s inquiry, I do not believe there is a familial tendency for tetraploidy to occur although the formation of tetraploid cells is a common intermediate found in the development of certain cancers. And yes, there is a very high likelihood you can have a successful pregnancy even with the other factors working against you! Best wishes and thanks for writing.
Dr T

Labels: aneuploidy, chromosomal abnormalities, nondisjunction, polyploidy, recurrent pregnancy loss, tetraploidy, triploidy

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Methotrexate - Easy to Use, Easy to Abuse

I received the two comments below from readers and use this opportunity of their tragic experiences to revisit a concern that I raised about two years ago regarding methotrexate therapy for the presumptive diagnosis of ectopic pregnancy….

Melissa O. said...

I was told I had an ectopic pregnancy and was advised I was in need of a Methotrexate shot. I got it. One week later my hormone level was continuing to rise. Low and behold 4 days later my ultrasound showed I was carrying twins. The Dr.'s had presumed ectopic too early. Getting the shot caused me to loose Twin A and to give birth to a very much underweight 28 weeker. This experience has changed my life forever. My son fought to survive...he continues to today now 13 months old. I would hope anyone who is told they have an ectopic pregnancy would be cautious when it comes to this shot. Yes I agree it helps if your life is in danger due to an ectopic pregnancy. Just take time to ensure there is no doubt that's what it is. My Dr couldn't see the baby so assumed ectopic, however carrying twins like I was you’re not able to see as early as a single pregnancy. My son is paying everyday because of my mistake and doing as one Dr. said make sure you have more than one confirmation, it could cost you a perfectly healthy baby in the end.
Fri Jun 19, 05:45:00 PM 2009

Anonymous said...
Hi can someone help me? My husband and I were trying for a baby and I fell pregnant (good news). I started having a few brown spotting and slight cramping which I was advised by my GP to go to the hospital for a scan. Whilst there I had many tests and the doctors thought it might be ectopic and said he was going to keep me in for a few days to monitor my blood levels. I had a scan but being only five weeks it was hard to say. I was referred to another doctor on the ward and he told me it was ectopic. I trusted his knowledge and he said he needed to give me methotrexate now as it was Friday so the pharmacy would be shut. I was shocked but agreed of course. 3 days later I was told the baby is still alive and is in my womb. My blood levels increased after 3 days and then decreased from 7000 to 6000 on the 7 days. How long will it take to lose my baby as it’s hard to know its alive?
Fri Jul 03, 11:15:00 AM 2009

Ever since methotrexate became popular for treating ectopic pregnancies, I have seen the unfortunate scenario reported by our readers above played out time and time again. Methotrexate (MTX) is an analog of folic acid. It binds tightly to an enzyme called dihydrofolate reductase and when it does so, interferes with the production of tetrahydrofolates. In the end, this interferes with the normal production and repair of DNA by limiting the production of a key nucleotide, thymidine. Other metabolic effects are also known, but the take home message is that MTX can result in lethal damage to cells that are replicating, particularly those that are replicating rapidly, like certain cancer cells.

Because of its documented efficacy in the treatment of malignant trophoblastic cells (choriocarcinoma), MTX has been employed in recent years as an alternative to surgical therapy in selected cases of ectopic pregnancy (Lipscomb, et al. NEJM 2000;343:1325-29). Ectopic pregnancies, by definition, implant ‘outside the uterus’ with more than 95% occurring in the fallopian tubes and about 2.5% in the cornua of the uterus (where the fallopian tubes enter the uterus). For that reason, they are frequently referred to as ‘tubal pregnancies,’ although they can also occur in the cervix, ovary and intraabdominally. The fallopian tubes cannot restrict the growth of invasive placental tissues, as can the endometrium, and they certainly cannot accommodate a growing embryo beyond a certain point before they rupture and hemorrhage. Indeed, ectopic pregnancies can be quite deadly if not treated appropriately. They are still a major cause of maternal mortality, accounting for 10-15% of all maternal deaths, and they are the leading cause of death in pregnant women in the first trimester. A ruptured ectopic pregnancy is a true medical emergency.

Because of the rising incidence of ectopic pregnancy, the risk (maternal and medical-legal) of not identifying and treating an ectopic pregnancy in a timely fashion, and the widespread acceptance and success of MTX therapy as an alternative to surgical management of an ectopic pregnancy if caught early enough, there has been a coincident increase in the inadvertent use of MTX in unrecognized early intrauterine pregnancies. The usual scenario is one in which the pregnancy is not quite as far along as anticipated and the patient happens to present with complaints of abdominal pain or some spotting and no clear intrauterine pregnancy is identified by ultrasound. The ‘absence’ of an intrauterine pregnancy can be misdiagnosed because the pregnancy really is too early, but in at least one of the scenarios above was more likely the result of the inexperience of the individual(s) performing the ultrasound study. This situation can be especially confusing if the pregnancy hormone levels (hCG) appear to be low for the expected gestational age based on last menstrual period (as is often seen in women who ovulate later, and hence conceive later, in their cycles) or if a woman has a tender adnexal mass because a hemorrhagic corpus luteum (intraovarian bleeding at the site from which the egg was ‘hatched’) or torsion of an adnexal mass (rare this early in pregnancy) which might be very difficult to differentiate from an ectopic pregnancy.

Since MTX is a category X drug, known to be teratogenic in humans, it is important to ascertain the presence of an ectopic pregnancy rather than simply to use it empirically. Unfortunately, its use in advertently with an intrauterine pregnancy is most likely to occur during the time of neural tube and very early cardiac development, both of which rely on folate-dependent pathways. Various algorithms are in place that employ ultrasound imaging, quantitative hCG levels, and progesterone levels to differentiate abnormal from potentially normal pregnancies and these protocols can be useful in minimizing the chance of the inadvertent use of MTX and also in directing its use when appropriate for the management of an ectopic pregnancy. Perhaps the greatest risk of ectopic pregnancy is not suspecting that one could be present. Patients who are adequately counseled and followed closely are much less likely to end up in emergency situations.

To our readers above, I am SO SORRY for both of you. This is a failing of the medical system and is a growing concern of mine due to the ready accessibility and simplicity of use of methotrexate (and also another drug, misoprostol, that is used in the 'medical evacuation' of the uterus when an inevitable miscarriage is suspected). My feeling is that it should never be used in an asymptomatic or minimally symptomatic patient until either an ectopic pregnancy is seen, no intrauterine pregnancy is documented (by a competent sonographer) at hCG levels where an intrauterine pregnancy should readily be visible, the patient has significant 'risk factors' for an ectopic pregnancy (e.g., previous ectopic, known history of pelvic inflammatory disease or tubal reconstructive surgery) or when there are well-documented abnormalities in the rise of hCG that are highly suggestive of an ectopic pregnancy. My heart goes out to both of you.

Kind regards,
Dr T

Labels: Ectopic pregnancy, folate metabolism, methotrexate therapy

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