Fruit of the Womb

Intrahepatic Cholestasis of Pregnancy Warrants Aggressive Diagnosis and Treatment

2010-04-20T17:05:00.000-07:00

Anonymous has left a new comment on your post "Intrahepatic Cholestasis of Pregnancy - A Bitch of an Itch...":

Dr. T,
This is Amanda I commented a while back and I am now 26 weeks into this pregnancy and I had my doctor do some blood work because my symptoms are back for the ICP (intrahepatic cholestasis of pregnancy). All I have heard so far is the liver enzymes and they were 317 and 325. My question is what is the earliest you have ever seen an ICP baby delivered. I am worried that they might have to take this baby really early. My doctor said the enzymes are higher right now then they were in my 36th week of my last pregnancy. I am not having to much itching yet. We are waiting to hear from the Bile Acids, but he went ahead and started me on Urso(deoxycholic) acid 250mg one tablet two to four times a day. Does that dosage sound correct, because he had no clue how to give it. In my last pregnancy the ICP was diagnosed so late in the pregnancy we decided the Urso wouldn't have time to start helping. Is there anything else I should do, like to help prevent a delivery before 36 weeks?

Amanda,
Your liver enzymes are already more than modestly elevated for ICP. Has your doctor ruled out other causes for this? At the least I would suggest a gallbladder ultrasound, screens for hepatitis B and C, a complete blood count, LDH, amylase, lipase, and serum bilirubin levels. Sometimes an autoimmune hepatitis can present this way as well. If the bile acids are elevated and no other source for hepatic cholestasis is found then this is very likely a genetic form of ICP. I would suggest starting with an Urso dose of 500 mg twice daily. That can be increased if your symptoms worsen. Here is a link that will provide you with some more information on ICP and other things you might try to improve the discomfort of the condition (http://www.americanpregnancy.org/pregnancycomplications/cholestasispregnancy.html). Controlling the bile acids may be your best bet at keeping the baby ‘happy’ (ie, minimizing the risks for unanticipated fetal death) and delaying delivery until 36 weeks. Best wishes and let us know how things turn out.
Dr T

Combined First Trimester Screening for Aneuploidy Should be Just That - COMBINED

2010-04-19T17:19:00.000-07:00

GB has left a new comment on your post "Fetal Nasal Bone Assessment in First Trimester Scr...":

Hi Doctor T,

I had my NT scan at 12 w 4 days and following results.I am of Indian origin..

Age : 31
CRL 57.3 MM
NT 2.0 MM
FHR 152 bpm
Nasal Bone : Absent/Hypoplastic
Everything else including tricuspid valve flow was okay
Background Risk for Downs 1:750
Adjusted Risk:1:135

I subsequently had blood serum test which resulted ok as per labs
Free Beta HCG 1.617 MoM
PAPP A 2165
RE-ADJUSTED RISK based on blood1:956 now.
My OBs says that isolated NB is not a strong marker in South Asians and says that’s currently I should wait for Triple test and Genetic sonogram at 18 weeks.

Please go through my case and let me know what you think as I am worried and losing sleep.

To GB:
In my opinion you should have NEVER been given an adjusted risk based on the ultrasound findings alone. The power of the first trimester screening is in the COMBINED risk assessment that includes the serum markers. Breaking down the individual test results and giving separate adjusted risks based on those individual parameters is contrary to the spirit of the screening and the science behind the screening and results in exactly the situation you are in now. I must say that I agree with your physician – with a “readjusted risk” (the ONLY result you should have been given) of 1 in 956, my ONLY recommendation would be to simply have an MSAFP (not the entire serum screen) at 16 weeks and a good ‘genetic sonogram at 18-20 weeks. If that is reassuring, your risk is reduced by AT LEAST another 50%, placing you in the range of 1 in 2000 or less. That is better than a 15 year old based on age alone! Best wishes!
Dr T

Goodbye Blogger

2010-04-14T16:42:00.000-07:00

Dear Readers,

We were just informed today that "Blogger" will soon be unable to support the capabilities required to continue the current format for "Fruit of the Womb" and the other HealthLine Experts. But, we have also been reassured that access to past posts should still be available once the transition to a new format has taken place. I am praying that is so!

We have also been told that the "Comments" sections under the posts will be disabled as of TOMORROW (April 15)! I am not entirely sure what this means for all of you in the queue for responses to your questions, but I fear they will be lost and I am not sure if the new format will provide the same interactive activities that I have tried to maintain since the inception of this blog - perhaps they will be better. But, in truth I have focused most of my efforts on this site over the past year responding to individual readers and that has become a part of my daily routine. As many of you know, we had to work around the quirks of Blogger and that meant at times it took an effort to communicate with each other, but we managed to do that remarkably well over time anyway.

In all honesty, this is a sad day for me, mainly because of the age old fear of the unknown. I do not know if "Fruit of the Womb" will be actually carried into the new format or if this is the last post I will have under that title. I was told that we would be involved in the new format but the level and the specifics of that involvement are yet to be determined.

If this is my last day as author of "Fruit of the Womb" then I want to tell you how much I have enjoyed the years we have spent together. We did much more with this blog than was ever anticipated. Indeed, it is probably unique among such sites on the internet. We have developed a worldwide following, I have found many new friends, and we have helped each other through good times and bad. I look at this as one of the most rewarding endeavors of my entire life, grateful for the trust you put in me and also for the gratitude you have shown for my efforts. I do not think this is "Goodbye", but if it is, then I want to thank all of you from the bottom of my heart for your loyalty, your trust, and your great respect for what we have tried to accomplish here!
Kindest regards,
Dr T

Anti-M Isoimmunization

2010-03-31T18:03:00.000-07:00

• Mon Mar 29, 02:24:00 PM 2010, Anonymous said…
Hello, I just found out that I tested positive for the antibody screen. I have a B positive blood type and do not understand the risks with my baby or how it affects or how it occurs. I am 5 months pregnant and am very worried. I have 2 children and never had this problem before. I've read that "anti-M are of apparent natural occurrence and not clinically significant", but then I read only 22% of a random population will be negative for the M antigen. How is that natural?

To anonymous Mar 29: Anti-M antibodies are generally "naturally occurring" which means that you develop them as the result of exposure to M-antigens found in the environment - usually expressed on bacteria or viruses. This is the same way we develop antibodies to the major blood group antigens A and B which are also considered to be “natural antigens.”

In most cases the only type of antibodies that individuals develop to these types of antigens are of the IgM subclass. IgM antibodies are very large and cannot cross the placenta and cause any problems for the baby. Occasionally (as can also occur with the A and B major blood group antigens), an individual will develop IgG antibodies to the M-antigen. IgG antibodies CAN cross the placenta and, indeed, are actively concentrated on the fetal side. Usually, these IgG antibodies are antibodies to a wide variety of things that are “foreign” to our bodies that we have been exposed to during our lifetimes and they provide protection for the baby against common environmental pathogens (e.g., viruses and bacteria) for the first 4-6 months of the baby's life following birth.

However, if you have IgG anti-M antibodies and the baby happens to have M antigens on its red blood cells, the antibodies can attach to the red blood cells and mediate their destruction by the baby's own immune system, ultimately resulting in fetal anemia and, in the worst case scenario, fetal hydrops and even death (as can occur with "Rh-disease"). This is uncommon with anti-M antibodies, but has been described on numerous occasions in the published literature. As with "Rh-disease", the risk for fetal complications generally increases with the level of the IgG anti-M antibody titers you have.

The first steps for you are to find out if you have IgG antibodies and if your partner is M-antigen positive on his red blood cells. If he is not, then your babies cannot be affected. If he is, and you have IgG antibodies, then your antibody levels (titers) should be ascertained and followed serially during the pregnancy. Severe fetal anemia usually is a risk when high titer anti-M is present as IgG antibodies at 37ºC.

If the IgG anti-M titers are 32 or higher, then the baby should be monitored serially for evidence of significant fetal anemia (just like we do with Rh-isoimmunization) by performing peak systolic velocity (PSV) measurements on the baby's middle cerebral artery using Doppler Flow Velocimetry. If the baby does develop significant anemia, then it should be either transfused with M-negative blood or delivered, depending on the severity of the anemia and the gestational age at which the baby gets in trouble. It would be a good idea for you to discuss this with a specialist in Maternal-Fetal Medicine before you conceive again. Thank you for reading and for asking such a great question.
Dr T

Placenta Accreta: A Growing Problem

2009-12-25T16:47:00.000-08:00

Today's post is written in response to the questions raised by the reader below...

