Pregnancy in kidney transplant recipients - Hope with caution...

Being a parent is probably one of the most desirable and difficult tasks in life.
While ESRD is associated with a high rate of infertility related to hormonal changes and anovulation, most patients undergoing renal transplantation resume menstrual cycles and fertility in approximately 6 months!

Contraception is critical post-transplant due to potential teratogenicity of MMF (1st trimester pregnancy loss, facial and limb deformities as can be seeing on the figure). It is essential to plan ahead of time for patients interested in getting pregnant once renal allograft function is stable for at least 6 months. Conversion from MMF to AZA must be done at least 2 months prior to conception.
Best timing of pregnancy is unclear though waiting at least 1 year after transplant is generally recommended. Most common immunosuppressive regimens are tacrolimus or cyclosporine with AZA +/- prednisone.

 The incidence of birth defects in recent cohort was similar to the proportion in the general population of 3–5%. Few cases of successful in vitro fertilization (IVF) have been reported as well. Higher risk of pre-eclampsia (about 30%), prematurity (~35 weeks) and low birth weight have occurred in pregnant-transplant recipients. 

Approximately 30% of patients also suffer deterioration of kidney function after pregnancy. Overall perinatal mortality at 5.8% was almost six times higher among babies born to transplant recipients than among the general population.

Specific management: 
- If pregnancy occurs on MMF, stop medication right away and performed careful counseling to couple (about 40% risk of miscarriage and 30% risk of malformations)
 - Convert MMF to AZA. A dose of 500mg BID of Cellcept equals approximately 200mg AZA, though variability of metabolism and weight has to be taking into account. After conversion, monitor LFTs and WBC. No need to overlap drugs during conversion.
- Monitor CNI levels since they may vary during pregnancy (Monthly Levels – 1st and 2nd trimester and weekly levels on third trimester)
- Start calcium and vitamin D for bone protection in addition to folate-containing multivitamin
- Check TSH on each trimester
 - Stress dose steroids recommended during maternal distress and in labor (e.g. hydrocortisone 50mg during active labor).
 - There is paucity of data regarding breastfeeding and consequences of immunosuppressive drugs in the fetus.

Next time you see a young female transplant recipient, please don't forget to discuss about methods of contraception in addition to their usual immunosuppressive drugs!! Being aware of risks and planning ahead of time can prevent devastating consequences to the new parents...

Pregnancy and Dialysis

A woman with no past medical history was admitted to the ICU service with acute kidney injury secondary to atypical HUS. She was early in pregnancy and we were consulted in order to start dialysis. The management of a pregnant dialysis patient is no simple matter.

About 13-36% of TTP-HUS in women is associated with pregnancy. Pregnancy may be a risk factor for developing TTP-HUS because of hypercoagulability, loss of integral endothelial cell membrane proteins, decreased fibrinolytic activity and ADAMTS13 activity. Among all patients with pregnancy associated TTP-HUS, 8% occurs in the 1^st trimester, 16% in the 2^nd trimester and 77% in the 3^rd trimester or post-partum. 

There are a number of factors to think about in the management of pregnant dialysis patients:

1. Duration and frequency of dialysis:  Pregnant patient usually start on daily dialysis with a predialysis BUN goal of <50mg/dl. It has been shown that patients on nocturnal hemodialysis with an average of 48hours/week have better outcomes than women who dialyzed 20 to 26 hours/week.

2. Anemia:  Pregnant women usually require higher doses of erythropoietin and iron, with goal of Hg>10g/dl, and transferrin saturation>30%. These targets are based more on patients in the general dialysis population and are not evidence based. Pregnant women are usually anemic although their red cell mass increases.

3. Hypophosphatemia: Our daily phosphorous ingestion is 800 to 1600mg. 2.5g to 3.0g phosphorous is removed during a regular 4 hour dialysis treatment. Phosphorous levels will decrease in patients who receive intensive hemodialysis.   Hypophosphatemia can cause tissue hypoxia and intracellular depletion of adenosine triphosphate with impairment of glucose metabolism. In a pregnant patient, our goal is to keep the phosphorous level >3mg/dl with either po repletion or supplemental phosphorous in the dialysate.

