No benefit found with Intralipid Therapy. Ground Breaking New Study from BRI

Posted By Braverman IVF & Reproductive Immunology || 19-Jan-2017

  1. Control of inflammation: a key parameter to establish and maintain a healthy pregnancy

Pregnancy is one of the most complex process requiring a fine-tune communication between a receptive endometrium (uterus) and a developing and competent embryo.
This cross-talk is highly dependent on uterine microenvironment whose dysregulation through untimely activation of inflammatory processes can have devastating effects on pregnancy outcomes leading to miscarriages or obstetrical complications including but not limited to pre-eclampsia, preterm birth or even still birth.

A healthy pregnancy switches the maternal immune system toward a more tolerant, low inflammatory state.
Many autoimmune diseases or other conditions such as PCOS or endometriosis may lead to systemic inflammation and oxidative stress negatively impacting oocyte/embryo quality and may be involved in infertility and recurrent pregnancy loss (RPL). For more information, read our blog on the topic.

It is crucial to minimize these uncontrolled inflammatory changes to allow the establishment and the maintenance of a pregnancy.

  1. Omega 3: Fatty acid playing a key role in preventing inflammation

Fatty acids are classified based on the number of carbons that determines their lengths and the number of unsaturation (double bonds) that confer them specific properties. Fatty acid brought to your system in the form of triglyceride (by your diet) are a source of energy for your body.
Thus, the quality of the maternal diet is directly impacting maternal health, pregnancy and fetal outcomes, as well as the risk of pregnancy complications.

In the below section, we will explain you how a category of fatty acid, the Omega 3 (ω3) could have multiple beneficial effects on minimizing your inflammation and improving your chance for a healthy pregnancy.

  1. Omega 6 and Omega 3: dichotomic pathways
Both omega 3 and omega 6 fatty acids are essential components of phospholipids present in all tissues. They both synthesize lipids, support normal cell function as well as fetal development (1).

The precursors of the omega 3 (alpha -linoleic acid: ALA) and omega 6 (linoleic acid: LA) pathway are both essential fatty acids (your body can not synthesize them) and must be obtain through your diet (2).
As seen in the simplified Figure 1 below, ALA will give rise to two ω3 fatty acids: EPA and DHA (collectively referred as the omega 3), that play a major role in reducing inflammation and oxidative stress.
LA (ω6 pathway) will give rise to the arachidonic acid (AA) that is pro-inflammatory.
Although some omega 6 fatty acid (dihomo-γ-linolenic acid) could have anti-inflammatory properties, the ω6 pathway is considered as pro-inflammatory whereas the ω3 pathway is anti-inflammatory (3-4).

Figure 1: Omega 6 and omega 3 metabolic pathways.

The ω3 anti-inflammatory effects are multiple:

- It inhibits AA-derived eicosanoids by EPA incorporation to the membrane phospholipid at the expense of AA (5).

- It inhibits the Toll Like Receptor/NFKB pathway and the enzyme COX2 (enzyme responsible of the production of pro-inflammatory molecules) resulting in the inhibition of pro-inflammatory cytokine production (6-7).

- It suppresses T lymphocyte activation (8).

- It induces the production of resolvin (derived from EPA and DHA), maresin and protectin (derived from DHA only) which are potent anti-inflammatory factors (9) and have been shown to play key roles in preventing several pregnancy complications associated with excessive systemic and placental inflammation (10).

The ω3 anti-oxidative properties (11-12) are triggered through:

- the inhibition of reactive oxygen species (ROS)

- reduction of peroxide production

- reduction of the enzyme activity NOS (involved in reactive species production).

  1. Manipulating your fatty acid content through omega 3 supplement could restore a more balanced ω6/ω3 ratio, help minimize inflammation and be beneficial to pregnancy
  1. How can I improve my ω6/ω3?

Living in a westernized country, we have a diet that is very rich in omega 6 (processed food, fast-food, lots of meat, low amount of vegetables), therefore our ratio between omega 6 and omega 3 (ω6/ω3) is very high, reaching value of 20 or more.
This ratio, reflecting our propensity to stimulate anti- (ω3) or pro-inflammatory (ω6) pathways could be modulated by changes in your diet. Indeed, by reducing your ω6 intake (more vegetables, less meat) and increasing your omega 3 intakes by eating more fish and sea food, this could help established a more balanced ω6/ω3 ratio on the long term.
However, the efficiency of this process is generally very low. Indeed, up to 35% of ALA (precursor substrate of the ω3 pathway) is catabolized into CO2 for energy and won’t be able to induce EPA/DHA formation. Further, a diet richer in ALA will have higher rate of ALA oxidation (13).
In women, only 21% of ALA is converted to EPA and less than 9% gives rise to DHA (14). Moreover, there is a big variability in subject capacity to convert ALA to EPA/DHA even when the subjects have similar diet (15).
Therefore, the best option for a rapid and sustained change in ω6/ω3 ratio may be to directly supplement patient with EPA and DHA to short cut their moderately effective synthesis from ALA.

  1. ω3 beneficial effects during pregnancy?