Anonymous has left a new comment on your post "Hypoplastic Right Heart Syndrome (HRHS): A Reader'...":

Dear Dr T

I am 40 and pregnant for the 8th time. I have 2 kids both delivered by cesarean section and have had 3 D & C's, the most recent in March 2009. My second trimester blood work at 15 weeks for my current pregnancy showed elevated hCG (2.4MoM), AFP (2.4 MoM) and inhibin A (2.3MoM). Also uE3 (estriol) was 0.59 MoM. My first trimester blood work was normal (hCG 0.9MoM and PAPP-A 1.1MoM). Amniocentesis done at 17 weeks showed no fetal chromosome problems and fetal (amniotic fluid) AFP was 1.13 MoM (which is normal). I would like to know if I am at risk of placenta accreta or worse and how easy is it to diagnose this condition by ultrasound. I have my 20 week scan next week. I was told after the second trimester blood work that I may be at risk for growth restriction but no one has mentioned placenta accreta.

Thanks, M

To M Dec 17: That is an excellent question! As we will discuss below, you are at increased risk for placenta accreta because of your multiple uterine procedures and the abnormalities of your midtrimester serum screening might just be a hint that such an abnormality of placentation has occurred.

The first question that should be addressed is what is a placenta accreta? To understand this requires a basic understanding of the uterine anatomy. The innermost lining of the uterus is called the endometrium. This is a thin layer of a variety of very hormonally responsive cells that grow, proliferate, and finally regress (resulting in a ‘period’ if a pregnancy does not occur) during the normal menstrual cycle. Under the influence of progesterone, following ovulation in the second half of the cycle, the endometrium becomes ‘decidualized’ in preparation for the reception of an early embryo if a pregnancy does occur. The embryo attaches to and burrows into the endometrium and almost immediately begins to produce the cells that will eventually become the placenta. These cells, called trophoblasts, spread out within the endometrium (but not through it) and also invade the portion of the maternal blood vessels (spiral arterioles) that are contained within the endometrium to form the large vascular bed containing mother’s blood that will eventually bathe the placental villi and supply nutritional needs to the baby.

Beneath the endometrium is the myometrium. The myometrium contains multiple thick layers of smooth muscle cells that give the uterus its ability to contract and makes up the bulk of the uterus. Outside the myometrium is another very thin layer of cells called the uterine serosa. This is contiguous with the peritoneal lining of the abdomen and isolates the uterus from other structures within the abdominal cavity. Under normal circumstances, as the placenta develops, it grows only within the endometrium and is clearly separated from the myometrium by a structure called Nitabuch’s layer and the deepest layer of the endometrium called the decidua basalis. This separation is important, because under normal circumstances, after the birth of the baby, the placenta cleanly separates from the endometrium at this level and the maternal blood vessels that have been invaded by the trophoblasts within the endometrium rapidly contract, controlling maternal hemorrhage from the placental bed. A placenta accreta occurs when the placenta grows beneath where Nitabuch’s layer and the decidua basalis should be, anchoring the placenta to the myometrium from which it cannot readily separate following the delivery of the baby. Deeper invasion into the myometrium is called a placenta increta and if the placenta invades all the way through the uterus and the serosa, this is termed a placenta percreta. Placenta accreta occurs in about 75%-80% of such cases, placenta increta in about 15%, and placenta percreta in about 5%.

There are several mechanisms one might imagine that could lead to the development of a placenta accreta in an otherwise normal pregnancy. For example, the placental trophoblasts might not be able to respond to the normal signals that limit their growth and invasiveness and/or the maternal immune system might not be able to generate the appropriate signals. However, more often, it appears that defects in the endometrium, areas in which the endometrium has been damaged, attenuated, scarred, or denuded, placing the trophoblasts in close or direct contact with tissue layers not ordinarily ‘equipped’ to limit trophoblast invasiveness, are the primary reason placenta accreta, increta, and percreta occur. Such endometrial defects are usually the consequence of a variety of uterine operative procedures including D&Cs, myomectomies, extensive surgery for endometriosis, removal/correction of congenital uterine abnormalities (Mullerian abnormalities) such as septums, and endometrial ablation, or as the result of Asherman’s syndrome. Higher parity and advanced maternal age are also associated with increased risk for placenta accreta. In recent years, cesarean section has come to the fore as the primary factor contributing to the development of placenta accreta. Indeed, there is a clear association between previous cesarean section, a placenta previa, and the risk for a placenta accreta. Almost 25 years ago, Clark and colleagues (Obstet Gynecol 1985;66:89-92) showed that the risk of a placenta previa increases with the number of previous cesarean deliveries and that women who had four or more cesareans had a risk as high as 67% for a placenta accreta.

Accompanying placenta accreta are risks for both the mother and baby during pregnancy and at delivery. Placenta accreta is associated with bleeding, usually in third trimester, premature delivery, premature rupture of membranes, and necessity for cesarean delivery. Severe hemorrhage can occur as well as uterine rupture prior to the onset of labor, resulting in risk for fetal and maternal death. Obviously, severe hemorrhage can also occur at the time of delivery, requiring transfusion with blood products and even hysterectomy. If the placenta has invaded through the uterine wall (placenta percreta) into adjacent structures such as the bladder, bowel, or the broad ligament in which the major blood vessels supplying the uterus are enclosed, this can be an extremely challenging surgical procedure, especially if there is extensive intraperitoneal scarring from previous cesarean sections.

Sometimes the diagnosis of placenta accreta is very easy to make, especially when the placenta is overlying a previous uterine scar in the lower segment, there is not a clear separation between placenta and the myometrium (uterine muscle) and there is evidence of infiltration, into or through, the uterine muscle seen by ultrasound (Lerner, et al., Ultrasound Obstet Gynecol 1995;5:198-201). More often it is not a simple diagnosis. Only a small portion of the placenta might be involved or the myometrial invasion is on the lateral or posterior uterine walls. Efforts have been made to employ MRI to help sort out the suspected diagnosis (Palacios, et al., Acta Obstet Gynecol Scand 2005;84:716-724). This is safe enough in pregnancy and can be very helpful at times. Furthermore, unexplained elevations in the serum analytes (MSAFP and hCG) in midtrimester (the question raised by our reader) can sometimes be a hint that an accreta has occurred (Hung, et al., Obstet Gynecol. 1999;93:545-50).

Review of the management options for placenta accreta is beyond the scope of today’s discussion but perhaps can be the topic for another post in the future. However, the importance of maintaining a low threshold for suspicion in patients who have the risk factors noted above, taking steps to establish the diagnosis, and careful preparation for delivery if a placenta accreta is suspected cannot be underestimated to minimize morbidity and to optimize maternal and fetal outcome.

HAPPY HOLIDAYS TO ALL!!!!!!

Dr T

Hypoplastic Right Heart Syndrome (HRHS): A Reader's Query

2009-11-30T18:07:00.000-08:00

Before I respond to the reader below, I wanted to explain why you have not seen much of me lately at “Fruit of the Womb.” Those of you who have followed this blog for awhile may know that I had some medical problems of my own dating back the last 6-8 months. Unfortunately, despite a good response to coronary artery angioplasty and stenting, there were blockages that were not amenable to this procedure at the time. To make a long story short, I underwent coronary artery bypass surgery Nov 21 and was just discharged from the hospital on the 28th. Believe me, not my idea of a fun Thanksgiving!!! Up until two weeks ago, despite the fact I have not been writing new material for the site, I have been busy trying to answer many of the 60-100 questions per week that readers have left on older posts. Over the next few weeks, since my recovery will take awhile, I will try to catch up on some of those who were left behind. But, I am also going to push on with new material as it arises from reader queries and from within my day-to-day experiences. Thanks for your understanding and I hope all of you have a wonderful holiday season!
Dr T

Anonymous has left a new comment on your post "Amniocentesis Q & A":

Dear Dr. T,
Thank you very much for your informative blog. I am 33 years old, first pregnancy and I had excellent first trimester screening results as follows:

Draw date: 11 weeks 3 days
Free Beta hCG (MOM):0.78
PAPPA-A MOM: 1.39
NT (mm) 1.70
Down Syndrome Risk (after screening)= 1 in 7,195
Trisomy 18/13 Risk = 1 in > 10,000

I was very happy about those results, however, during my anatomy ultrasound at 19 weeks and 5 days, a serious congenital heart defect was identified on my baby girl's heart. She has a hypoplastic right heart. At this point, it was not possible to determine whether the tricuspid valve and/or pulmonary valve are partially/fully affected. The doctor assured me, however, that they could not see the blood flowing to the lungs. In addition, the doctor also saw a ventricular septum defect (VSD), which apparently is common in Down Syndrome babies but in my case it could also potentially be associated with the baby's complex heart condition, i.e.: tricuspid atresia. No other anomalies or markers were found on the ultrasound.