4. Calcium: 25 to 30 g of calcium is required for fetal skeletal growth. This demand requires transfer of 140mg/kg/day calcium across the placenta. To prevent osteopenia, it is recommended that an additional 1500mg of calcium be ingested daily during pregnancy.

In conclusion, adequate dialyses, treatment of anemia, maintenance of nutrition and electrolyte stability are the most important factors for a successful pregnancy in chronic dialysis patients. The outcomes of pregnancy in dialysis patients were reviewed in a previous blog post.

 

Our patient was started on 6 times/week hemodialysis for 4 hours each session.  Her phosphorous level was 2-2.5mg/dl after 1 week on hemodialysis.  With aggressive oral repletion and a regular diet, her phosphorous level was maintained at 3mg/dl upon discharge. 

Posted by Jie Cui

Azathioprine in pregnancy

We recently discussed this issue in conference and I thought it might be worth sharing a few interesting points:

Azathioprine is normally converted to the active metabolite 6-mercaptopurine. However, in pregnancy the placenta can metabolize azathioprine to thiouric acid, an inactive metabolite. In addition the fetal liver does not have inosinatopyrophosphorylase which therefore largely protects the fetus from exposure to active compounds.

Azathioprine has been classed as FDA category D - positive evidence of risk.
Despite conflicting data, general expert opinion suggests that azathioprine may be considered for use during pregnancy in certain situations (where the potential benefits outweigh potential risks).

In terms of breast feeding, in a small study, active metabolites have been detected in small quantities in breast milk. Overall the significance of this remains to be fully determined. Manufacturers have taken the official stance to warn against breast feeding while taking the drug.


As with all considerations of alterations in immunosuppressive dosing, careful consideration of risks and benefits should be explored in detail with the treating physician before any change is undertaken.

Pregnancy in the Dialysis Patient

While recently reading about hypogonadism in the dialysis population, I came across this review on the pregnancy outcomes in women on dialysis, summarizing observational studies published between 1995 and 2009. I have participated in only a few pregnancy-planning discussions with women with CKD, but they have all been emotionally tough. None of my patients were dialysis patients, however, whom I would have predicted would have even worse outcomes with pregnancy as has been reported for CKD (for example, a rate of preterm delivery of 63% and perinatal death of 4% reported recently here).


The results of this review suggest that the outcomes in women on dialysis, while better than expected in some aspects (for example rate of live birth of 79%), still carry significant risks for the mother and baby (for example, a perinatal death rate of 17.6%).


Among women of childbearing age on dialysis, DaVita reports that only 1-7% can get pregnant – due to complete cessation of the menstrual cycle, or anovulatory cycles. However, some women continue to have menstrual cycles – as you’ll be smart to remember next time you’re asked about a female PD patient with a bloody peritoneal fluid effluent.


Among those who do get pregnant (222 pregnancies studied in this review), an astonishing 79% resulted in a live birth, although only 8% were term births (71% were premature for an overall preterm delivery rate of ~85%!). The two most common reasons for premature birth were premature labor (approximately 1/3rd) and fetal distress (another 1/3rd). Of the remaining 1/3rd, intrauterine growth restriction and hypertensive disease were most common. The rate of delivery by c-section in the subgroup where this data was available, was 37%.


Among the fetal/neonatal complications, prematurity was most common. Three cases of fetal abnormalities were reported, including one case of right-sided pulmonary agenesis. The rate of polyhydramnios was 32%, postulated to be due to increased diuresis by the fetal kidneys due to elevated urea. There were 19 neonatal deaths and 28 perinatal deaths among 159 live births for which this data was reported, yielding a neonatal mortality rate of 11.9% and perinatal mortality rate of 17.6%. It is not clear if perinatal mortality includes neonatal mortality in this article, though the latter percentage by itself is a sobering figure.