ω3 have been used for years to treat patients affected by cardiovascular diseases and reduce their hyperlipidemia and has been proved to be totally safe.
When ω6/ω3 ratio goes from 10 to 4 in patient with cardiovascular disorders, there is a reduction of 70% in mortality (16).

In fertility, an increased ω3 intake prior to conception was shown to positively impact embryo morphology in a study on women undergoing IVF cycle (17).
ω3 appear to promote vascular development in the endometrium as seen by in vitro study (18). Many other studies showed that a higher ω3 intake:

  • can reduce the risk of miscarriage (19).
  • Increase uterine blood flow (20).
  • Increase the length of pregnancy and reduce preterm birth (21).
  • Reduce placental inflammation when taking during the first trimester and through the pregnancy (22).

The figure below can summarize how ω3 can help reduce maternal inflammation/ oxidative stress (23). They directly act on placenta to increase anti-oxidant production that will counteract the effects of reactive oxygen species (ROS). Resolvins and protectins (products of DHA and EPA metabolism) can reduce placental PGE2 (the prostaglandin associated with partition) and reduce placental inflammation. Altogether, these effects can reduce the risk of pregnancy losses or complications.

Figure 2: Summary of ω3 pleiotropic effects on maternal/placental inflammation

  1. Focus on our Intralipid study: what did we learn from our data?
  1. No significant effect of Intralipid in our patient population

Intralipid is a lipid emulsion (an emulsion containing ω3 and ω6 fatty acid among other fatty acid) used for over 50 years as an intravenous nutrition method.
It is one of the most used drug in fertility treatment whose use has showed a total safety during pregnancy.
We tried to find any immunological evidences that could explain how Intralipid infusion modulate maternal immune response thus allowing the establishment and maintenance of pregnancy.
In our set of patients, Intralipid did not show any dramatic effects on immune factors (no further reduction of NKa levels in pregnant patients on Intralipid as compared to patients not using it). Further, Intralipid was not shown to improve pregnancy rate (as compared to other therapies).

  1. Lower ω6/ω3 ratio at baseline linked pregnancy to success

We decided to focus on determining if Intralipid similarly modulate the fatty acid content among patients. Strikingly, we found that patients could respond in totally opposite way to Intralipid infusion (at the same frequency and dosage).
Some patients will have significantly increased linoleic acid levels (LA, ω6) while others will have a significant decrease in linoleic acid levels (LA, ω6) in response to Intralipid infusion. Without getting into details and to keep it as simple as possible, patients with higher LA levels post Intralipid infusion were found to have lower ω6/ω3 ratio at baseline (before Intralipid infusion and embryo transfer) and were significantly more successful as seen in the Figure 3 below (43.75% will have a successful pregnancy versus 0% for patient with high ω6/ω3 ratio and therefore less miscarriage 31.25% versus 66.7% for the high ω6/ω3 ratio group).

Figure 3: Transfer outcome per patient based on their ω6/ω3 at baseline.
p value <.05: *, p value <.01: **, p value <.001: ***. Different letters mean that the difference is statistically significant, p<.05

Inversely, if a patient has high ω6/ω3 at baseline, the Intralipid infusion will further increase her ratio, leading to an activation of the ω6 pathway (as seen by lower LA levels post Intralipid infusion as they are used as substrate to fuel the ω6 metabolic pathway) leading to more inflammation.

  1. Lower ω6/ω3 ratio correlates with lower Th17 levels at baseline

In our data, patients with a low ω6/ω3 at baseline have also low Th17 levels that have been linked to pregnancy losses in our data set.
So having lower ω6/ω3 ratio could be of benefit for the outcome of a pregnancy.

Figure 4: Th17 levels at baseline in relation to basal ω6/ω3 ratio.
p value <.05: *, p value <.01: **, p value <.001: ***.

  1. Omega 3 supplement: the best option to restore optimal parameters

These findings led us to hypothesize that ω6/ω3 ratio at baseline is a key factor determining the potential for a pregnancy to succeed.
As explained in this blog, ω6/ω3 directly reflects your fatty acid content and your potential to preferentially activate the ω6 (pro-inflammatory) or ω3 metabolic pathway (anti-inflammatory).

At Braverman Reproductive Immunology, we are now systematically screening all our patients for fatty acid levels and using them to determine three parameters:

  • ω6/ω3 ratio
  • Potential for inflammation reflecting the direct competition between EPA and arachidonic acid in triggering pro- versus anti-inflammatory pathway. It has been shown to be more elevated in patients with inflammatory conditions (24).
  • Omega 3 Index: this index reflecting the long-term intake of EPA+DHA has been largely used in the cardiovascular medical field to determine patients who are in a protective zone versus those at risk for cardiac arrest.
    During pregnancy, higher omega 3 index have been linked to reduced risks for preterm birth (25).

Based on these parameters, patients are categorized into one of three categories:

  • Low risk
  • Intermediate risk
  • High risk

Specific dose of EPA+DHA are recommended to restore optimum parameters before embryo transfer or attempt to conceive. A maintenance dose is then recommended to maintain the patient in the low risk category throughout the pregnancy.


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