After talking to the genetic counselor, my risk was increased from 1 in 7,195 to 1 in 10, that is, a 10% chance of having a baby with a chromosomal problem. I then had an amnio 3 days ago - which went fine, no cramping, no bleeding, no fluid leaking, no fever so far. I got my FISH results yesterday indicating that the baby is chromosomally normal for the anomalies tested by FISH (T21, T13, T18, X, and Y). I was ready to celebrate when the genetic counselor said that FISH accuracy is 98% because there might have been some maternal cell contamination due to blood contained in the FISH sample. She also said that this is very unlikely but then why did she have to make such a remark?

Thus, I guess my questions to you are:
(i) How reliable are FISH results in this case?
(ii) How often is such a rare complex heart defect (Hypoplastic Right Heart Syndrome) found in Down Syndrome babies?

I am trying to have some piece of mind while I await for the final amnio results. I am hoping that my baby's heart problem is isolated and not linked to a chromosomal syndrome. I am scheduled for a fetal echocardiogram next week.
Thank you very much for your time and kind help.

Congenital heart defects occur in 0.8-1.1% of ALL pregnancies which reach delivery and about 10% of babies that undergo spontaneous abortion. At least 30 to 60% of these are not detected until after the birth of the baby despite repeated ultrasound evaluations during the course of the pregnancy. Fortunately mild abnormalities (such as isolated ventriculoseptal defects – VSDs) and even many complex congenital heart defects (such as hypoplastic left heart syndrome) are not associated with easily recognizable chromosomal abnormalities. Atrioventricular (endocardial cushion defects) defects are more commonly associated with chromosomal abnormalities (as seen in 30-50% of babies with Down syndrome – trisomy 21).

Hypoplastic right heart syndrome (HRHS) is actually one of the most rare complex congenital heart conditions occurring at about 1/4 the incidence of hypoplastic left heart syndrome. HRHS seems to most often be the consequence of the development of a very small (atretic or hypoplastic) pulmonary valve Which connects the right ventricle to the pulmonary artery), resulting in a small pulmonary artery beyond that valve (necessary for transporting blood from the heart to the lungs after birth) as well as a small ventricle, small tricuspid valve, and atrium on the right side of the heart as well. During development of the heart, good blood flow through all these structures is necessary for them to achieve normal size. So the severity of HRHS depends to some extent on both the timing and the degree of the insult to the pulmonary valve - the earlier and the more severe, generally the worse the HRHS.

Babies are able to survive in the uterus because they have two physiologic shunts for blood under normal circumstances – the foramen ovale (a large opening between the right atrium and the left atrium that assures the passage of the most highly oxygenated blood from the placenta into the left ventricle and subsequently to the brain) and, the ductus arteriosus which is a vascular connection between the aorta and the pulmonary artery. Both of these connections normally close shortly after delivery and, when the fetal heart anatomy is normal, this assures good blood flow to the lungs from the right ventricle as the lungs take over control of providing the most highly oxygenated blood to the left ventricle and out through the aorta into the systemic circulation. When these connections close in a new born with HRHS, there is inadequate blood flow to the lungs and the baby becomes blue (or cyanotic) as a consequece of inadequate oxgen for its tissues…

With regard to our reader’s questions, I would have the following comments:
The FISH results will pick up about 98% of the chromosomal abnormalities for which the laboratory is set up to screen. It will NOT pick up all chromosomal abnormalities and it is unlikely to pick up by itself subtle chromosomal abnormalities (microdeletions or additions) or isolated genetic defects. It is not very likely that your baby has Down syndrome. However, there does appear to be an increased risk for having another baby with a complex congenital heart defect and this may eventually lead your geneticists to seek some of these abnormalities in your baby and in you or your spouse.

Discussion of this is beyond my level of expertise, but examples of these include: isochromosome 5p (Paulick J, et al., Prenatal Diagn 2004;24 : 371–4); interstitial deletion of chromosome 5 (Gibbons, et al, Am J Med Genet 1999;86:289-93); interstitial deletion of chromosome 2 (Sharma J, et al., Int. J Cardiol 1997; 62:199–202); deletion 22q11 (Marino, et al Genet Med 2001;3:45-8); deletion of chromosome 22q11.2 associated with thymic hypoplasia (Chaoui, et al., Ultrasound Obstet Gynecol 2002;20:546-52).

Your greater challenge will be the weeks ahead if the diagnosis is confirmed and all I would suggest at this point is that you talk extensively with the Pediatric Cardiology and Surgery teams, members of the NICU and perhaps even other couples who have had a baby with HRHS. I wish you all the best….
Kind regards,
Dr T

Metformin Use During Conception and Pregnancy

2009-09-25T16:02:00.000-07:00

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.

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

2009-09-06T19:25:00.000-07:00

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

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

2009-09-03T17:00:00.000-07:00

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

Polyploidy as a Cause of Early Pregnancy Loss

2009-08-31T09:21:00.000-07:00

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

Methotrexate - Easy to Use, Easy to Abuse

2009-07-11T16:18:00.000-07:00

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

Composite Results are the Strength of First Trimester Screening for Aneuploidy

2009-07-09T18:42:00.000-07:00

The reader below faces what appears to be a growing dilemma for patients (and their providers) in the laboratory reporting of results from first trimester screening for aneuploidy. The data that supports this screening modality has always emphasized that the power of the screening test is in the COMPOSITE test results and NOT the individual ‘analytes’ which include the actual nuchal translucency measurement along with the hCG, PAPP-A, and other factors.

As can be seen from the ‘results’, she is being given risk results for trisomy 21 (Down syndrome) that range between 1 in 47 ( based on the biochemical screening alone) to 1 in 612 (based on the ultrasound evaluation of the baby). The COMPOSITE (and in my mind the KEY information) is the 1 in 292 “adjusted risk” but as a patient (and even as a doctor), how are you going to sit with reconciling the great disparity in risks in a way that will help you make the most unbiased decisions possible regarding further evaluation of the baby and, particularly, the invasive diagnostic studies which carry their own inherent risks…?

Singapore Mother has left a new comment on your post "Understanding Interpretation of First Trimester Sc...":

Dear Dr. T,

I am 39 years old. The results of my test are as follow:

@ 12 weeks + 0 days

Crown-rump length (CRL) 56.1mm
Nuchal translucency (NT) 1.4mm

Maternal Serum Biochemistry
Free B-hcg 129.4 IU/I = 1.993 MoM
PAPP-A 0.557 IU/I = 0.578 MoM

Trisomy 21
1:122 (Background risk)
1:612 Adjusted risk (US)
1:47 Adjusted risk (BC)
1:292 (Adjusted risk)

Kindly please shed some light... Thank you so much!

To Singapore Mother July 7: Personally, I think it is VERY confusing and unfair to present the data to patients in this way. The strength of the first trimester screening is in the COMPOSITE results and NOT the individual tests - and yet you were given the risk assessment based on those individual tests. All that can do is make you worry about the greates ‘risk’ estimate and any laboratory that does this should be banned from first trimester screening because they are presenting 'data' out of both sides of their mouths without providing adequate counseling to the patients or realistic expectations as to what balanced information most providers can offer! Albeit, this is just my opinion.

