Celiac Disease and Pregnancy

In our last post, we responded to several questions from a reader named Kate concerning the implications of low PAPP-A levels detected during the course of first trimester screening for aneuploidy. Not addressed in our last post were her two other comments: Is there a correlation with celiac disease and placental health or low PAPP-A levels? I have read reports of celiac disease causing many of same risk factors associated with low PAPP-A.

To begin to address these issues, it is important to discuss first what celiac disease is to better understand how it might have an impact on pregnancy. Celiac disease (CD) is the result of intolerance of the gastrointestinal tract to gluten. Gluten is a protein contained in wheat, barley, and rye and is therefore present in many cereals, pasta, flour, breads and as an additive in many processed foods, medicines, vitamins, and even lip balm. As the consequence of an abnormal immune response (with production of antibodies such as antigliadin type IgA and IgG and IgA antitransglutaminase), individuals with CD damage their own intestinal villi that are necessary for the absorption of nutrients into the blood stream. Thus celiac disease can result in not only gastrointestinal symptoms, but malabsorption and nutritional deficiencies that can have significant consequences on the long-term health of an individual if CD is not recognized and treated. However, the complications related to CD can be dramatically reduced by strict adherence to a “gluten-free” dietary regimen.

The tendency to develop CD appears to be genetically inherited but there is a great variability in age of onset, severity of symptoms, and consequences of the condition even within families. Fasano and colleagues (Arch Int Med 2003;163:268-92) estimated that in the U.S., about 1 in 133 people have CD. Rodrigo reported (World J Gastroenterol 2006;12:6585–6593) that 4 to 12 percent of an affected person’s first-degree relatives will also have the disease. Gastrointestinal symptoms of CD include abdominal pain and bloating, chronic diarrhea, pale, foul-smelling and fatty stool, occasionally vomiting and constipation, and weight loss. Even in the absence of significant gastrointestinal complaints, individuals with CD may develop conditions such as iron deficiency anemia, osteoporosis and bone pain or arthritis, chronic fatigue, depression, anxiety, numbness and tingling in the hands and feet, oral ulcers, and even seizures. Dermatitis herpetiformis, an itchy, blistering skin rash, affects 15 to 25 percent of individuals with celiac disease. CD has even been implicated in menstrual irregularity, infertility, and recurrent early pregnancy loss. There is also an association of CD with chronic liver disease and intestinal cancer.

With all that said and done, let’s begin to look at the consequences of celiac disease for pregnancy. Nørgård and colleagues (Am J Gastroenterol 1999;94:2435-40) reviewed birth outcomes in Danish women with CD between 1977 and 1992. They found that before women were first treated for CD there was an increased risk of low birthweight (odds ratio [OR] = 2.6, 95% CI = 1.3-5.5) and intrauterine growth retardation (OR = 3.4, 95% CI = 1.6-7.2). Pregnant women who were given dietary counseling before delivery had no increased risk of low birthweight and no babies with intrauterine growth retardation. Therefore, treatment of women with CD is important in the prevention of fetal growth retardation. Similarly, Ludvigsson and colleagues (Gastroenterology 2005;129:454-63) compared pregnancy outcomes in 1149 offspring of women diagnosed and treated for CD prior to birth and 929 offspring to women diagnosed after delivery. They found that “undiagnosed CD was associated with an increased risk of intrauterine growth retardation (OR = 1.62; 95% CI: 1.22-2.15), low birth weight (OR = 2.13; 95% CI: 1.66-2.75), very low birth weight (OR = 2.45; 95% CI: 1.35-4.43), preterm birth (OR = 1.71; 95% CI: 1.35-2.17), and caesarean section (OR = 1.82; 95% CI: 1.27-2.60). In contrast, a diagnosis of CD made before the birth was not associated with these adverse fetal outcomes.” Again, the risks of CD, at least with regard to fetal growth, can often be dramatically reduced by identification and treatment of women with CD.