Among the maternal complications, hypertensive disease was the most common, though at a reported 30% it is much lower than I would have predicted. Among the 14 women in the cohort on PD, 4 developed peritonitis and 2 developed uterine bleeding so significant to require surgical intervention and, in one case, hysterectomy. The specific adjustments to renal replacement management for pregnant women were not discussed in detail, though included increased time and frequency of dialysis, which was associated with decreased rate of polyhydramnios and improved fetal outcomes.


As it is still a relatively rare event, I would love to hear from any of you who have helped manage pregnant women on dialysis.


Marta Hristova MD

Physiological changes of pregnancy

Here are some interesting points I picked up at an ASN review to reinforce Gearoids post discussing changes in reference values during pregnancy and Michael's board review post which covers a lot of the physiology also.

Kidneys increase by 1-2cm in length and up to 30 - 70% in volume, due to an increase in both vascular and interstitial compartments.

The collecting system becomes dilated, with up to 80% of women having evidence of hydronephrosis. The right side predominates, as the gravid uterus is more often dextro-rotated. This can predispose to the development of UTIs due to urinary stasis.

Plasma volume steadily rises by 30-50 % up to around 32 weeks, causing a dilutional anaemia. Total body water can increase by 6-8 litres – most women have some clinically detectable edema.

Cardiac output increases, initially via increased heart rate of 10-20%, followed later by an increase in stroke volume of >20% by week 8. This results in an overall increased cardiac output of 40-50% by week 24. However, systemic vascular resistance falls throughout pregnancy, leading overall to a decrease in mean arterial blood pressure of around 10mmHg by the second trimester.

The net result is increased tissue perfusion – GFR increases by up to 50% by the middle of the second trimester, with corresponding decreases in serum creatinine of similar magnitude. This is maintained until the mid-third trimester, after which it begins to decline towards pre-pregnancy levels.

Despite increases in GFR, glomerular blood pressure appears to remain relatively protected by concomitant reductions in afferent and efferent arteriole resistance.

Proteinuria – there is some debate if ‘normal’ amounts of proteinuria during pregnancy exist, or if any proteinuria should be seen as abnormal. Certainly, new proteinuria, progressively increasing proteinuria or levels over 0.3g/day should ring alarm bells. The presence of hypertension with any proteinuria mandates extremely close follow-up and blood pressure control. Return to normal protein excretion after pregnancy may take up to 5 months.

Glucosuria – mild glucosuria can occur in the absence of hyperglycaemia due to increased filtered load and reduced tubular capacity for reabsorption.

Acid-base – a mild chronic respiratory alkalosis usually exists due to normal hyperventilation in pregnancy, caused by progesterone-mediated stimulation of respiratory centres.

Osmolality – a reduction in Posm of 5 - 10mOsm/Kg occurs. The osmotic threshold for AVP release and thirst are reduced (possibly by hCG), allowing maintenance of this new set-point. Note also, the placenta releases vasopressinase, necessitating an increased rate of AVP production. Overall, serum sodium can therefore fall by 4-5 mmol/L during pregnancy.

Finnian Mc Causland MD

Is this normal?

When seeing consults on the maternity floor, figuring out the normal values at the various stages of pregnancy can be a frustrating experience. There are well recognized hemodynamic and biochemical changes which occur from the earliest stages of a normal pregnancy and failure to recognize them could lead to misdiagnosis. Up to now, determining what was normal or abnormal could be difficult but last year a group from Texas published a meta-analysis which pulled together various sources to provide a comprehensive list of normal values for commonly used lab tests during the different trimesters.

See this previous post concerning some of the renal adaptations associated with a normal pregnancy.

Board Review; Pregnancy answer

Each of the following choices is expected to occur during pregnancy except for A and D. Let’s go through each of the possible choices.

A. This in partially incorrect. Hyperventilation (with resultant hypocapnea, not hypercapnea) occurs during pregnancy and is largely a consequence of stimulation of the respiratory center via progesterone. Therefore, in pregnancy you typically see a chronic respiratory alkalosis which is compensated by renal excretion of bicarbonate. Luckily, in pregnancy the oxygen-dissociation curve is not dramatically altered due to increased 2,3 DPG levels in pregnancy and normalization of blood pH through renal compensation.

