From Womb to Womb

Worldwide, women suffer an estimated 2.65 million stillbirths each year. Despite those huge numbers, we only understand some of the factors that are responsible. In low- and middle-income countries (where most of the world’s stillbirths occur), diseases like malaria can put pregnant women at risk of stillbirths. In wealthier countries, the biggest risks include smoking and obesity. But these factors only go partway to explaining why some women have stillbirths, leaving many cases unaccounted for. The benefits that would come from that knowledge could be enormous.

One way to learn about reproductive health is to observe how our primate cousins have babies. And a new study on marmosets offers some hints about the causes of stillbirth. It suggests that a mother’s health during pregnant may not be the whole story. In fact, some of the risk factors may arise before mothers are even born.

Marmoset triplets. Photo courtesy Julienne Rutherford
Marmoset triplets. Photo courtesy Julienne Rutherford

The first thing that one notices about the white-tufted ear marmoset (Callithrix jacchus) is its wildly adorable face–a tiny visage framed by shocks of white fur. Marmosets are interesting to scientists not because they’re cute, but because of their intriguing way of having kids. While most primate females have a single offspring at a time, marmoset  typically have twins. Some marmoset mothers even have triplets.

This is a tricky strategy for passing on marmoset genes. Marmoset babies can weigh between a fifth and a quarter of their mother’s weight. Imagine a 135-pound woman giving birth to two 16 pound babies–and then nursing them. The strategy only works because marmosets live in groups. A breeding female and male marmoset are attended to by helpers–usually related females that suppress their own ability to have babies while they assist the breeding female. They take turns carrying the babies and getting food. The father even helps out, too.

Despite all the help, however, female marmosets sometimes have stillbirths. Recently, Julienne Rutherford, a biological anthropologist at in Department of Women, Children, and Family Health Science at the University of Illinois at Chicago, went on a search for the factors that put a marmoset at greatest risk of having one.

She and her colleagues studied a marmoset colony at the Southwest National Primate Research Center in San Antonio, Texas. The center keeps detailed records for all the marmosets, from birth to death. Rutherford and her colleagues analyzed the reproductive history of 79 female marmosets since 1994. And when they were done with the analysis, one factor in particular jumped out of the data. Females that were born in sets of triplets are three times more likely to lose a fetus than females born as twins.

The scientists looked at the other data to figure out what was happening. The risk of stillbirth wasn’t just part of an overall problem with fertility. Triplet females were just as likely to get pregnant as twin females. It’s just that they were less likely to carry their pregnancies to a successful term.

Perhaps the result was just a shadow of a much bigger pattern. Scientists have long known that women who were low weight at birth end up at greater risk of stillbirths when they get pregnant. The same goes for other female primates. It was therefore possible that triplet female marmosets were at greater risk of stillbirths simply because triplet marmosets are smaller at birth than twins. Rutherford and her colleagues looked over the records to see if that was the case.

It wasn’t. Triplet females are born at a range of weights, and extra size offer them no protection against stillbirths. The big triplet females are also at risk of having stillbirths when they grow up.

Something must be happening in the marmoset womb that is leaving an invisible mark on triplet females for their entire life. As a female primate embryo develops, it grows the ovaries and uterus it will eventually use to bear its own young. The development of those organs is normally choreographed by the hormones that swirl around the embryo’s body. Sharing a uterus with two other embryos may disrupt that choreography. Most triplet females are born along with at least one brother, for example. It’s possible that the male hormones produced by their brothers  interfered with their own development.

Since women typically only have one baby at a time, there isn’t a simple lesson in Rutherford’s research for medicine.  But it may encourage scientists to to widen their search for the cause of stillbirths. Yes, the health of a woman while she’s pregnant is enormously important to a successful pregnancy. But her reproductive health may be altered before she’s even born.

Scientists have done very little research on this possibility in humans. One of the few studies looked at the legacy of the so-called “Dutch Hunger.” In the winter of 1944/45, the Netherlands suffered a famine. Many women who were pregnant at the time suffered from malnutrition. Scientists have followed their children ever since to see what effect the famine had on them before they were born. In 1997, researchers found that the women were just as fertile as women from well-fed mothers. But their children were at greater risk of stillbirth or of dying just after birth [pdf].