However, because CD is the result of an aberration of the immune response, reminiscent of that seen in autoimmune conditions, the questions remain, could this abnormal immune response also contribute to poor pregnancy outcome in ways other than impairing fetal growth and what are the mechanisms of the impairment in growth and perhaps other suboptimal pregnancy outcomes in women with CD? It is well-known that people with CD are at greater risk for having or developing other autoimmune conditions such as type 1 diabetes, autoimmune thyroid, liver and adrenal disease, and other autoimmune conditions such as rheumatoid arthritis and Sjogren’s syndrome. Conceivably, autoantibodies causing these conditions could cross the placenta to the baby and cause complications. Indeed, in the case of Sjogren’s syndrome, this is often associated with the production of antibodies (anti-Ro (SS-A) and anti-La (SS-B)) that can cause congenital heart block and cardiac malformations.

Although an association of CD with systemic lupus erythematosus and antiphospholipid antibody syndrome has not been widely recognized, there have been very recent case reports of the same (Gupta, et al., Rheumatol Int. 2008;28:1179-80; Jorge, et al., Rev Esp Enferm Dig 2008;100:102-3). Furthermore, the presence of anticardiolipin antibodies have been demonstrated in some patients with CD (Karoui, et al., Dig Dis Sci. 2007;52:1096-100) and CD antibodies have been demonstrated in some patients with antiphospholipid syndrome (Shamir, et al., Lupus 2004;13:214)! If this holds true, there is a subpopulation of pregnant women with CD who will be at increased risk for thromboembolic complications and, perhaps, abnormalities of placentation that could lead to intrauterine growth restriction, pregnancy-induced hyperetensive disorders, premature delivery, and even ‘unexplained’ fetal death. And, to answer Kate’s question, when this is associated with an abnormality of placentation, there is a very good chance that first trimester PAPP-A levels will be on the low side – indeed, perhaps we should be screening for CD in women with low PAPP-A and also we should consider screening of women with known CD for PAPP-A to possibly help identify that subpopulation of women at risk for the pregnancy complications we have noted above.

Diagnosis of CD is usually made by the detection of anti-tissue transglutaminase (tTGA) and anti-endomysial (EMA) antibodies in the blood (and confirmed by duodenal biopsy). Anti-gliadin antibodies can also be demonstrated in many individuals with CD. The question then arises, could these CD-associated antibodies cause damage to the placenta and/or the fetus and compromise pregnancy outcome? Robinson and colleagues (Placenta 2006;27:148-57) have demonstrated that tissue transglutaminase (tTG) protein and mRNA are expressed in stromal cells and trophoblasts in first trimester and at term, with higher levels later in pregnancy and suggested that this could be a target for CD-associated antibodies. To support this hypothesis, Bustos and colleagues (Am J Reprod Immunol 2006;55:201-7) have shown that the prevalence of positive antibodies for antigliadin type IgA and IgG and IgA antitransglutaminase in women with recurrent pregnancy loss RPL was significantly higher than controls (P < 0.04).

In a very interesting article, Hadziselimovic and colleagues (Fetal Pediatr Pathol 2007;26:125-34) looked at the amount of gliadin that was present in term placentas of compliant (women who maintained a gluten-free diet) and noncompliant CD patients and correlated that with placental damage to the extravillous trophoblasts and fetal birth weight. They described the extravillous trophoblasts in the noncompliant women as being “overloaded with gliadin” whereas there was moderate to no gliadin present in the controls. “The weight of newborns was lower if extravillous trophoblasts were loaded with gliadin (-2.24SD) (p = 0.004)” and there was increased apoptosis (cell death) of the trophoblasts in the placentas of the noncompliant women.

In conclusion, there appear to be various mechanisms by which CD might deleteriously affect pregnancy outcome, and perhaps others we have not yet explored, such as specific nutrient deficiencies that might lead to certain fetal anomalies. The ‘autoimmune’ component of CD seems to play a major role in terms of fetal growth impairment as pregnancy progresses and perhaps by increasing the risk for early abnormalites of placentation that could contribute to both early pregnancy loss and later pregnancy complications. The reassuring point we can glean from the literature regarding CD and pregnancy is that strict adherence to a gluten-free diet appears to overcome many of the risk factors that have been correlated with CD. I wish that could be true for some of the other major pregnancy complications we face on a regular basis!