B. This is correct. During pregnancy the intestinal absorption of calcium nearly doubles as early as week 12 of pregnancy and is likely the major maternal adaptation to meet the fetal need for calcium. As intestinal calcium absorption increases, extra calcium is either deposited in the fetal skeleton, the maternal skeleton or is excreted by the kidneys. Renal calcium excretion is increased as early as the 12th week of gestation and 24 hour urine values (corrected for creatinine excretion) can exceed the normal range. Conversely, fasting urine calcium values are normal or low, confirming that the hypercalciuria is a consequence of the enhanced intestinal calcium absorption. Pregnancy is recognized as a risk factor for kidney stones and the absorptive hypercalciuria of pregnancy is one reason for this.

C. This is also correct. During pregnancy kidney size can increase by 20%. This increase in kidney size also corresponds to an increase in GFR and renal blood flow.

D. This is incorrect. Remember that filtration fraction (FF) is the ratio of glomerular filtration rate (GFR) to renal blood flow (RBF). The filtration fraction represents the proportion of fluid reaching the kidneys which eventually passes into the tubular lumen. In pregnancy, although the GFR is increased, RBF is increased to a greater extent. Therefore, FF actually decreases in pregnancy. Since the increase in GFR and RBF is not associated with an increase in FF, there is no risk of secondary FSGS in pregnancy. This is supported by small studies.

E. This is correct. During pregnancy, urinary protein excretion increases from normal nonpregnant levels of 60–90 mg/24 hours to 180–250 mg/24 hours in the third trimester. Even if slightly increased during pregnancy, urine protein excretion rarely reaches levels that are detected by usual screening methods, such as 1+ on urinary dipstick (i.e., 30 mg/dL, which is roughly equivalent to 300 mg in 24 hours). Although the mechanism for this possible increase has not been established, it seems likely that absorption of filtered protein in the proximal tubule is reduced.

F. This is correct as well. During pregnancy, physiologic changes occur in volume- and osmoregulation that effect plasma osmolality and sodium concentration. During a normal pregnancy, the average plasma osmolality decreases by 5-10 mmol, and the sodium concentration is decreased by 5 mmol/l. This drop in plasma osmolality has been explained by a phenomenon termed ‘reset osmostat’. A ‘reset osmostat’ is when the osmotic threshold above which ADH-release and a thirst stimulus occur changes. This threshold is decreased to a lower steady state value during normal pregnancy. The mechanism that causes the reset-osmostat phenomenon is unknown.

On a lighter note, the “Gross Clinic” has completed its restoration and is currently on exhibit at the Philadelphia Museum of Art. It is a must-see for any devotee of medicine.
Michael Lattanzio DO

Board question: Hypertension-1 answer

The best answer is D.

Lifton et al. described a single gene mutation on the hormone-binding domain of the mineralocorticoid receptor (MCR). Individuals with this missense mutation develop early-onset hypertension with characteristic low renin and aldosterone levels. The mutation causes the MCR to be constitutively active, regardless of aldosterone levels, and transforms the MCR so that steroid hormones that are typically antagonistic become agonistic (in particular, progesterone and cortisone).

During pregnancy, when progesterone levels increase 100-fold, the MCR becomes hyperactive and leads to sodium reabsorption and potassium secretion via the principal cell of the distal collecting tubule (Figure above). The avid sodium retention and volume expansion appropriately suppress renin and aldosterone levels. This condition is not associated with proteinuria, edema, or neurologic changes, which distinguishes it from pre-eclampsia.

Given the low levels of aldosterone, this condition is refractory to standard medical therapy aimed at reducing aldosterone levels through RAAS blockade. In fact, mineralocorticoid receptor antagonists can actually exacerbate hypertension in this condition! Delivery of the fetus may be necessary to treat severe, refractory hypertension during pregnancy.

Essential hypertension results from a complex interplay of both genetic and environmental influences. Uncommonly, an isolated genetic mutation can engender hypertension, like in this case. These monogenic forms of hypertension affect either electrolyte transport in the distal nephron, or the synthesis and/or activity of mineralocorticoids, leading to a common final pathway of increased distal tubular reabsorption of sodium and chloride, volume expansion, and hypertension.