The long and short of your results are that you have a 1 in 292 risk of Down syndrome which is less than half your age alone risk. Some laboratories will still report this as "screen positive" because it falls below there cut off, but that also means your baby has a 291 out of 292 chance of being chromosomally normal. If the odds still worry you, then you can have either a genetic amniocentesis done or simply have an expert sonogram done at 18-20 weeks. If the latter is 'normal' your a priori risk is reduced by at least another 50%. Best wishes and let us know how things turn out.
Dr T

Abnormal First Trimester Screen in a Woman with Chronic Kidney Disease

2009-07-07T17:54:00.000-07:00

Hello Dr. T:
I am also new to the whole blogging thing. I am currently 13 weeks 3 days, and was told at my last prenatal appointment that based on my first trimester screening, I have a 1 in 235 chance of having a baby with Downs syndrome. I am only 23 years old, and I wasn't sure if this is horrible. I thought most people had a 1 in 275 chance, but looked it up online and came to find out that it’s more like 1 in 1200, so naturally was very concerned. I was wondering if you could shed some light on this whole odds thing, because I'm sort of freaking out. I do have kidney disease MPGN type 1 and Graves disease, not sure if that makes a difference. I have one other child he's 4 and very healthy, with no disabilities whatsoever. Hope you can help me understand this a bit more.
Thanks

To Leilani:
The risks for having a baby with Down syndrome and many other chromosomal abnormalities resulting from nondisjuntion increase with age with the actual risks also varying by pregnancy trimester. At your age your chance of delivering a baby with Down syndrome is only about 1 in 1250 and the chance of having a baby with any chromosomal abnormality only about 1 in 500. The first trimester chances that the baby could have a chromosomal abnormality are 20-30% greater than these because such babies have a higher chance of getting lost along the way. Your 1 in 235 risk based on the first trimester screening is equivalent to that of a 35 year old woman in first trimester. Hear me loud and clear, however, just because the risk screening result is therefore ‘abnormal’, that does NOT mean the baby necessarily has Down syndrome. Indeed, it has a 234 out of 235 chance (>99%) that it does not.

You did not tell me the actual results of your tests, but it is possible that your kidney disease skewed the risk assessment if you are not clearing the serum analytes (hCG and PAPP-A) normally, particularly the hCG. Indeed, if you have membranoproliferative glomerular nephritis (MPGN), that is often associated with decreased kidney function and about 20% of the pregnancy hormone hCG is typically excreted by the kidneys (that’s why you can do a pregnancy test on urine samples). If this led to a higher circulating hCG level, that might increase your 'risk' for Down syndrome but not the chance the baby actually has it.

If on the other hand (or in addition to), the PAPP-A level is on the low side, that might further increase your ‘risk’ for Down syndrome. Your kidney disease is an autoimmune condition in which your own antibodies attack the kidneys and cause activation of a series of chemicals called the complement system. Complement helps to further damage anything the antibodies attach to (and normally it is a very important means of fighting off organisms that cause infections). However, unlike hCG, PAPP-A clearance does NOT seem to be impaired in some patients with autoimmune kidney disease (Rysavá, et al., Kidney Blood Press Res 2007;30:1-7) and therefore your kidney disease might lead to an elevation of the hCG alone when compared to the PAPP-A levels. The greater the difference in the multiples of the median (MOMs) of those two pregnancy products, the greater your calculated ‘risk’ for Down syndrome.

You should also be aware that women who have autoimmune diseases, particularly those that affect the kidneys, are also at greater risk for having an abnormal placenta – a small and/or a poorly vascularized placenta – that can eventually lead to poor fetal growth, hypertensive disorders of pregnancy (preeclampsia), and need for early delivery. This could further reduce your PAPP-A out of proportion to the hCG (which is also made by the placenta) and increase the Down’s risk even further.

It is true that young women can have babies with Down syndrome and indeed, about two-thirds of babies with chromosomal abnormalities are actually born to women at low risk based on age alone. However, in your case, I am betting on your risk being elevated because of your autoimmune kidney disease. My suggestion would be to 'lay low' for a bit and simply have a good genetic sonogram done at about 18 weeks. If that is normal, it will reduce your ‘risk’ by at least 50%. Of course, you always have the option to have an amniocentesis done at 15-16 weeks if you just have to know for sure as soon as possible. Best wishes and let us know how things turn out.
Dr T

A Second Chance

2009-07-05T17:14:00.000-07:00

Dear Readers,

About a month ago, I started writing again and had at least tried to begin responding to the many queries that have kept coming in the door – some left on posts that are a year or two old. (And for all of you out there who have asked, those old posts are still ‘open’ so that you can leave a question or comment and they will be forwarded to me). Due to the volume of the queries, I had to limit my responses to some of the most recent ones and to those that are not adequately addressed in the original posts or in the ‘strings’ of comments that follow.

Anyway, despite my best intentions, I am afraid I was side-tracked early in my return engagement by another round of medical problems. I had actually been under the weather for awhile, but had thought it was secondary to all the administrative responsibilities I had had as interim chair as well as my clinical load. To make a long story short, I had a series of tests that culminated in a cardiac catheterization 3 days ago and placement of stents in one of my coronary arteries that was 99% blocked. It just goes to show, “It’s always something.”

Mind you I am not overweight and have always exercised religiously, even at the expense of time spent with my family, and that is probably what had saved me to this point (I do come from a family with BAD GENES - a very poor track record of early onset and severe arteriosclerotic cardiovascular disease). Indeed, I actually passed the exercise portion of the stress test with flying colors to the amazement of my doctors because when they looked at my perfusion studies, the whole anterior wall of my left ventricle was hardly getting any blood. In all honesty, I feel I was only days to weeks away from a heart attack or lethal arrhythmia that may well have put me in the grave.

So today I decided to test out my new stents! I went out and walked 4.5 miles and for the first time in ages, I had no tightening in my chest or shortness of breath. Indeed, there were several times during the walk that I wanted to burst into a run, but sensibly controlled my exuberance for the sake of my right groin (the entry site for the heart catheter). When I got back to the house, my pulse was only 80. But, the most amazing thing I noticed was the ‘fog’ that had clouded my concentration for the preceding months, and truly had made writing a burden, had also been lifted. I was thinking clearly again!

In the big scheme of things, I feel as though I have been spared a relatively early grave and, as so often happens under these circumstances, that has given me a sense that my work on this earth is not yet done. It’s not too often we get second chances like this and I wanted to tell you all that at least part of that work is attention to this blog. Please bear with me again as I get back into the routine and thank you for hanging on as loyal readers through all of my down time over the past six months.

Sincerely yours,
Dr T

A Loss of Twins and Missed Opportunities for Cerclage

2009-06-13T11:53:00.000-07:00

Recently, a reader left the comment below. The value and use of cervical cerclage continues to come into question. There are major institutions in this country where it is not considered to be a useful procedure and have abandoned or severely limited its use to selective patients in deference to ‘conservative management’, often now involving the administration of progesterone during the pregnancy. I have addressed my feelings on cerclage in a series published on this site many months ago (between August 18 and September 26, 2008). My feelings have not changed. There is a big difference between getting a couple of extra weeks to an extremely early pregnancy, or holding off delivery long enough to ‘get steroids on board’ for fetal lung maturation, and delivering a baby beyond 30 weeks gestation when the risk of long-term complications of prematurity are greatly diminished. Barely a week goes by on our service when a patient would have lost a pregnancy in the manner detailed below except for the timely recognition of cervical insufficiency and the placement of a cerclage in later midtrimester…

On June 10 Anonymous wrote:
I have read one of your previous articles regarding cervical cerclage. I was diagnosed with endometriosis, treated with laproscopy and subsequently underwent many IUIs and one cycle of IVF without success. My second IVF cycle was successful, but due to preterm premature rupture of membranes (PPROM) at 21 weeks, lost healthy twins. No history of diabetes or hypertension. Doctors could not diagnose the reason for PPROM, may be due to cervical incompetence. I was on total bed rest, but had some vaginal bleeding at 11 weeks. I just wanted to know if cervical incompetence could have been diagnosed before and cervical cerclage would have been useful. What are my chances of undergoing normal conception?

To anonymous June 10:
Conception and successful carriage of a pregnancy are separate issues. It sounds like you had (and may still have) cervical insufficiency with the twin pregnancy. I firmly believe that all multiple gestations, particularly those resulting in infertility patients, should be carefully evaluated for premature cervical changes by transvaginal ultrasound beginning as early as 16 weeks. If cervical changes were picked up early enough, a cerclage may well have been successful in preventing your pregnancy loss.

Twenty-five years ago, detecting and treating cervical incompetence in a 'first pregnancy' was rarely successful. The diagnosis of cervical incompetence (insufficiency) was a diagnosis of exclusion, usually after one or more premature deliveries or midtrimester pregnancy losses. But because of the increased surveillance by ultrasound, it is almost a weekly event on our service.

With a subsequent pregnancy, I would recommend serial cervical evaluation by ultrasound even if you have a single baby. You might also be a candidate for an elective/prophylactic cerclage at 13-14 weeks if you have any other risk factors such as a congenital uterine abnormality or previous cervical surgery (e.g., LEEP or conization). In addition, even if you and your providers decide only upon serial ultrasound evaluation, you might consider weekly injections with 17-OH-progesterone caproate beginning at 16-18 weeks as well. I am sorry for your loss, but with careful follow-up and pregnancy management, you should be successful in the future.
Kind regards,
Dr T

Low hCG and PAPP-A in a Patient with an Autoimmune Disorder

2009-06-09T19:39:00.000-07:00

The following comment was left on an old post "Affect of Smoking on PAPP-A Levels in First Trimester." The case is interesting because it reminds us that abnormal maternal serum markers in first trimester might be the result of factors unrelated to fetal chromosomal abnormalities....