Given how long people live, tracing the effects of pregnancy on stillbirths is going to be slow work. Female marmosets, on the other hand, can start having babies before they’re two years old. Rutherford and her colleagues are taking advantage of the fast life of marmosets by following a number of females from birth to first pregnancy. The scientists are using ultrasound to take pictures of the marmosets’ developing reproductive systems, and measuring their hormone levels along the way.

This new research may allow Rutherford to pinpoint the reason that it’s so risky to be a triplet mother. And it may let her offer some ideas about how to make human childbirth healthier, too.

12 thoughts on “From Womb to Womb

  1. It would be interesting to know if the stillbirth rate among triplet females depended on the sex of the two siblings. If intra-uterine hormones are the problem, then females with two brothers should have higher stillbirth rate than those with two sisters.

  2. That’s a great question, Tim. Unfortunately, we were hampered by inadequate sample size. A female with two sisters comes from an all-female litter which was very rare. It was that rarity that kept us from being to fully explore the impact of the brother effect in triplets – almost all of our triplets had at least one brother. There wasn’t a dose respond effect, i.e. having one vs. two brothers didn’t seem to make a difference. It is possible that there is a threshold over which one additional brother has no greater effect. We just don’t know yet.

  3. Another example of what Michel Odent calls “primal health” – or “womb ecology.” I’m not a scientist, but as someone who works in the community with pregnant women, I am encouraged to see an interest in pregnancy that recognizes the long-term impact of the uterine environment in new ways. All part of changing the cultural conversation about pregnancy, birth, and postpartum. I will be looking for more information about the research as you move forward.

  4. This is a long-shot, but in the triplets including a male, is it possible that a variation of fetal microchimerism could be relevant? If the female marmosets carried cells from their male litter-mate, and the male cells survived to a female’s adulthood, could that condition trigger something akin to the Bruce Effect?

    It would be fascinating if there is a way to detect the presence of male DNA in the females prior to maturity/mating. Or perhaps an aberrant overexpression of AZGP1, levels of circulating AZGP1. Or something unusual about MHC Class I when compared to females without male litter-mates.

    Perhaps there is some odd difference that would distort/confuse the pregnant female’s ability to recognize the pheremones of her mate and thereby trigger a result like the Bruce Effect.

  5. How common are male-female twin sets? If the triplet effect were caused by sharing a womb with a brother, wouldn’t you expect to see the same effect in brother/sister twin births? Surely there would be sufficient data points on that?

  6. Indeed there were, and we report those results in the paper:

    In short, twin litters were split pretty evenly into male-female and female-femal litters. Female twins who shared the womb with a brother lost nearly three times more fetuses than those who had a sister in utero. For triplets the difference was around 2.5 times greater when there was 1 or more brothers but because most of the triplets had at least one brother, we couldn’t definitively say this was more than if there were zero brothers (i.e. the difference wasn’t statistically significant because we didn’t have enough all-female triplets for comparison.)

  7. As a gravida 7 para 1 human I looked back into family reproduction and found my father’s aunt had the same situation in the 1920’s– a series of miscarriages and ultimately no children. Have 1100yr family history. fascinating research. Maternal side had lots of twins and miscarriages.

  8. To me, this study shows more that certain hormones in-utero play a strong role in fertility of both mother and baby, and baby’s babies, and less about actual twin studies. It is a well known fact that hormones play a role in fertility, i think this study may help narrow that balance a little more. I wish I could be a part of a study like that.

  9. this article makes me very curious to the genetic heritability of twins in humans as i am in one of two sets of twins and in my own immediate family there has been two cases of still births

  10. My father was born in 1913, then my mother was born in 1923. Unfortunetly my parents lost their first baby in miscarriage as it was stillborn as my late close uncle who was the family physician had told me. I have my 3 brothers and my 1 sister all who are older than I am younger as I am last born.

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