Other low renin, monogenic forms of hypertension include:

• Familial Hyperaldosteronism Type 1 (aka, glucocorticoid-remediable aldosteronism)
• Familial Hyperaldosteronism Type II
• Syndrome of apparent mineralocorticoid excess
• Liddle syndrome
• Pseudohypoaldosteronism type II (aka, Gordon syndrome)
• Congenital Adrenal Hyperplasia

They provide excellent fodder for any number of board-style questions!

Michael Lattanzio DO

Board question of the week: Hypertension-1

A 26-year-old primigravid woman is admitted during her 34th week of pregnancy with severe, refractory hypertension. She was noted to have mild hypertension prior to pregnancy. Her family history is remarkable for pregnancy-related hypertension in her aunt. Her blood pressure decreased early in the course of the pregnancy, but then rose dramatically, reaching 170/100 mmHg at 29 weeks despite antihypertensive therapy. She denies any edema or neurologic changes.

Her chemistries are listed below:

Na-143 K-3.6 Cl-110 HCO3-28 BUN-8 Creat-0.5 Uric Acid-3

Urinalysis negative for blood and protein

Urine electrolytes:

Urine sodium 20 meq/L, Urine potassium 75meq/L

Renin and Aldosterone level were both suppressed

Due to worsening blood pressure, a Caesarian section was performed, and the patient delivered a healthy baby girl. Her blood pressure control stabilized shortly after delivery.

The answer and explanation will be posted on Monday July 7th

Michael Lattanzio DO

*RFN board questions are meant to help introduce concepts about nephrology related diseases and do not represent actual questions seen on the ABIM exam.

HCG in Kidney Disease

That cardiac biomarkers, including Troponin and BNP, can be elevated in CKD or ESKD without necessarily having clinical significance is familiar to most of us. Whether you believe that an elevated Troponin in ESKD is due to diminished clearance or some constant low-level myocardial damage of unclear significance, most would be comfortable dismissing borderline positive results without suggestive signs or symptoms.

Recently I was asked an interesting question pertaining to pregnancy testing in CKD and ESKD. A dialysis patient had a serum HCG level that was borderline positive. The patient and her physicians wanted to know whether this could be a false positive related to her kidney disease or whether she may in fact be in the first weeks of a pregnancy. After searching the literature and conferring with my OB colleagues, here is what I found:

Here is a case report and a nice review of the topic. Not surprisingly HCG levels can be falsely elevated in CKD, though for quite a variety of reasons. These include decreased clearance of HCG, increased levels of other gonadotropins that cross react with the HCG assay, including LH and FSH, as well as other cross-reacting substances including cold agglutinins and heterophile antibodies.

How to distinguish? The urine HCG assay does not cross-react with these substances, and so, if the patient still makes urine, confirmatory testing with urine HCG is a reasonable first step. In ESKD patients who no longer make urine, progesterone levels can be used as a next step especially when more immediate knowledge of pregnancy status is required. If progesterone is low, viable pregnancy is unlikely, though serial serum HCG levels should be monitored to rule out non-viable pregnancy (egs, ectopic). If there is no urgency to determining pregnancy status, follow-up serum HCG to see if doubling occurs at expected intervals should be performed. In my patient's case, her serum HCG level one week later was the same as that one week prior, and the serum HCG was deemed to be elevated due to decreased clearance in ESKD.

Magnesium Therapy in Eclampsia/Pre-Eclampsia

Eclampsia and pre-eclampsia are characterized by the new onset of hypertension and proteinuria after 20 weeks of gestation in a previously normotensive woman. One of the major causes of morbidity to both mother & fetus is the occurrence of seizures. Fortunately, decades of experience with intravenous magnesium have led to a generally safe and effective use of this medication as an anticonvulsant. iv Mg is indicated both as a seizure prophylactic agent (in severe pre-eclampsia) as well as for the prevention of recurrent eclamptic seizures.