Hi! I just got my 1st trimester screening test results today, and would love you thoughts.

I will be 40 years old when I deliver. I was 12 weeks when I did the testing.

NT: 1.5
Nasal Bone present
Free b - HCG: 0.29 MoM
Papp A - 0.34 MoM

Down syndrome risk: 1:1600
Trisomy 18 & 13: 1:50 (normal for my age 1:150)

I have an autoimmune condition, polymyositis that is under control. I am taking 12.5mg prednisone 1xday. I am ANA and Jo-1 positive.

Can you please help me understand these results? I am trying to look at the fact that it is only a 2% chance of the trisomy abnormalities, but it is difficult.

Are there any other reasons that my blood levels would be so low for both? Is there anything I should be precautionary about through the rest of my pregnancy because of this?

Thanks,
WJD

The combination of the low hCG and the low PAPP-A is typically a pattern seen in pregnancies complicated by trisomies 18 and 13 (in contrast to an elevated hCG coupled with a low PAPP-A in Down syndrome – trisomy 21). Both hCG and PAPP-A are produced by the trophoblasts of the placenta and low values could be the result of either a small placental mass or decreased production because of metabolic dysfunction. Both of these factors might be at work in trisomies 18 and 13.

However, in your case, there is also the possibility that your baby is chromosomally normal but has an abnormality of placentation that resulted from your autoimmune disorder. The immune system probably plays a very important role in normal placentation and the presence of certain autoantibodies (e.g., antiphospholipid antibodies, lupus anticoagulants, and anti-beta-2-glycoprotein-1) are thought to be associated with increased risk for abnormalities of placentation resulting from abnormal trophoblast migration and invasion of the maternal spiral arterioles. Indeed, if you have not been screened for these specific autoantibodies, I would recommend that you have that done. Such pregnancies are at increased risk for poor fetal growth (intrauterine growth restriction), fetal loss, pregnancy-induced hypertensive disorders, and early delivery. If you have any of these other autoantibodies, you might also be at increased risk for thromboembolic complications as well.

Whenever we find a pregnancy that has low hCG and PAPP-A levels and a chromosomally normal baby, it is recommended that fetal growth be followed at serial intervals, Doppler flow studies (e.g., umbilical, uterine , and fetal middle cerebral arteries) be done to evaluate impaired placental perfusion from either the fetal or maternal side and evidence of fetal blood flow redistribution (preservation of the brain at the expense of perfusion of ‘nonessential’ organs because of reduced placental transfer), and both mother and baby be monitored carefully for evidence of compromise. Your doctors can give you specific details of what should be done with regard to the latter.

Best of luck to you and please let us know how things turn out.
Dr T

Return of Dr. T

2009-06-08T17:57:00.000-07:00

It has been several months since I have written and I have missed all of you. I was a little burned out by trying to keep up with my interim Chair and clinical responsibilities as well as the blog, but the greatest reason was that ‘Blogger’ was misbehaving and had been for many months – you couldn’t leave your comments and I couldn’t respond. I felt like I was talking to the wall and it was the need for and the feedback I got from the interactions with all of you that had given me the energy and inspiration to keep going up to that point.

Well, we finally have a new Chair and last week, ‘Blogger’ must have gotten a fix because more than 900 comments showed up in my mailbox in two days! So, now I have another dilemma…there is NO WAY I can answer all of you. However, in one of the batches of mail was the note below from Danita. I want to share it with you because it reminded me what I envisioned and have attempted to provide as my role on this site and it has been a strong incentive to return to the keyboard today…..

Hello Dr. T--it's Danita.
I originally posted a comment on your blog on August 14, 2008. I just wanted to give you a quick update. My son who was born at 26 weeks 6 days, and weighed 2 lbs. 9 oz. is now a healthy 9 month old. I was told like many of the other women that my baby probably wouldn’t make it. I was admitted to the hospital at 23 weeks after my water broke, and I was immediately placed on bed rest. I continued to leak fluid, and eventually after a week I did not have any fluid surrounding my baby. I was nervous, scared, and honestly confused by all of the facts that were being presented to me. I just wanted to let you know that I truly appreciate the encouragement that you provided to me as well as the other women that have, or are experiencing these difficult times during what is supposed to be the happiest time of our lives. You were honest, and gave me a sense of hope. After spending 4 long months in the NICU we finally got to bring him home in December of 2008. My son left the hospital a healthy baby with no medication, no oxygen--nothing. This is the same baby that I was told probably would not make it…I just had to share my journey, and my experience. I would like to send my condolences to the women on this blog who have experienced a loss. I have experienced that pain, and I know it is a very emotional time. I want to tell those same women along with all the other women on the blog to keep their faith strong. I know it is hard--- I’ve been there…but I wanted to share my story with all of you. I am not here to give you false hope, but maybe I can give you hope period. Dr. T— keep doing your thing!
Thank you again,
Danita

So, I am going to renew my pledge to push on with Fruit of the Womb. Although I will not be able to respond to all of the comments that have been left, I will try to catch up with the more recent ones and will certainly go back through ALL of the others to find common themes and situations that might be of general interest or are uniquely intriguing and thought-provoking. Much has gone on in Maternal-Fetal Medicine since we have talked last and I will try to catch everyone up on some of the more exciting advances as well.

It’s gonna be GREAT to be back!
Dr T

Quintuplet Story: A Physician's Perspective - 4

2009-02-09T08:20:00.000-08:00

On April 6, 2007, at 27 6/7 weeks, Joy began having more “pelvic pressure” and the decision was made to give her corticosteroids to accelerate fetal lung maturation. Serial ultrasounds had shown that one of the babies was developing intrauterine growth restriction and was having more difficulty pushing blood through its placenta as well, so the general sense was that delivery would probably be necessary soon. On that evening she began having regular contractions.

Initially magnesium sulfate was given to try to break her labor and then indomethacin was added but she continued to contract. At that point, a second dose of corticosteroids was given and I received a call at home to end my vacation early. By the time I arrived, Joy was having considerably more discomfort with her contractions. The cervix was noted to be stretched around the cerclage and the presenting baby’s head was well-applied to the cervix. As promised, I looked her in the eye and said, “It is time” and she nodded knowingly and agreed.

A “CODE 5” was called and the five NICU teams arrived within a short period of time from all over the city. At about 4:00 AM (4:11-4:13 AM to be exact) on April 7, 2007, Abram, Adal, Ian, Noelani, and Nadia were delivered to Joy and Andres Gonzalez at 28 weeks gestation by cesarean section in Greenville, South Carolina. The response and the entire “operation” went as smoothly as was planned and could have been hoped for and, fortunately, Joy had a relatively uncomplicated post-operative course.

The babies could not have been born into a stronger or more nurturing family. As difficult and dangerous as the pregnancy was for Joy, the time since the delivery (now almost two years) has proven how important the power of faith, love, and friendship can be to overcoming all obstacles. The first-born, Abram, had problems following delivery that led to a series of medical complications and hospitalizations that have stressed the family's resources, financially, and I am sure, personally, and may well continue to do so, but there has not been one instance during that time when we were visited by Joy, Andres, and all the children that there were not smiles on their faces, optimism in their voices, and enough love in their hearts to brighten all of our spirits.

Into each of our lives come events leading to memories that we carry with us until we’re gone. That has been especially true for me in medicine. There are many patients who, unbeknownst to themselves, sometimes gave to me more than I gave to them, and I will never forget those folks. Their memories are as clear to me now as the day they happened. They are the foundation of my approach to the practice of medicine, guiding my deductive and intuitive senses, and my inspiration to awaken early every day to a new set of challenges. They have made me a better physician and a better person. Such is the case with the Gonzalez family, and I am so grateful that they have let me be a part of their lives.
Dr T

Quintuplet Story - A Physician's Perspective - 3

2009-02-07T18:08:00.000-08:00

...The following day, I had a long discussion with Joy and Andres about what to expect over the next 3-4 weeks, the discomforts, the psychological drain, the ever-present concerns for outcomes and the risks. The uterus is now the size of a term one. She had gotten to the point where she developed a rapid heart rate (tachycardia) and low blood pressure (hypotension) in almost any position. I explained that the placentas are like having 5 large arteriovenous (A-V) malformations (direct connections between the arterial and venous sides of the circulatory system) and that this was stressing her already stressed heart.