Labels: celiac disease, PAPP-A

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Low PAPP-A and Celiac Disease in Pregnancy

One of the reasons I love the comments we get from our readers is that they often make me look at pregnancy-related conditions and complications from a different perspective. I stated from the outset of this blog that I was looking forward to participating in the learning experience with our readers. Such is the opportunity afforded to us by Kate’s concerns below…

Kate said...

Dear Dr.T,
I have been following your site and articles ever since my NT (nuchal translucency - combined first trimester screening) and your information, insight and attentive responses to your readers have been exemplary. Thank you SO much for writing and responding to all of us! I am 36 years old with my first baby and currently 16w3d. No history of smoking or drinking. At my NT everything looked good: my Down’s risk was 1:800 and trisomy 18/13 1:7000. I did not need to do an amnio. However my PAPP-A was .44MOM (10th percentile). I also have "suspected" Celiac disease which I will be retested for later.

I have been concerned with this low PAPP-A and when I asked my OB she was not very helpful. So in reading you articles I have gained insight but have further questions:
1) The report said my .44MOM was at 10th percentile...yet I saw many other readers with .4 etc. and were considered 5th percentile (which is a percentile cited as of concern)...am I marginally at 10th percentile and is there a big difference? Should I be concerned?
2) Is there correlation with celiac disease and placental health or low PAPP-A levels? I have read reports of celiac disease causing many of same risk factors associated with low PAPP-A.
3) The other day, I felt a gush of fluid and went to the OB where she tested me for amniotic fluid. She only did a Nitrazine and "thought" all was fine. I revisited PAPP-A levels and their correlation with PROM (premature rupture of membranes)...do you have any insight or advice on this? As a first time mom, I don't even know what a gush of amniotic at 16 weeks might feel like. But moreover...I am concerned about PAPP-A, celiac disease , and PROM.
Many thanks Dr. T!

To Kate:

Let me briefly answer the first and third questions before spending more time with the second in another post. Multiples of the median (MoM) are a measure of how far an individual test result deviates from the median. The ‘median’ is the middle of a distribution: half the scores are above the median and half are below the median. It is less sensitive to extreme values than the mean and this makes it a better measure than the mean for highly skewed distributions. The median is found by arranging all the observations from lowest value to highest value and picking the middle one. MoM is commonly used to report the results of medical screening tests, as is done with the concentrations of the maternal serum markers in both first and second trimester screening tests during pregnancy, where the median is highly variable and dependent on the gestational age. This allows comparison between laboratories and helps to ‘standardize’ interpretation of tests for sake of comparison that may be performed differently in different laboratories. In your case, the MoM for your PAPP-A value at 16 3/7 weeks is 0.44. This is less than half the median for that gestational age and places you between the 5th and the 10th percentiles, but this is not what we consider to be extremely low as would be the case at the 1st percentile. In your case, I would not see that as cause for panic!

All that said and done, as we have discussed in previous posts, the further the PAPP-A is below the median, the greater the risk is for certain pregnancy-related complications such as intrauterine growth restriction, premature labor, unexplained fetal demise, pregnancy-induced hypertensive disorders, and cesarean delivery. However, on an individual basis, the absolute risk is difficult to predict and some women with extremely low PAPP-A values have none of these complications. In the case of preterm delivery, a recent article by Spencer and colleagues (Ultrasound Obstet Gynecol 2008;31:147-52) concluded that women with PAPP-A levels in the range of yours had about twice the risk of delivery before 37 and 34 weeks.