Generally, iv magnesium is given first as a loading dose (e.g., 6 grams iv bolus given over 15-20 minutes) followed by a continuous infusion of 2 grams per hour. An important caveat to be aware of as nephrologists is that as magnesium is excreted by the kidneys, individuals with acute or chronic renal failure are especially susceptible to hypermagnesemia and its toxic effects. This is not so uncommon, as thrombotic microangiopathy is often seen in women with advanced pre-eclampsia/eclampsia. Up-To-Date recommends giving the full loading dose (6 grams) but a reduced continuous infusion rate of 1gram per hour in individuals with moderately reduced GFR (Cr less than 2.5 mg/dL) and NO continuous infusion rate for individuals with a severely-reduced GFR (Cr greater than 2.5 mg/dL). Although the measured serum Mg concentration does not totally correlate with symptoms, the suggested therapeutic range is between 4.8 - 8.4 mg/dL.

Early magnesium toxicity can be detected as a loss of deep tendon reflexes (typically occuring at levels between 10-12 mg/dL) with more severe symptoms (respiratory paralysis, cardiac arrest) occuring at Mg levels greater than 12 mg/dL. Calcium gluconate can be given as a cardiac stabilizing agent in these instances. Mg therapy may also transiently suppress PTH release and can result in a mild hypocalcemia.

Gestational Diabetes Insipidus

Changes in the regulation of serum osmolarity is just one of the many chances that occurs during the normal physiologic response to pregnancy.  Beginning with the first trimester, the plasma osmolarity level, serum Na, and osmolarity thresholds for the thirst and ADH responses are decreased by about 10 mosm/kg, a phenomenon which generally lasts through term.  

Later on in pregnancy, however, levels of circulating ADH actually decrease--due to production of the enzyme vasopressinase, which drastically enhances the turnover of ADH.  In most cases, the presence of vasopressinase counterbalances the decreased threshold for ADH secretion.  However, in individuals with gestational diabetes insipidus--a rare disorder in which vasopressinase production is excessive--can develop polyuria, polydipsia and excessive thirst, usually manifesting during the third trimester.  

Gestational diabetes insipidus, if severe, can be treated with DDAVP--a synthetic peptide analogue of ADH (pictured above) which is resistant to endogenous vasopressinase activity.

Immunosuppressant Drugs in Pregnancy

Is something missing in your life?  Is it the opportunity to take multiple-choice exams?  If so, check out this 10-question ASN-sponsored practice test designed to prepare Nephrology Fellows to be ready for the upcoming Nephrology Boards in November.  You can cut & paste the link is here since I'm having some problems embedding it for some reason:

www.asn-online.org/ite 

Quick teaching point I picked up from the exam:  reviewing the management of immunosuppressant drugs in the kidney transplant patient who is pregnant.  

CNI's (cyclosporine & tacrolimus) are okay, as are steroids and azathioprine.  The two main drugs to watch out for are MMF (Cell Cept), which is a known teratogen in animal studies, and sirolimus (rapamycin) which is a suspected teratogen.  Kidney transplant patients who are on either Cell Cept or rapamycin should have these agents switched to a safer immunosuppressant (e.g., azathioprine) if they are considering pregnancy.  

Pre-Eclampsia & HELLP!

The pre-eclampsia story (which I have mentioned previously on this blog) is one of the triumphs of basic nephrology research over the past few years, and apparently the folks at the ASN thought so as well, as Dr. S. Ananth Karumanchi received the Young Investigator Award this year.  He gave a very nice overview of this story at his talk.  To summarize:  most women with pre-eclampsia have high levels of sFlt-1, a VEGF receptor antagonist elaborated by the placenta.  When transferred to pregnant rats, purified sFlt-1 recapitulates the thrombotic microangiopathy phenotype, proving that sFlt-1 is not only correlative but also causative.  Intriguingly, Dr. Karumanchi presented data showing that routine blood samples from pregnant women several weeks PRIOR to their diagnosis of pre-eclampsia showed elevated sFlt-1 levels.  This suggests that an assay for sFlt-1 could well be used for early identification of women who will go on to develop pre-eclampsia.  