We talked about my concerns of uterine rupture, discussed plans for the delivery itself, hopefully under very controlled circumstances rather than as an emergency, and discussed the immediate peripartum concerns related to rapid fluid shifts that might increase her risk for congestive heart failure and pulmonary edema at the time of delivery. We revisited the concern that a hysterectomy might be necessary at the time of delivery as the result of uterine rupture, placenta accreta, or uterine atony with hemorrhage. I distinctly recall that she was not at all enthralled with that possibility if there was anything that could be done to prevent it. I informed them that earlier in the day, planning with Dr. Ohning from the NICU (Neonatal Intensive Care Unit) and his staff had begun in earnest now.

Over the next three weeks, she did very well. She flirted with preterm labor and continued to have the expected discomforts associated with hypotension, tachycardia, and general discomfort. At that point, I sent the following letter to my colleagues…

Joy Gonzalez is 27 weeks today. I have seen her just about every day she has been here, but I will be on vacation next week (but mostly in town) and wanted to apprise you all of where she stands.

Currently, she is on a running dose of indomethacin 25mg q6h. We are scanning the babies twice weekly to confirm well-being, assess amniotic fluid, and to do Doppler flow studies, including evaluation of patency of the ductuses when we can. At this point, unless the amniotic fluid begins to drop, I would stay the course with the indomethacin. That and the combination of vistaril and stadol in the early evening have helped control her uterine activity and anxiety. If the amniotic fluid drops, and everything else looks good, consider stopping the indomethcin for 48-72h. If the indomethcin has been the contributing factor to the decline in fluid, it will correct in that period of time. If it does not, or if there is differential correction, then we are probably dealing with placental insufficiency problems.

I took her off metronidazole earlier this week because of nausea and light-headedness and that seemed to help a lot. That can be restarted if her vaginal discharge returns and is bothersome to her. She was complaining of more “pressure” today (and over the past several days). The presenting baby is sitting right on the cervix but is still ballotable. The cervix remains long, but is extremely soft. There is no cervical dilation or tearing because of the cerclage at this point.

She continues to gain weight and her laboratory parameters have been stable. Albumin remains in the 2.3-2.4 range. She has made a major effort with regard to caloric intake. Her platelet count has drifted down, but was back in the 170,000 range yesterday. She has no abnormalities of her LFTs (liver function tests), LDH, etc. We have not done a formal glucola screen on her because all of her labs have always had glucose in the 70-80 range until yesterday’s random sugar (within an hour or so of breakfast) returned at 124. I still don’t know if a screen is worthwhile, but we might consider a fasting and 2hr pc evaluation to see if she has developed some carbohydrate intolerance along the way.

Her blood pressure is good, there is no edema, but her reflexes have become brisk within the past week. She has no specific complaints and is in the best spirits I have seen since she was admitted.

I have not yet given her steroids (to accelerate fetal lung maturity). My feeling there has been that if she gets to the point where we use magnesium to stop contractions or perhaps at 28 weeks, if not needed sooner, we could give them to her then. As the next step in tocolysis, if that becomes necessary, I would avoid nifedipine, consider a single dose or two of terbutaline (very carefully) to assess her response and tolerance to this, but probably go with the magnesium. If she needs magnesium, the plan is to transfer her to L&D. It is possible to get FHR(fetal heart rate) tracings on ALL of the babies and I suggest we start doing this every other day from this point forward.

We have worked closely with the nursery, L&D, and anesthesia to prepare for the delivery and everyone appears to have their roles well-defined. The plan will be to deliver her in O.R. C, nursery staff will take the first 3 babies to the ‘NICU annex’ we have set up in the recovery room directly handed off by us from the operating table, and the last 2 babies will be placed by us in the two warmers set up in O.R. C. The goal will be to make EVERY effort to deliver her on L&D. If she has complications and needs to be recovered in the SICU, that can be done afterwards. Anesthesia was pushing us to deliver her downstairs in the main O.R., but that creates almost an untenable situation for the nursery (and believe me, we have looked into that option). So unless we are in an extraordinary situation, please insist on delivering her upstairs.

Joy has a special request that we attempt to deliver the babies in the ‘order’ in which they have been evaluated antepartum. We have periodically drawn the orientation of the babies on her abdomen AND THEIR POSITIONS HAVE NOT CHANGED. This is not an unusual request under these circumstances and if it can be honored, that would be much appreciated. She would also like us to do “everything possible” to preserve her uterus.

The last is a special request on my part. I will tell her today that I may not be readily available over the next 11-12 days. After my vacation this week, I am then scheduled to go to that CDC meeting on the 10th and 11th. However, over the next week or so, I will try to get in to see her periodically. I will have my beeper and cell phone on and would truly appreciate a call if there is any significant change in her status. I would also like to be able to come in to assist with her delivery if at all possible. She is a very special patient to me and I know she would appreciate it too if I could be there to help out.

Thanks!

Quintuplet Story - A Physician's Perspective - 2

2009-02-06T16:13:00.000-08:00

On the whole, the pregnancy progressed well. At about 13 weeks, we placed a high cerclage in her cervix. This stitch around the cervix was intended to help prevent subclinical cervical changes leading to early labor as well as a means of providing us a ‘safety net’ and perhaps some opportunity to interrupt premature labor should that ensue. Between 15 and 17 weeks, she gave me my first real scare of the pregnancy. Her nemesis of nausea and vomiting which she had managed to keep under reasonable control as an outpatient returned with a vengeance. She required two hospitalizations in mid-January 2007 and during those stays her electrolytes were abnormal and blood protein levels dropped precipitously to dangerously low levels. Her hemoglobin had also dropped dramatically in only 6 weeks. From past experiences with high order multiples, I knew this deterioration in her nutritional status could be the first sign that we might have difficulty getting the babies to a point of good viability. Electrolytes can be readily replaced, but if protein is not maintained in the blood, then sooner or later, she would begin to leak fluid into her soft tissues and lungs. Fortunately, with medications, dietary adjustments, and a great effort on Joy’s part, the blood chemistries stabilized and then improved and the pregnancy went on.

From that point forward, she was seen weekly in our office. At her 20 week check, the babies’ growth and anatomy appeared normal and the cervix had maintained its length with the cerclage in good position. At 21 weeks, she complained that she was having increased uterine contractions, especially when she was on her feet, and was again “having more trouble eating, but I am working on that.” By this point she had gained more than 30 lbs since her first prenatal visit and more than 40 lbs since she had conceived. On February 23 at 22 weeks, her laboratory studies were rechecked and the results were very encouraging – her blood protein levels had climbed to a level comparable to that at the beginning of the pregnancy and her hemoglobin levels had stabilized since her January admissions.

Over the next week, however, she developed a low-grade fever and upper respiratory infection and, as a consequence, had a hard time keeping up with her fluid and food intake. When she was seen in the office on March 3 with these complaints at 23 weeks she was having uterine irritability, her cervix had shortened to just above the level of the cerclage (still providing 25-30 mm of cervical length), she now had protein in her urine, and her blood protein levels had again dropped to the point they were at during her January admissions. In addition her white blood count was elevated in a way that suggested an infection, presumably, upper respiratory in view of her symptoms but with the concern on my part that this could also be intrauterine because of the frequent, mild uterine contractions she was having. She had developed mild swelling in her lower extremities but, fortunately, her blood pressure was normal. On that day, we admitted her to the hospital and she understood that this would probably be for the duration of the pregnancy.

She was begun on bed rest and antibiotics at the time of the admission. Fortunately, with intravenous fluids and improved dietary intake, her uterine contractions resolved and her condition again stabilized. Her laboratory studies did show that she had a significant amount of protein in her urine and we knew that this would make it even more difficult to maintain her blood protein levels if she was losing protein by this route as well as across the placentas supporting the growth of the babies. We also knew this could be the first sign that she was developing preeclampsia.

A week after admission, the babies were found to be growing well by ultrasound and their total estimated weight was in the range of 7 lbs. We were now at 24 weeks and the general feeling was “so near yet so far.” Survival of babies at this gestational age in our neonatal intensive care unit (NICU) is in the range of 50%, but we also knew there were very high risks for long-term complications for survivors born at this early time. I remember this day well, because I gave Joy a hanging ornament with five dangling ornaments that was inscribed “Hang in there.”...