You do raise an interesting question though and that is related to the risk of premature rupture of membranes (PROM) and low PAPP-A. I had not heard, or even thought, about that association before you raised the question. Certainly, premature labor and delivery in general is often preceded by PROM, but in the case premature delivery in association with a low PAPP-A, we tend to think more in terms of this being necessitated by fetal and/or maternal complications. Interestingly, I did find and article by She and colleagues (Taiwan J Obstet Gynecol. 2007:46:242-7) that reported that low maternal serum levels of pregnancy-associated plasma protein-A during the first trimester are associated with subsequent preterm delivery with preterm premature rupture of membranes and the authors concluded that this may be the result of “a trophoblast invasion defect in the maternal-fetal interface” which sets up the series of events leading to both PROM and preterm labor.

So Kate, thanks for the great questions and we will continue with your concerns related to celiac disease and pregnancy in our next post. And, to all our readers, have a very HAPPY THANKSGIVING!

Labels: celiac disease, PAPP-A

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Oral Contraceptives and Infertility?

Hello to all my readers and Happy Thanksgiving! It has been about a month since I have managed to get any of your comments in my mailbox and I am afraid ‘Blogger’ is still having problems in that I cannot respond to about half of the questions I have received. Included in the batch I did receive is the comment from Andria below. She expresses concerns about one of the common myths and misconceptions related to oral contraceptives – that they can actually cause infertility if taken regularly or for ‘too long’….

Andria said...

Hi, I'm 22 yrs old and I'm a little worried that my body has gotten dependent on my birth control pills. After I had my very first period, I never missed one. I did know much about keeping track of them; I just knew it came every month, just not around the same time every month. When I first started taking my pills I took them for a few months then stopped. I always heard if you took them for too long you could become sterile. So I would take a break from them and then get back on them. Last year when I stopped taking the pills I only had 3 periods that year. I wasn't sexually active. I went to my doctor, but he just prescribed me some pills to bring down my period then told me to start taking my pills again. I did, and then stopped in January. I've only seen my period once since July. I took a home pregnancy test yesterday just to rule out pregnancy, but I'm starting to wonder if I will be able to get pregnant if to have a regular period I need to be on my pills since once I stop taking them, it has now disappeared. Any help will be appreciated.
Fri Oct 24, 02:30:00 AM 2008

Kenneth F. Trofatter, Jr., MD, PhD said...

To Andria Oct 24: The pills do not cause sterility. According to your history, you had irregular menstrual cycles even before you started on birth control pills. It is unlikely that even starting and stopping the pills as you have been doing (which is NOT recommended), has caused your current absence of menstrual periods (amenorrhea). It is much more likely that you are not ovulating regularly (oligoovulatory) or not at all (anovulatory) and this is the result of some underlying 'hormonal imbalance' that preceded your use of the pills and is worsening with time. The most common cause of this is polycystic ovary syndrome (PCOS), but you could also have a thyroid disorder, hyperprolactinemia, or other factors that are contributing to your problems. My suggestions are that you should be evaluated for these conditions and then to stay on the pills faithfully until you are ready to get pregnant. You should also see a doctor before you try to conceive to get suggestions for improving your prospects for a good pregnancy outcome and to help you get pregnant if you are still not ovulating regularly.

Even women who do not have menstrual irregularity prior to use of oral contraceptives, may have some aberration of their menstrual cycles after discontinuing birth control pills. More than half will ovulate (and have a ‘normal’ period) within 4-6 weeks after stopping the pills. However, some women may have prolonged or somewhat irregular cycles for up to a year afterwards before resuming their normal cycles. This is more common in women who are older or who have never had children.

There do not appear to be a long-term effects of oral contraceptives in terms of impairing fertility. Indeed, some women with ovulatory irregularity and infertility may benefit from a period of oral contraceptive use prior to attempting conception due to their suppressive effects on the hypothalamic-pituitary axis and ovarian function, particularly women with PCOS and perhaps those with endometriosis. Furthermore, oral contraceptive use has the benefits of being associated with a decreased risk of cervical, ovarian, and uterine cancer.