One missing piece to the puzzle, however, was that sFlt-1 injection in rats did not seem to produce any liver pathology.  How does one explain the existence of the related HELLP Syndrome (HELLP = hemolysis, elevated liver enzymes, and low platelets) with this supposedly unifying theory for pre-eclampsia?  It turns out that another circulating protein produced by the placenta--soluble endoglin--may be responsible for this.  Circulating endoglin levels are higher in individuals withi HELLP, and co-njection of both sFlt-1 + soluble endoglin into animals leads to both endothelial and liver damage.  

Treating Lupus Nephritis During Pregnancy

It is somewhat controversial whether or not pregnant women with lupus experience flares more frequently than their non-pregnant counterparts.  Regardless, however, the issue of a lupus flare in a pregnant patient is not uncommon, especially considering that the disease tends to affect young females.

In general, the mainstays of treatment for lupus flares during pregnancy are AZATHIOPRINE and STEROIDS; both have had a pretty good track record for safety in pregnancy.  Low-dose cyclosporin A may also be a consideration, and for patients in whom there is evidence of anti-phospholipid antibody syndrome, clot prophylaxis should be initiated with aspirin or low-molecular weight heparin.  

Drugs specifically to be avoided in lupus pregnancies are CYCLOPHOSPHAMIDE (which unequivocally causes birth defects, especially during the 1st trimester) and MYCOPHENOLATE MOFETIL (which recently has been shown to result in ear and other facial malformations such as cleft lip and cleft palate).  

Anti-hypertensive Medications in Pregnancy

Managing hypertension in pregnancy is difficult in the sense that there is not a lot of data to guide us. Most of the drugs listed as "safe during pregnancy" are considered so largely based on many years of experience.

With that said, here are a list of medications which can be used, and those which should be avoided:

1st line agents: labetalol, hydralazine, alpha-methyl dopa, and calcium-channel blockers.

some possible side effects : beta-blockers (which are associated with low birth weight) and diuretics.

definitely contraindicated: ACE-inhibitors; ARBs. The classical teaching was that ACE-inhibitors were tolerable during the 1st trimester but needed to be avoided after that; more recent suggests that even 1st trimester ACE-I use is associated with an increased risk of fetal malformations.

sFlt-1 & Pre-eclampsia

One of the most exciting new advances in the field of pre-eclampsia has been the relatively recent discovery of the role of sFlt-1 in pre-eclampsia.

sFlt-1 (which stands for "soluble Fms-like tyrosine kinase) is a circulating protein which is able to bind to and inhibit vascular endothelial growth factor (VEGF). It was initially noted that there is an increased level of sFlt-1 in the blood of pregnant women with pre-eclampsia which rapidly goes away following delivery. Furthermore, injection of sFlt-1 into pregnant rats results in hypertension, proteinuria, and endothelial dysfunction causing a thrombotic microangiopathy pattern of injury (all the cardinal features of pre-eclampsia), implying that the elevated sFlt-1 levels are not just associative with pre-eclampsia but also causative (see Maynard et al, JCI 2003). The current model is that VEGF is required for maintenance of a healthy endothelium; the release of sFlt-1 by placental cells inhibits VEGF activity and thereby deprives endothelial cells of this necessary stimulus.

One might therefore be able to treat pre-eclampsia by designing inhibitors of sFlt-1, or perhaps by overwhelming the inhibitor with exogenous VEGF.

Ovarian Hyperstimulation Syndrome

I saw my 2nd case this year of renal effects of Ovarian Hyperstimulation Syndrome (OHSS).

OHSS is a complication of in vitro fertilization therapy, in which pharmacologic doses of gonadotropin therapy can lead to enlarged ovaries filled with multiple cysts, the result of multiple follicles maturing simultaneously. The follicles release multiple growth factors (e.g. VEGF) which increase capillary permeability, often resulting in massive ascites, weight gain, and volume overload. In both cases I have been consulted on, the patients have had significant intravascular volume depletion and hypovolemic hyponatremia as a result of significant 3rd-spacing.