Quintuplet Story - A Physician's Perspective

2009-02-05T17:53:00.000-08:00

Before I became distracted by a plethora of administrative responsibilities, I was in the middle of writing a series about multiple gestations. Although I did not want to spend a lot of time discussing 'high order multiples' (three or more babies) in this series, I did want to highlight some of the medical and ethical dilemmas of such pregnancies (which have again been raised with the recent delivery of octoplets in California) and thought that this might best be done by reviewing the course of a patient from our own practice. As some of you may recall, about a year ago, I posted a note with my thoughts regarding the first birthday of the Gonzalez quintuplets. Fortuitously, over the past month, the family asked that I compose a 'forward' to a book they are writing about their experiences during the pregnancy and following delivery. Over the next several days, I would like to include the draft of that 'forward' so that our readers can gain a better appreciation for the issues involved in such cases...

I first met Joy Gonzalez on November 7, 2006. I remember the date well because it was my birthday and little did I realize at the time what I wonderful birthday gift she would turn out to be. Joy was sent to me for consultation from our specialists in Reproductive Endocrinology and Infertility (REI). She had conceived quintuplets, was now 6 weeks pregnant, and all five babies were alive by ultrasound evaluation. She was well aware of the potential for having a ‘high order’ multiple pregnancy resulting from her infertility treatment, but no preconceptional counseling could have prepared her for the reality of having conceived five babies. My task and responsibility that day was to put that reality into an honest and realistic perspective, a perspective that frequently runs contrary to the popular press portrayal of such pregnancies.

It had actually been many years since I cared for a patient carrying more than three babies. Earlier in my career, such pregnancies, usually the result of infertility treatment, seemed more common, but as the specialists in REI have honed their craft over the years, the occurrence of more than three babies has diminished. There were good reasons to support this approach. The maternal and fetal complications related to such high order multiple pregnancies are well-documented and, even with the remarkable advances in neonatal intensive care, the pregnancy risks are too high to justify intentional efforts that result in more than twins. But, despite the usual precautions to prevent this from happening, here we were with five.

During this first conversation with Joy, I remember being very cautious and candid about the prospects for the pregnancy. She was not a good candidate for a successful outcome under these circumstances with great risks for both her and the babies. Her starting weight was in the range of 108 lbs, she was no more than 5’ 4” tall, she was already having difficulties with nausea, vomiting, and dehydration (problems that had plagued her previous singleton pregnancy until delivery), and she had delivered just a year earlier by cesarean section at 36 weeks for fetal complications during labor. Despite being physically in ‘good shape’ she had had a past history of “bone pain” and had been found to have low bone density (osteopenia). There are risks associated with each of these factors and we proceeded to review these and others with her during that visit.

Without going into detail herein, our discussion focused on a variety of issues. As is always the case in such pregnancies, there are the obvious concerns related to the ‘hormonal load’ of five separate placentas (often contributing to a ‘hyperthyroid-like” state, particularly in early pregnancy), premature labor and delivery, severe hypertensive disorders of pregnancy, gestational diabetes, profound maternal nutritional deficiencies secondary to nausea, vomiting, and the fetal demands (over which she would have no control) and the simple difficulties of maintaining an adequate dietary intake, increasing the risks for fluid and electrolyte imbalances and, later in pregnancy, relative ‘fluid overload’ and even heart failure or pulmonary edema associated with the extraordinary demands on the maternal cardiovascular system. Because she had previously had a cesarean section, she also was at increased risk for uterine rupture, even prior to the onset of labor, with the possible loss of her uterus, the babies, and even her own life. Beyond these medical concerns, we reviewed the additional demands such a pregnancy will place on her family life, both during and after the pregnancy, and interpersonal relationships, financial resources, and those that will be imposed by public scrutiny which may impinge on personal privacy and at times may be less than supportive.

Once these concerns were reviewed with Joy, my professional responsibility was to be quite frank. Joy was told that the medical complications of the pregnancy might threaten both her life and the lives of her babies, that her husband could come out of this pregnancy with no wife or mother to their young daughter, no babies, and that even if the pregnancy got to the point where the babies might survive, the survival might not be without long-term complications. She knew that she would have a difficult course ahead of her and as is always the case in these circumstances, she also knew that she would have some very difficult decisions to make along the way, not the least of which was the pressing decision as to whether or not she would even try to continue the pregnancy with all five babies. I told her that I could not make these decisions for her but I did promise her that whatever decisions she made, we would be there to support her and that we would do everything we could to optimize the pregnancy outcome for her and her family.

Joy left that day to discuss this with her husband, Andres, and returned firm in her resolve. She would continue the pregnancy as is and would put her faith in us to help her and the babies get through the difficult times. At that point I remember looking her in the eye and touching her hand saying, “You have to promise me only one thing and that is when I look you in the eye again and tell you it is time to have the babies, I need you to trust me, regardless of how far along we get in the pregnancy.” She agreed. I also remember thinking to myself at the time that she will need all our tricks and all our prayers to see her through. At that point, we outlined a “plan” for her care during the pregnancy. Part of the “plan” was that we keep the details of the pregnancy out of the public eye until she and Andres felt comfortable enough to face that challenge. Shortly after that visit, I reviewed my concerns about the pregnancy and the “plan” with the other members of our Maternal-Fetal Medicine group and emphasized the importance of respecting her privacy both during and after the pregnancy. Staff members were also informed of this strict responsibility....

Inauguration Day Thoughts

2009-01-20T18:01:00.000-08:00

At the time of the swearing in ceremony for President Barack Obama, I was supposed to be at two different meetings. I didn’t go to either of them. Instead, I went to the OB/GYN Residents’ lounge and turned on the television to watch what will surely go down as one of the most significant events in American history. The room was completely empty, except for me, and that in itself is unusual, but the stark contrast between my solitude during the ceremony and the jubilant throng of more than a million on the Washington mall was somewhat disturbing for reasons I didn’t understand. Vaguely I sensed that it was a moment that should be shared. Indeed, my first thought was that every American should have had the opportunity to take a break from whatever they were doing and watch the ceremony and the speech that followed. Why in a country that cherishes and has worked so hard for a free and democratic society do we not make national elections and inauguration days special holidays?

The proceedings did not disappoint. Ella Fitzgerald’s rendition of “My Country Tis of Thee” was moving and endearing and I will never forget the new President’s smile when she sang the last note. The quartet’s performance of the John Williams’ arrangement was nothing less than stunning – four of the world’s greatest artists, each from very different backgrounds, performing together with uncontained joy and enthusiasm. When Itzhak Perlman hit the first cord on the violin, tears instantly welled-up in my eyes and streamed down my cheeks (at that point I was quite content to be alone), something that had happened to me only once before when the violins began the opening movement of Handel’s “Messiah” while I was a member of the chapel choir at Duke University too many years ago. When the time came for the actual swearing in of the new President and everyone was asked to stand, I found myself rising to my own feet, in respect for the moment and with great sense of awe in my heart for having the opportunity to be a witness to the event.

But regardless of all that transpired before, there is no doubt in my mind that the highlight of the ceremony was the Presidential address which followed. Fully aware that the world would be focusing on every word, listening to the messages, spoken and implied, assessing his demeanor, sincerity, integrity, and forcefulness of the presentation, President Obama rose to the occasion and delivered a speech that will surely be recorded as a defining moment of his presidency and the history of the United States. He did not mince words. In a few short minutes, he reminded us of our past, where we have come from, what we have been through, what that has cost us, and what that has given us as a great nation. It was a message of challenge, it was a message of hope, and it was a message that stressed the necessity of working together, not just as a country, but as a world to preserve that same world for the generations that will follow. To me, one of the most memorable quotes came early in the speech: “…we have chosen hope over fear, unity of purpose over conflict and discord…the time has come to set aside childish things…to reaffirm our enduring spirit...to choose our better history.” The message allows for people to continue believing what they want, but the hard decisions we make moving forward as a nation need to be based on critical evaluation and evidence rather than simple emotion.

I find a special hope in the President’s message and in the months of oratory that preceded the election – and that is a hope for a new emphasis on the health of women and children in this country. During the last 8 years, short-sighted policies in health care and the economic down turn have led to reduced access to care, the highest teen pregnancy rates in years, an epidemic of obesity that will affect generations to come, and great disparities in morbidity and mortality that fall clearly along socioeconomic and ethnic lines. We must invest in the health and well-being of our youngest citizens and our pregnant women if we are ever to address the containment of health care costs in the future. Untold millions of dollars wasted on “abstinence only” education programs must be redirected to early and ongoing educational efforts that emphasize the importance of responsible family planning and means of pregnancy prevention before an individual is prepared to be a good parent. Regular physical, health, and nutritional education need to be brought back into our schools. Such an approach will lay the foundation for a healthier America; a country with citizens who feel better about themselves will also feel more confident and better about the future of their country and will be in a much better position to contribute to its success. I may be an idealist, but these things are possible and I think we have a new President who has the foresight and aptitude to give us a fresh start on our future.