Best wishes. Dr T
Sat Nov 22, 04:58:00 PM 2008

Labels: oral contraceptives and fertility

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Prematurity Awareness Day - 2008

Today is Prematurity Awareness Day. At a local press conference sponsored by the March of Dimes, I had the opportunity to discuss some of my thoughts on this subject with a reporter. When I started my residency, the prematurity rate sat between 8% and 9%. Today one in every eight babies (530,000 per year) in the U.S. is born prematurely and in my home state of South Carolina the rate is even higher – one in five to six babies. (Incidentally, during the same time period since my residency, cesarean delivery rates have gone from about 12% to 35%).

Complications related to prematurity now make it the leading cause of death among newborns and during the first year of life – now surpassing birth defects. This holds true despite the remarkable advances that have been made in neonatal care that have pushed survival into the range of 23 weeks gestation. In general, first year medical costs for preterm babies across the board are at least 10 times greater than that for babies born at term. The 2006 Institute of Medicine special report, “Preterm Birth: Causes, Consequences, and Prevention,” concluded preterm birth costs our nation $26 billion annually. Factoring in the continued rise in preterm birth as a percentage of all deliveries, the population increase, the immediate expense related to the acute care of extremely premature neonates (and the ongoing expenses due to complications of prematurity among survivors), the enormous number of late preterm deliveries (and their ongoing expenses due to complications of prematurity!), and the inflation in health care costs, I would wager that the total cost is now much more than twice that annually.

Despite the fact that we have a long list of factors that we know are associated with increased risk for preterm birth, we continue to lose ground in the battle against it. Funding for women’s health initiatives related to prenatal care is inadequate, educational programs that focus on planned pregnancy, preconceptional counseling and early entry to prenatal care, adequate nutrition and weight control, stress reduction, cessation of smoking and other substance abuse, are not widespread enough (nor begun early enough in life), and efforts to scrutinize and control the high rates of labor induction, as well as primary and repeat cesarean deliveries are thwarted by providers, hospitals, and patients themselves.

Especially frustrating to me are the factors over which we could have a significant impact, but where we are falling further and further behind: teen pregnancy rates are the highest they have been in years; obesity is morbidly epidemic and beginning younger and younger in life; patients in our area are presenting later for prenatal care (forget preconceptional care); racial disparities in preterm birth rates are widening; more than 20% of pregnant women in South Carolina continue to smoke; access to care is being deleteriously affected by Medicaid cuts, poorly-controlled Managed Medicaid programs, and a growing percentage of underinsured and completely uninsured women in their reproductive years; and reimbursement for providers of obstetrical care is inadequate to cover expenses when one factors the total amount of time required in patient management during the pregnancy, labor, and delivery and the liability risks and overhead costs associated with that care.

Personally, I support and applaud the efforts of the March of Dimes to address the many issues related to preterm birth. Since 2003, the organization has focused its attention on raising public awareness and expanding programs that provide information and support to families affected by preterm birth. But, this is an effort that will require support, financially and organizationally, at a much higher level if the dismaying trends are to be reversed and a true impact realized.

The first step in this is not necessarily underwriting large research programs to identify the ‘cause’ or a ‘treatment’ for preterm birth. Preterm birth is not a disease, it is the final common pathway of the many factors that variably contribute to it in different individuals. We must, however, continue the efforts by groups such as the March of Dimes to educate patients, providers, employers, and politicians regarding the extent of the problem and its long-term consequences on the health, healthcare costs, and welfare of our people. We must also focus our attention on preventive and ‘therapeutic’ programs to address some of the major issues mentioned above – programs that will improve the general health of women in their prereproductive and reproductive years – improving the prospects that their children will not be destined to repeat the cycles of the prior generations.

Labels: preterm birth; late preterm birth

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Blogger Problems!?!

Just a quick note to all my readers...I know many of you have tried to leave comments and would like my responses, but there apparently are some 'blogger problems' that are beyond my control and as yet unresolved. I do not have the opportunity to preview and select what appears in the 'Comments' sections of my posts. Once you submit a comment, it is screened by someone at Healthline and then forwarded to me. Once I answer it, both the comment and my response appear under the post at which the original comment was left. None of the comment threads are closed, so you can leave a question or response under ANY of the posts you read and, theoretically, it will get to me. It is then YOUR responsibility to remember where you left it if you want to see my response!