Multiple Gestations - 3 - Common Complications

2009-01-02T16:47:00.000-08:00

Although we have focused our discussion of multiple gestations to this point on twins, higher order multiples (i.e., triplets, quadruplets, quintuplets, etc) also occur but, fortunately, much less often than twins. The hypothesis of Hellin predicts that if the frequency of twinning (n) in a population is known, the frequency of triplets can be estimated as n-squared, the frequency of quadruplets as n-cubed, the frequency of quintuplets as n-to the 4th power, etc. For example, if 1 in 30 pregnancies is twins then about 1 in 1100 would be triplets, and 4 in 100,000 would be quadruplets. Actual findings of higher order multiples in the population support these predicted distributions.

The incidence of twins has increased steadily over the past two decades in the U.S. Although assisted reproductive technologies have contributed to an increase in all multiples and, especially, high order multiples, better monitoring of the infertility patient and general agreement among reproductive endocrinologists to recommend the transfer of no more than two embryos in in vitro fertilization cycles, has stabilized the rise in the latter in recent years. Specific issues related to ‘placentation’ as discussed for twins in the previous post also apply to higher order multiples as do proportionate increases in pregnancy complications.

The most common fetal and neonatal complications in multiple gestations are related to premature delivery. The mean gestational age for delivery of twins is about 35 weeks, triplets about 32 weeks, and quadruplets about 29 weeks. In the U.S., as we mentioned previously, multiples account for about 3% of all deliveries, but they also contribute to about 25% of the very low birth weight (VLBW; < 1500 g) babies that are born. In 2001, 57% of twins and 92% of triplets were born at less than 37 weeks compared to only 10% of singletons. In that same year, 10% of twins, 35% of triplets, and more than 70% of higher order multiples resulted in VLBW babies. Martin and colleagues (National Center for Health Statistics Report 2003;42) reviewed birth weight data from 2002 and found the mean birth weight for singletons was 3,332 g, whereas that for twins was 2,347 g, triplets 1,687 g, and quadruplets 1,309 g. It is significant to note that 80% of the triplets and higher pregnancies were the results of the ‘successes of infertility programs throughout the country. It is also interesting to note that women who require infertility treatment to conceive are at even greater risk for preterm and low birth weight babies than women who spontaneously conceive multiple gestations (Schieve, et al., NEJM 2002;346:741; Dhont, et al., Am J Obstet Gynecol 1999;181:688; McElrath, et al., Obstet Gynecol 1997;90:600).

Early gestational age at delivery, low birth weight, and intrauterine growth restriction at these early gestational ages contribute to the morbidity and mortality accompanying multiple gestations. U.S. Vital Statistics data indicate that twins are about 7 times more likely than singletons to die during the first month of life (and 5 times more likely to die during the first year) and triplets are about 20 times more likely to die in the first month (and 12 times more likely during the first year). Multiple gestations require a high rate of admission to neonatal intensive care units and are at risk for all of the common complications of prematurity, both acute and chronic, such as respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity, and chronic lung disease. Despite the dramatic advances that have been made in early neonatal care, worldwide data suggests that multiples are 4 to 10 times more likely to result in cerebral palsy and permanent handicaps than singleton pregnancies. The short- and long-term costs of health care for multiples are staggering when compared on a per baby basis to singleton pregnancies.

Maternal complications during pregnancies with multiples also contribute to morbidity, mortality, and health care costs above that seen for singletons at every stage of pregnancy. There are greater risks for miscarriage in first and second trimesters, severe nausea and vomiting of pregnancy (hyperemesis gravidarum), bladder and kidney infections, iron deficiency anemia (and frank maternal malnutrition with higher order pregnancies), thromboembolic complications, gestational diabetes, hypertensive disorders of pregnancy, including severe preeclampsia syndromes, acute fatty liver of pregnancy, as well as premature rupture of membranes, early, and cesarean deliveries. Abnormalities of placentation and uterine overdistention increase the risk for bleeding complications both during the pregnancy and at the time of delivery. If a woman with multiples has previously had a cesarean delivery, she may also be at greater risk for uterine rupture prior to the onset of, or during, labor. Multiple, and sometimes prolonged, hospitalizations related to any of these complications contribute to the increased costs of health care for these pregnancies and are characteristic of high order multiples. Indeed, the higher the order of the multiple pregnancy, the greater the risk for each of these complications…

Multiple Gestations - 2 - Placentation in Twins

2008-12-29T10:22:00.000-08:00

Another area of confusion for patients relates to the actual development of the placentas (placentation) of twins. Perhaps this is where the patient mentioned at the outset of our last post had problems understanding – her different gendered babies did have a large, single, fused placenta. So, let’s spend a few minutes in this post clarifying the issue of placentation…

In singleton pregnancies, the baby is surrounded by the ‘bag of waters’ and the balloon that comprises that bag is actually made up of two separate layers that are adherent to each other. The layer on the fetal side of the balloon is the amnion and the layer on the placental side is the chorion. In dizygotic ('fraternal') twins, the babies are just like two separate singleton pregnancies and are always contained within completely separate sacs, each made up of both amnion and chorion. This is then termed diamnionic, dichorionic placentation. Under these circumstances, the babies may still have either completely separate placentas or they may have placentas that are ‘fused’- grown together to appear as one placenta. Even when the placentas are ‘fused’ in diamnionic, dichorionic, pregnancies, it is very rare for the blood vessels from one baby’s placenta to cross to the placental side of the other baby. The importance of this will become clearer as we continue our discussion over the next few posts.

The diamnionic, dichorionic placenta can usually be readily identified by ultrasound. The ‘membrane’ separating the babies contains 4 layers – two chorions sandwiched between two amnions. This appears fairly thick by ultrasound. Furthermore, if one looks at the actual insertion site of the membranes on the placenta (s), this will have a v-shaped appearance with the chorions and some placental tissue extending a small distance into the 4-layer membrane separating the babies. This ultrasound finding has been given various names, but I was taught to call this the ‘twin peak’. After the babies are born, the intervening membrane is very opaque due to its relative thickness and, if not known sooner, diamnionic, dichorionic placentation can usually be confirmed at that time.

With monozygotic (‘identical’) twins, the issue of placentation is a little more complicated and depends upon when the single embryo divides into two. If the embryo divides within 3 days of fertilization, the ‘identical’ twins will have diamnionic, dichorionic placentation just like the dizygotic twins mentioned above. This occurs in about 20-30% of all monozygotic twins. If the division occurs between days 4 and 8, the twins will most likely be diamnionic (two amnions) contained within a single chorion – diamnionic, monochorionic placentation. This occurs with 70-80% of monozygotic twins. If the division occurs between days 8 and 13, the placentation is most likely to be monoamnionic, monochorionic – both babies contained within a single ‘bag of waters’; and, division after this will often result in monoamnionic, monochorionic twins that are also ‘conjoined’, sharing various degrees of body parts and internal organs. The latter two stituations, fortunately, occur in only about 1% of monozygotic twins.

Diamnionic, monochorionic twins can usually be readily identified by ultrasound as well. The intervening membrane is very thin (containing only the two amnions) and there is no ‘twin peak’ evident where the amnions connect with the placenta. (In cases of monochorionic twinning, it is not uncommon for there to be vasculature connections between the two sides of the placenta as will be discussed in a later post). In monoamnionic, monochorionic placentation, no intervening membrane is seen and the babies are found to be freely floating together within a single sac, often having their umbilical cords intertwined or even knotted. The two umbilical cords in monoamnioic twins can usually be seen arise in very close proximity to each other at their placental insertion sites.

Pregnancy complications and perinatal mortality are directly correlated with the type of placentation. In the case of perinatal mortality, the rate in diamnionic, dichorionic twins is about 8.9%, still more than twice that seen in singleton pregnancies. Perinatal mortality rates in diamnionic, monochorionic twins are as high as 25%; and in momoamnionic, monochorionic twins this is usually in the range of 50-60%. Major contributors to these high rates of loss in twin pregnancies include prematurity, intrauterine growth restriction, congenital birth defects, maternal preeclampsia and a condition termed ‘twin-to-twin transfusion’ syndrome (sequence), all of which will be discussed in upcoming posts to this series…