Unfortunately, not only have there been problems getting your comments to me, but when they do arrive in my box, they are not always in a format to which I can then respond. I imagine ALL the comments you have left are in cyberspace somewhere and will probably appear in my mailbox at some time in the near future and all at once. Please do not leave the same comment repeatedly or under several different posts since blogger is already constipated and I don't want him/her to explode.

Thanks for your indulgence and patience. I promise to get back to you soon with a series of new posts. I think we finally have a shot at getting a new Chair of our department in the near future and that would relieve me of my administrative distractions! It has been a VERY long year for me and I am looking forward to getting back to the things I enjoy doing the most - especially you guys!

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Prothrombin G20210A Mutation

As we have written about on several occasions, pregnancy loss is a very traumatic experience for many couples and their families – especially when there are recurrent episodes of loss. It is a basic human need to seek an explanation for such events, partly as a means of gaining closure and partly in the hope of finding a condition that can be treated, thereby improving prospects for another pregnancy. Although evaluation of the couple with pregnancy losses will sometimes identify a specific reason for the losses, in many instances, no concrete etiology is found. During the process of evaluation, it is not unusual to identify factors that may or may not be contributing to the problem, or that might have some other implications for the health of the woman who has experienced pregnancy losses. The reader below may well fit into this latter category and represents the plight of many women who are evaluated for recurrent pregnancy loss…

Karen said...

Dr. T - I am 39 years old. I have a 16 year old son who was born at 24 weeks due to a placental abruption (he is perfectly fine today) and a 3, 2 and 1 year old from my current marriage. We wanted to have one more child and had 2 miscarriages this year. The 2nd miscarriage was at 15 weeks and my OB tested me and we found out I have Prothrombin G20210A gene mutation, a blood clotting disorder. I'm somewhat confused how my last 3 children were born with no problems other than I have an incompetent cervix. At my age, is this clotting disorder a high risk to my health/life? I would love to have another child, but I also REALLY want to be here for the 4 I have now. I'd love to hear your thoughts.

Karen

Kenneth F. Trofatter, Jr., MD, PhD said...

To Karen:
It is less likely the Prothrombin G20210A mutation had anything to do with your two miscarriages in view of your previous obstetrical history apart from the miscarriages. Much more common causes at your age are chromosomal abnormalities of the babies, an intrauterine abnormality such as a fibroid, scar tissue, or polyp, a hormonal abnormality such as thyroid disease, or an autoimmune condition. You have not told me the extent of your evaluation for “thrombophilias” that could contribute to your pregnancy losses, however, I am presuming you were at least screened for the more common genetic and acquired thrombophilias that have been variably linked to pregnancy loss and poor pregnancy outcome based on the fact you were identified as being a carrier of that prothrombin mutation.

About 2% of the population is heterozygous (carrying one dose) of the prothrombin mutation G20210A. This and the Factor V Leiden mutation are the two most common genetic causes of thrombophilia. Having the prothrombin mutation increases the risk of developing deep venous thrombosis (DVT), usually the result of a blood clot in the deep veins in the legs, and pulmonary embolus (PE) - a blood clot that travels to the lungs, usually from DVT - from approximately 1 in 1000 people to 2-3 in 1000 people each year. Having homozygous prothrombin mutations increases the risk even more. However, many people with the prothrombin mutation will never develop a blood clot in their lifetime. Factors that increase risk include age, pregnancy, obesity, family history of DVT/PE, smoking, diabetes, and the presence of other thrombophilias among many others.

So, those are my thoughts. The best thing you have going for you is the OB history of successful pregnancies in the past. If your doctor chooses to treat you during pregnancy to prevent venous thromboembolic events, at this point no more than prophylactic therapy is indicated. Good luck and thanks for writing.
Dr T

Labels: prothrombin mutation, recurrent pregnancy loss, thromboembolic complications and pregnancy, thrombophilias

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